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Kong F, Jiang J, Du M, Dong R, Chen G, Zheng S, Wang J. CXCL6 Is a Novel Biliary Marker and a Downstream Target of MMP7 in Biliary Atresia. Hepatol Res 2025. [PMID: 40515742 DOI: 10.1111/hepr.14217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2025] [Revised: 05/21/2025] [Accepted: 05/23/2025] [Indexed: 06/16/2025]
Abstract
AIM MMP7 has been identified as a potential biomarker for biliary atresia (BA) diagnosis. However, the mechanism of MMP7 and its downstream signaling pathway remain unknown in the pathogenesis of BA. Herein, this study was performed to figure out MMP7's downstream target. METHODS Single-cell RNA sequencing (scRNA-seq) was performed to screen out MMP7's downstream molecule CXCL6. QRT-PCR, immunohistochemistry, western blot, and ELISA were used to determine the expressions of MMP7 and CXCL6 in the liver and serum of BA and controls. Immunofluorescence was conducted to validate the hepatic cellular expressions of MMP7 and CXCL6. In vitro, overexpression and knockdown of MMP7 in biliary epithelial cells (BECs) were established to verify the MMP7's regulation on CXCL6. RESULTS ScRNA-seq demonstrated that MMP7 and CXCL6 were exclusively expressed on cholangiocytes and up-regulated in BA when compared with normal controls (NC). QRT-PCR, immunohistochemistry, western blot and ELISA validated the higher expressions of MMP7 and CXCL6 in the liver and serum of BA when compared with non-BA cholestasis (CS) and NC. Immunofluorescence further verified the biliary localization of MMP7 and CXCL6 in BA. Hepatic and serum CXCL6 expressions were positively correlated with MMP7 expressions, and both expressions were correlated with the stages of fibrosis in BA. Overexpression of MMP7 promoted CXCL6 expression, while knocking down MMP7 inhibited CXCL6 expression in BECs. CONCLUSION CXCL6 is a downstream target of MMP7, and is identified as a novel biliary marker in BA. The production of CXCL6 by MMP7 may exert pathological roles in the liver fibrogenesis of BA.
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Affiliation(s)
- Fanyang Kong
- Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Department of Pediatric Surgery, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China
| | - Jingying Jiang
- Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Department of Pediatric Surgery, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China
| | - Min Du
- Department of Pediatric Gastroenterology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China
| | - Rui Dong
- Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Department of Pediatric Surgery, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China
| | - Gong Chen
- Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Department of Pediatric Surgery, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China
| | - Shan Zheng
- Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Department of Pediatric Surgery, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China
| | - Junfeng Wang
- Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Department of Pediatric Surgery, Ministry of Health, Children's Hospital of Fudan University, Shanghai, China
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Meng L, Du M, Li H, Kong F, Yang J, Dong R, Zheng S, Chen G, Shen Z, Wang J. Single-cell transcription reveals hepatocyte-to-cholangiocyte reprogramming and biliary gene profile in biliary atresia. Hepatol Commun 2025; 9:e0710. [PMID: 40366121 PMCID: PMC12055120 DOI: 10.1097/hc9.0000000000000710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 03/06/2025] [Indexed: 05/15/2025] Open
Abstract
BACKGROUND Ductular reaction (DR), characterized by the expansion of biliary epithelial cells in the portal area, is a typical hepatic pathology for biliary atresia (BA). The cellular source and function of DR remain poorly understood. Herein, we performed single-cell RNA sequencing (scRNA-seq) in BA to resolve the complexity of DR in BA. METHODS A total of 4 BA and 3 normal control livers underwent scRNA-seq. The epithelial cells were extracted from all cells for further analysis. The cell types, functions, and differentiational trajectory of epithelial cells were determined. The biliary markers and transcription factors (TFs) were identified by combing public bulk and scRNA-seq data and validated by immunohistochemistry. RESULTS ScRNA-seq identified the existence of biliary reprogramming in BA, and the reprogrammed cells expressed both hepatocyte and cholangiocyte markers. When compared with hepatocytes, genes of epithelial-mesenchymal transition, fibrosis, inflammation, and RNA metabolism were enriched in cholangiocytes and upregulated in BA. Pseudotime analysis depicted a differentiation trajectory from hepatocytes across reprogrammed cells to cholangiocytes in BA. Matrix metalloproteinase 7 (MMP7), VTCN1, and LAMC2 were identified as the biliary markers, and KLF5 and HNF1B were determined as the biliary TFs in BA. All the biliary markers and TFs were upregulated in BA when compared with controls. CONCLUSIONS Dissecting the cellular source and function of cholangiocytes is essential to understand the pathological role of DR in BA. The identified specific biliary markers and TFs provide important insights into its potential diagnosis and mechanism exploration for BA in the future.
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Affiliation(s)
- 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, P.R. China
| | - Min Du
- Department of Pediatric Gastroenterology, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Haodong Li
- Department of Pediatric Orthopedics, Children’s Hospital of Fudan University, Shanghai, P.R. China
| | - 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, P.R. China
| | - Jiajian Yang
- Department of Pediatric Surgery, Children’s Hospital of Fudan University (Xiamen Branch), Xiamen Children’s Hospital, Xiamen, P.R. 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, P.R. 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, P.R. 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, P.R. China
| | - Zhen Shen
- 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, P.R. China
| | - Junfeng Wang
- 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, P.R. China
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Khalili-Tanha G, Radisky ES, Radisky DC, Shoari A. Matrix metalloproteinase-driven epithelial-mesenchymal transition: implications in health and disease. J Transl Med 2025; 23:436. [PMID: 40217300 PMCID: PMC11992850 DOI: 10.1186/s12967-025-06447-w] [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: 02/15/2025] [Accepted: 03/30/2025] [Indexed: 04/14/2025] Open
Abstract
Epithelial-mesenchymal transition (EMT) is a process in which epithelial cells, defined by apical-basal polarity and tight intercellular junctions, acquire migratory and invasive properties characteristic of mesenchymal cells. Under normal conditions, EMT directs essential morphogenetic events in embryogenesis and supports tissue repair. When dysregulated, EMT contributes to pathological processes such as organ fibrosis, chronic inflammation, and cancer progression and metastasis. Matrix metalloproteinases (MMPs)-a family of zinc-dependent proteases that degrade structural components of the extracellular matrix-sit at the nexus of this transition by dismantling basement membranes, activating pro-EMT signaling pathways, and cleaving adhesion molecules. When normally regulated, MMPs promote balanced ECM turnover and support the cyclical remodeling necessary for proper development, wound healing, and tissue homeostasis. When abnormally regulated, MMPs drive excessive ECM turnover, thereby promoting EMT-related pathologies, including tumor progression and fibrotic disease. This review provides an integrated overview of the molecular mechanisms by which MMPs both initiate and sustain EMT under physiological and disease conditions. It discusses how MMPs can potentiate EMT through TGF-β and Wnt/β-catenin signaling, disrupt cell-cell junction proteins, and potentiate the action of hypoxia-inducible factors in the tumor microenvironment. It discusses how these pathologic processes remodel tissues during fibrosis, and fuel cancer cell invasion, metastasis, and resistance to therapy. Finally, the review explores emerging therapeutic strategies that selectively target MMPs and EMT, ranging from CRISPR/Cas-mediated interventions to engineered tissue inhibitors of metalloproteinases (TIMPs), and demonstrates how such approaches may suppress pathological EMT without compromising its indispensable roles in normal biology.
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Affiliation(s)
- Ghazaleh Khalili-Tanha
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Evette S Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Derek C Radisky
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA
| | - Alireza Shoari
- Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, USA.
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Li Q, Ye C, Gao W. Prognostic Value of Combined Detection of MMP-7 and ALP Levels in Children With Biliary Atresia Post-Kasai Surgery. Pediatr Transplant 2025; 29:e70004. [PMID: 39777956 DOI: 10.1111/petr.70004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 10/25/2024] [Accepted: 12/08/2024] [Indexed: 01/11/2025]
Abstract
OBJECTIVE Biliary atresia (BA) remains a prevalent indication for pediatric liver transplantation (LT). We investigated the prognostic value of the serum matrix metalloproteinases 7 (MMP-7) and alkaline phosphatase (ALP) level combined detection for BA children post-Kasai surgery. METHODS This study retrospectively enrolled 85 BA children who underwent Kasai surgery. They were divided into the native liver (NL) and LT groups based on their three-year postoperative prognosis. Serum MMP-7 and ALP levels were measured by ELISA. The relationship of intraoperative serum MMP-7 and ALP levels with preoperative gamma-glutamyltransferase (GGT), and their impact on the risk of postoperative LT were analyzed by Pearson's correlation coefficient and Kaplan-Meier curves. The independent risk factors (IRFs) for postoperative LT and the predictive value of the serum MMP-7 and ALP level combined detection for postoperative LT in BA children were analyzed by Cox regression analysis and receiver operating characteristic (ROC) curves. MedCalc software compared the areas under the ROC curves (AUC). RESULTS Significant differences were observed between the two groups in BA classification, postoperative jaundice clearance rate, and cholangitis occurrence. Intraoperative serum MMP-7 and ALP levels were higher in the LT group and positively correlated with preoperative GGT. High MMP-7 and ALP levels were IRFs for postoperative LT, while significant jaundice clearance was a protective factor. Combined MMP-7 and ALP detection (0.926 AUC, 91.30% sensitivity, 87.18% specificity) significantly improved the prediction for LT. CONCLUSION High MMP-7 and ALP levels are IRFs for post-Kasai surgery LT in BA children, with their combination providing superior predictive value.
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Affiliation(s)
- Qingzhi Li
- Department of Neonatal Surgery, Anhui Children's Hospital, Hefei, China
| | - Chaoxiang Ye
- Department of Neonatal Surgery, Anhui Children's Hospital, Hefei, China
| | - Wei Gao
- Department of Neonatal Surgery, Anhui Children's Hospital, Hefei, China
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Nyholm I, Hukkinen M, Pakarinen MP. Predicting and managing liver fibrosis in biliary atresia. Semin Pediatr Surg 2024; 33:151473. [PMID: 39884181 DOI: 10.1016/j.sempedsurg.2025.151473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025]
Abstract
Regardless of the underlying etiology and success of PE, progressive liver fibrosis and eventually cirrhosis represent the dominant pathology and the end-stage of BA. Ascending bile duct injury-induced cholestasis, inflammation and ductular reaction provide profibrogenic cytokine environment leading to myofibroblast activation and rapid progression of fibrosis especially after unsuccessful portoenterostomy. Although liver fibrosis and development of cirrhosis play a crucial role in determining BA outcomes, the exact prognostic significance and dynamics of mild to moderate liver fibrosis remain unclear. Manual scoring systems categorizing the degree of liver fibrosis are prone to intra- and interobserver variability, whereas novel combinations of digital pathology with artificial intelligence quantification can provide accurate information on fibrosis structure and dynamics at the level of individual collagen fibers. Although several studies have analyzed noninvasive assessment of fibrosis at time of PE, including imaging-based elastography and different serum biomarkers, current knowledge on their accuracy during the postoperative follow-up of BA is scarce. While therapeutic management of liver fibrosis in BA remains in its infancy, the resolution potential for liver fibrosis has been demonstrated after successful PE. Achievement of effective antifibrotic treatment may require combination of different therapies with complementary modes of action like anti-inflammatory medication, antioxidants and bile acid lowering agents.
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Affiliation(s)
- Iiris Nyholm
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, New Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Maria Hukkinen
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, New Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Mikko P Pakarinen
- Section of Pediatric Surgery, Pediatric Liver and Gut Research Group, New Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden.
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Jeropoulos RM, Arroyo J, Davenport M. Predicting and optimising outcome for biliary atresia. Semin Pediatr Surg 2024; 33:151479. [PMID: 39884180 DOI: 10.1016/j.sempedsurg.2025.151479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 01/07/2025] [Indexed: 02/01/2025]
Abstract
Biliary atresia (BA) remains a disease of significant morbidity and mortality world-wide. Early and accurate diagnosis facilitates early intervention and improves outcomes. The gold standard in diagnosing BA is a liver biopsy followed by cholangiography, usually performed intra-operatively. Serum markers, like the aspartate aminotransferase-to-platelet ratio, matrix metalloproteinase-7 and several inflammatory cytokines have been recently investigated as non-invasive alternatives with varying degrees of success. Newer immunohistochemical analysis of liver biopsies, such as the expression of secretin receptors and Ki-67, from infants with BA have improved our understanding of the disease process and has shed a little light in predicting post-operative outcomes. There is little standardisation in the care of BA post operatively, though administration of steroids, prevention and treatment of cholangitis with antibiotics and anti-viral therapy for CMV+ve infants are becoming universally accepted as treatment. Experimental stem cell treatments show promise although remain in the out-of-reach future for now in routine clinical practice. This chapter aims to comprehensively describe recent knowledge on predicting the clinical outcomes of infants with BA, as well as optimising their care post operatively.
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Affiliation(s)
- Renos M Jeropoulos
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Jorge Arroyo
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom
| | - Mark Davenport
- Dept of Paediatric Surgery, Kings College Hospital, London SE59RS, England, United Kingdom.
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7
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Tam PKH, Wells RG, Tang CSM, Lui VCH, Hukkinen M, Luque CD, De Coppi P, Mack CL, Pakarinen M, Davenport M. Biliary atresia. Nat Rev Dis Primers 2024; 10:47. [PMID: 38992031 PMCID: PMC11956545 DOI: 10.1038/s41572-024-00533-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/10/2024] [Indexed: 07/13/2024]
Abstract
Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.
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Affiliation(s)
- Paul K H Tam
- Medical Sciences Division, Macau University of Science and Technology, Macau, China.
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
| | - Rebecca G Wells
- Division of Gastroenterology and Hepatology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Clara S M Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Vincent C H Lui
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China
| | - Maria Hukkinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Carlos D Luque
- Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina
| | - Paolo De Coppi
- NIHR Biomedical Research Centre, Great Ormond Street Hospital for Children NHS Foundation Trust and Great Ormond Street Institute of Child Health, University College London, London, UK
| | - Cara L Mack
- Department of Paediatrics, Division of Paediatric Gastroenterology, Hepatology and Nutrition, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, WI, USA
| | - Mikko Pakarinen
- Section of Paediatric Surgery, Paediatric Liver and Gut Research Group, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Mark Davenport
- Department of Paediatric Surgery, King's College Hospital, London, UK
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Jiang J, Dong R, Du M, Chen G, Yang J, Xie X, Yang Y, Yan W, Zheng S. Serum matrix metalloproteinase-7 for discriminating biliary atresia: a diagnostic accuracy and validation study. J Transl Med 2024; 22:636. [PMID: 38978022 PMCID: PMC11229253 DOI: 10.1186/s12967-024-05442-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 06/27/2024] [Indexed: 07/10/2024] Open
Abstract
BACKGROUND Prompt and precise differential diagnosis of biliary atresia (BA) among cholestatic patients is of great importance. Matrix metalloproteinase-7 (MMP-7) holds great promise as a diagnostic marker for BA. This study aimed to investigate the accuracy of age-specific serum MMP-7 for discriminating BA from other cholestatic pediatric patients. METHODS This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases (n = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients (n = 318, with 172 BA) and validated in a prospective cohort (n = 687, including 395 BA). RESULTS The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946-0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0-90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9-93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6-96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0-30 days, which was 86.4% (95% CI: 75.0-94.0%), 95.5% (95% CI: 77.2-99.9%), 98.1% (95% CI: 89.7-100%), and 72.4% (95% CI: 52.8-87.3%), respectively. CONCLUSIONS The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.
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Affiliation(s)
- Jingying Jiang
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Children's Hospital of Fudan University, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Rui Dong
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Children's Hospital of Fudan University, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Min Du
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Children's Hospital of Fudan University, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Gong Chen
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Children's Hospital of Fudan University, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Jingyun Yang
- Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA
- Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
| | - Xinbao Xie
- Department of Hepatology, Children's Hospital of Fudan University, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Yifan Yang
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Children's Hospital of Fudan University, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Weili Yan
- Department of Clinical Epidemiology, Clinical Trial Unit, Children's Hospital of Fudan University, 399 Wan Yuan Road, Shanghai, 201102, China.
| | - Shan Zheng
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, Key Laboratory of Neonatal Disease, Children's Hospital of Fudan University, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China.
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9
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Pandurangi S, Mourya R, Nalluri S, Fei L, Dong S, Harpavat S, Guthery SL, Molleston JP, Rosenthal P, Sokol RJ, Wang KS, Ng V, Alonso EM, Hsu EK, Karpen SJ, Loomes KM, Magee JC, Shneider BL, Horslen SP, Teckman JH, Bezerra JA. Diagnostic accuracy of serum matrix metalloproteinase-7 as a biomarker of biliary atresia in a large North American cohort. Hepatology 2024; 80:152-162. [PMID: 38446707 PMCID: PMC11191042 DOI: 10.1097/hep.0000000000000827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 12/20/2023] [Indexed: 03/08/2024]
Abstract
BACKGROUND AND AIMS High levels of serum matrix metalloproteinase-7 (MMP-7) have been linked to biliary atresia (BA), with wide variation in concentration cutoffs. We investigated the accuracy of serum MMP-7 as a diagnostic biomarker in a large North American cohort. APPROACH AND RESULTS MMP-7 was measured in serum samples of 399 infants with cholestasis in the Prospective Database of Infants with Cholestasis study of the Childhood Liver Disease Research Network, 201 infants with BA and 198 with non-BA cholestasis (age median: 64 and 59 days, p = 0.94). MMP-7 was assayed on antibody-bead fluorescence (single-plex) and time resolved fluorescence energy transfer assays. The discriminative performance of MMP-7 was compared with other clinical markers. On the single-plex assay, MMP-7 generated an AUROC of 0.90 (CI: 0.87-0.94). At cutoff 52.8 ng/mL, it produced sensitivity = 94.03%, specificity = 77.78%, positive predictive value = 64.46%, and negative predictive value = 96.82% for BA. AUROC for gamma-glutamyl transferase = 0.81 (CI: 0.77-0.86), stool color = 0.68 (CI: 0.63-0.73), and pathology = 0.84 (CI: 0.76-0.91). Logistic regression models of MMP-7 with other clinical variables individually or combined showed an increase for MMP-7+gamma-glutamyl transferase AUROC to 0.91 (CI: 0.88-0.95). Serum concentrations produced by time resolved fluorescence energy transfer differed from single-plex, with an optimal cutoff of 18.2 ng/mL. Results were consistent within each assay technology and generated similar AUROCs. CONCLUSIONS Serum MMP-7 has high discriminative properties to differentiate BA from other forms of neonatal cholestasis. MMP-7 cutoff values vary according to assay technology. Using MMP-7 in the evaluation of infants with cholestasis may simplify diagnostic algorithms and shorten the time to hepatoportoenterostomy.
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Affiliation(s)
- Sindhu Pandurangi
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Medical Center of Dallas, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Reena Mourya
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Medical Center of Dallas, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Shreya Nalluri
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Lin Fei
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
| | - Shun Dong
- University of Kansas School of Business, Lawrence, Kansas, USA
| | - Sanjiv Harpavat
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Texas Children’s Hospital, Houston, Texas, USA
| | - Stephen L. Guthery
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of Utah and Intermountain Primary Children’s Hospital, Salt Lake City, Utah, USA
| | - Jean P. Molleston
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Philip Rosenthal
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, University of California, San Francisco, California, USA
| | - Ronald J. Sokol
- Section of Pediatric Gastroenterology, Hepatology and Nutrition, University of Colorado School of Medicine, Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Kasper S. Wang
- The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Vicky Ng
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Ontario, Canada
| | - Estella M. Alonso
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
| | - Evelyn K. Hsu
- Division of Pediatric Gastroenterology and Hepatology, University of Washington School of Medicine and Seattle Children’s Hospital, Seattle, Washington, USA
| | - Saul J. Karpen
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition Children’s Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Kathleen M. Loomes
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - John C. Magee
- Division of Transplant Surgery, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Simon P. Horslen
- Division of Pediatric Gastroenterology, UPMC Children’s Hospital, Pittsburgh, Pennsylvania, USA
| | - Jeffrey H. Teckman
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Pediatrics, Cardinal Glennon Children’s Hospital, Saint Louis, Missouri, USA
| | - Jorge A. Bezerra
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Medical Center of Dallas, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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10
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Davenport M. Serum matrix metalloproteinase-7 (MMP-7): As good as it gets? Hepatology 2024; 80:18-19. [PMID: 38441947 DOI: 10.1097/hep.0000000000000835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 02/21/2024] [Indexed: 06/20/2024]
Affiliation(s)
- Mark Davenport
- Department of Paediatric Surgery, Kings College Hospital, London, UK
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11
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Yin T, Chen S, Zhou R, Liu W, Diao M, Li L. Relationships of serum MMP-7 and clinical characteristics in choledochal cyst children. BMC Surg 2024; 24:195. [PMID: 38914992 PMCID: PMC11194885 DOI: 10.1186/s12893-024-02488-y] [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: 02/18/2024] [Accepted: 06/21/2024] [Indexed: 06/26/2024] Open
Abstract
BACKGROUND Matrix metalloproteinase-7 (MMP-7) is associated with biliary injury. This study aimed to evaluate the relationships of serum MMP-7 with clinical characteristics in choledochal cysts (CDC) children. METHODS Between June 2020 and July 2022, we conducted a prospective study of CDCs who underwent one-stage definitive operation at our center. Serum MMP-7 was measured using an enzyme-linked immunosorbent assay. We evaluated the relationships between serum MMP-7 and age, laboratory tests, imaging examinations, liver fibrosis, MMP-7 expression, and perforation. RESULTS A total of 328 CDCs were enrolled in the study, with a median serum MMP-7 of 7.67 ng/mL. Higher serum MMP-7 was correlated with younger age at diagnosis (p < 0.001), larger cyst sizes (p < 0.001), higher liver fibrosis stages (p < 0.001), and higher incidence of perforation (p < 0.01). Liver MMP-7 was mainly expressed in intrahepatic and extrahepatic biliary epithelial cells. The area under the receiver operating characteristic curve (AUROC) was 0.630 (p < 0.001) for serum MMP-7 in predicting perforation. When serum MMP-7 was combined with γ-glutamyl transferase (GGT), the AUROC increased to 0.706 (p < 0.001). CONCLUSIONS Serum MMP-7 was associated with biliary obstruction in CDCs. Patients with high serum MMP-7 were more likely to have severe liver damage and biliary injury, with higher incidences of liver fibrosis and perforation.
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Affiliation(s)
- Tong Yin
- Capital Institute of Pediatrics-Peking University Teaching Hospital, Beijing, China
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Suyun Chen
- Department of Pediatric Urology, Fujian Children's Hospital, Fujian, China
| | - Ruijie Zhou
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Wei Liu
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China
| | - Mei Diao
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China.
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences 2021RU015, Beijing, China.
| | - Long Li
- Department of General Surgery, Capital Institute of Pediatrics, Beijing, China.
- Research Unit of Minimally Invasive Pediatric Surgery on Diagnosis and Treatment, Chinese Academy of Medical Sciences 2021RU015, Beijing, China.
- Department of Pediatric Surgery, Tsinghua University Affiliated Beijing Tsinghua Changgung Hospital, Beijing, China.
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12
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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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13
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Allam AA, Khedr MA, Elkholy SS, Yassin TAER, Fouad OA. Bile duct matrix metalloproteinase-7 expression: a new modality for diagnosis of biliary atresia. EGYPTIAN LIVER JOURNAL 2024; 14:17. [DOI: 10.1186/s43066-024-00320-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 02/29/2024] [Indexed: 01/04/2025] Open
Abstract
Abstract
Background
Biliary atresia (BA) is an obliterative cholangiopathy of infancy that results in cholestasis and liver fibrosis. This fibrosis is due to an imbalance in extracellular matrix (ECM) breakdown and deposition. The mechanism by which the progressive injury occurs is not fully elucidated. Matrix metalloproteinases (MMPs) are involved in ECM turnover but also have non-ECM-related functions. Matrix metalloproteinase 7 (MMP7) has been suggested as a promising biomarker in diagnosing BA.
Objective
The aim of this study was to assess the hepatic expression of MMP-7 in infants with BA.
Patients and methods
The study was a retrospective-prospective case–control study that included 50 patients who were categorized into two groups, BA group (25 patients) and non-BA cholestatic patients as a control group (25 patients). Liver biochemistry, liver biopsy, histopathology, and immunohistochemical staining for primary antibody MMP-7 were performed for all studied patients.
Results
Bile duct MMP7 expression was significantly higher in infants with BA than in non-BA cholestasis (P = 0.003), While the hepatic MMP-7 intensity did not differ significantly between both groups (P > 0.05). Bile duct expression of MMP-7 had a significant positive correlation with the BA Score (P = 0.017), while hepatic MMP-7 intensity had a significant positive correlation with alanine transaminase levels (P = 0.007) and a significant negative correlation with γ glutamyl transferase in the BA group (P = 0. 038). There was no statistically significant difference among different stages of fibrosis as regards the median of the hepatic MMP-7 intensity score and MMP-7 bile duct expression in infants with BA. There was no statistically significant difference between infants with successful and failed Kasai as regard the hepatic MMP-7 intensity and its bile duct expression.
Conclusion
Bile duct expression of MMP-7 measured by immunohistochemistry is useful for the diagnosis of BA, but it is limited in predicting the stage of liver fibrosis and the outcome of Kasai portoenterostomy (KPE).
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14
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Hasanzadeh A, Beiromvand M, Rafiei A, Kazemi M, Bahreini A, Khanahmad H. Expression of Matrix Metalloproteinases in Human Cystic Echinococcosis. Curr Mol Med 2024; 24:244-251. [PMID: 36617714 DOI: 10.2174/1566524023666230106163928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 11/13/2022] [Accepted: 11/22/2022] [Indexed: 01/10/2023]
Abstract
BACKGROUND Cystic echinococcosis (CE) is a zoonotic disease caused by the Echinococcus granulosus senso lato (E. granulosus s.l.) larval stages. Parasitederived products have been shown to regulate host matrix metalloproteinases (MMPs), contributing to CE pathogenesis and progressive liver fibrosis in intermediate hosts. The current study aimed to investigate the potential role of MMP1, 7, 8, and 13 in E. granulosus s.l-induced liver fibrosis. METHODS Thirty CE patients with active, transitional, or inactive hydatid cysts were enrolled in this study to determine the inductive effects of E. granulosus on the expression of MMP-1, MMP-7, MMP-8, and MMP-13 in healthy liver tissue and fibrotic liver tissue using qRT-PCR. RESULTS According to the WHO-IWGE classification, patients with functional cysts (CE1 and CE2) had the highest percentage (46.6%). MMP-1, MMP-7, MMP-8, and MMP-13 expression levels were significantly higher in fibrotic liver than in normal liver tissue. MMP-13 and MMP-1 had the highest and lowest expression levels among MMPs. Compared to the normal group, the fold change for MMP-13 in the fibrotic group was greater than 12 and had the highest AUC value (AUC= 0.8283). CONCLUSION Our findings suggest that E. granulosus-derived products might be involved in regulating host MMPs. Thus, MMPs may be considered potential biomarkers for predicting CE prognosis. Because of the non-normal distribution of our patients' CE types, further research, particularly on circulation MMPs, is needed to confirm the potential role of MMPs in CE pathogenesis and to follow up on CE patients.
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Affiliation(s)
- Azadeh Hasanzadeh
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Parasitology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Molouk Beiromvand
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Parasitology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Abdollah Rafiei
- Infectious and Tropical Diseases Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
- Department of Parasitology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mohammad Kazemi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amin Bahreini
- Department of Surgery, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Hossein Khanahmad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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Sosna B, Aebisher D, Myśliwiec A, Dynarowicz K, Bartusik-Aebisher D, Oleś P, Cieślar G, Kawczyk-Krupka A. Selected Cytokines and Metalloproteinases in Inflammatory Bowel Disease. Int J Mol Sci 2023; 25:202. [PMID: 38203373 PMCID: PMC10779120 DOI: 10.3390/ijms25010202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a collective term for two diseases: ulcerative colitis (UC) and Crohn's disease (CD). There are many factors, e.g., genetic, environmental and immunological, that increase the likelihood of these diseases. Indicators of IBDs include extracellular matrix metalloproteinases (MMPs). The aim of this review is to present data on the role of selected cytokines and metalloproteinases in IBD. In recent years, more and more transcriptomic studies are emerging. These studies are improving the characterization of the cytokine microenvironment inside inflamed tissue. It is observed that the levels of several cytokines are consistently increased in inflamed tissue in IBD, both in UC and CD. This review shows that MMPs play a major role in the pathology of inflammatory processes, cancer, and IBD. IBD-associated inflammation is associated with increased expression of MMPs and reduced ability of tissue inhibitors of metalloproteinases (TIMPs) to inhibit their action. In IBD patients in tissues that are inflamed, MMPs are produced in excess and TIMP activity is not sufficient to block MMPs. This review is based on our personal selection of the literature that was retrieved by a selective search in PubMed using the terms "Inflammatory bowel disease" and "pathogenesis of Inflammatory bowel diseases" that includes systematic reviews, meta-analyses, and clinical trials. The involvement of the immune system in the pathophysiology of IBD is reviewed in terms of the role of the cytokines and metalloproteinases involved.
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Affiliation(s)
- Barbara Sosna
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Angelika Myśliwiec
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Klaudia Dynarowicz
- Center for Innovative Research in Medical and Natural Sciences, Medical College, University of Rzeszów, 35-310 Rzeszów, Poland; (A.M.); (K.D.)
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland;
| | - Piotr Oleś
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Grzegorz Cieślar
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
| | - Aleksandra Kawczyk-Krupka
- Department of Internal Medicine, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego 15 Street, 41-902 Bytom, Poland; (B.S.); (P.O.); (G.C.)
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16
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Jiang J, Liu S, Du M, Deng J, Chen G, Yang Y, Dong R, Fang Z, Zheng S. Measurement of MMP-7 in micro-volume peripheral blood: development of dried blood spot approach. Front Pediatr 2023; 11:1293329. [PMID: 38034822 PMCID: PMC10684727 DOI: 10.3389/fped.2023.1293329] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 10/31/2023] [Indexed: 12/02/2023] Open
Abstract
Purpose Serum matrix metalloproteinase-7 (MMP-7) is significant in differentiating biliary atresia (BA). This study aims to develop a new peripheral blood quantitative collection device to detect MMP-7 levels via dried blood spot (DBS). Methods This is a diagnostic accuracy test. Serum and DBS MMP-7 concentrations were measured using an ELISA kit. Intraoperative cholangiography and subsequent histological examinations were used to confirm BA diagnoses. Results A total of 241 infants with obstructive jaundice were enrolled, among whom 168 were BA. Linear regression showed DBS MMP-7 correlated well with serum MMP-7 (R = 0.93, P < 0.001). The best cut-off value of serum MMP-7 for BA was 25.9 ng/ml, achieving the area under the ROC curve (AUC) of 0.962 (95% CI: 0.941, 0.983), and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 86.9%, 94.5%, 97.3% and 75.8%, respectively. The best cut-off value of DBS MMP-7 for BA was 12.5 ng/ml, achieving the AUC of 0.922 (95% CI: 0.888, 0.956), and the sensitivity, specificity, PPV, and NPV were 86.9%, 89.0%, 94.8%, and 74.7%, respectively. The dried blood spots were intervened under different storage conditions, including 1-5 days at room temperature, 2 or 3 days at 30 °C and 2 or 3 days at 37 °C. The DBS MMP-7 concentration under different storage conditions had good correlation and consistency with that at -80 °C. Conclusions Serum and DBS MMP-7 correlate well, both of which have high accuracy in the diagnosis of BA, while the requirements for the storage of DBS are low.
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Affiliation(s)
- Jingying Jiang
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Children’s Hospital of Fudan University, Shanghai, China
| | - Shuyang Liu
- Department of Data & Analytics, WuXi Diagnostics Innovation Research Institute, Shanghai, China
| | - Min Du
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Children’s Hospital of Fudan University, Shanghai, China
| | - Jiale Deng
- Department of Data & Analytics, WuXi Diagnostics Innovation Research Institute, Shanghai, China
| | - Gong Chen
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Children’s Hospital of Fudan University, Shanghai, China
| | - Yifan Yang
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Children’s Hospital of Fudan University, Shanghai, China
| | - Rui Dong
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Children’s Hospital of Fudan University, Shanghai, China
| | - Zhuo Fang
- Department of Data & Analytics, WuXi Diagnostics Innovation Research Institute, Shanghai, China
| | - Shan Zheng
- Department of Pediatric Surgery, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, Children’s Hospital of Fudan University, Shanghai, China
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Biswal S, Biswas D, Mahalik SK, Purkait S, Mitra S. Assessment of Matrix Metalloprotease - 7 (MMP7) Immunohistochemistry in Biliary Atresia and Other Pediatric Cholestatic Liver Diseases. Fetal Pediatr Pathol 2023:1-10. [PMID: 37906276 DOI: 10.1080/15513815.2023.2276780] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/20/2023] [Indexed: 11/02/2023]
Abstract
Background and aims: Biliary atresia (BA) is a progressive fibro-obliterative cholangiopathy. The histopathological diagnosis is often challenging and an immunohistochemical marker is often sought as an adjunct. We evaluated MMP7 immunohistochemistry in BA and other non-BA pediatric cholestatic liver diseases. Materials and methods: MMP7 immunohistochemistry was applied in 5 age-matched normal control, 23 cases of BA and 43 cases of non-BA pediatric cholestasis including 16 cases of choledochal cyst (CC), and a multiplication score was obtained by multiplying the intensity and percentage positivity in the cholangiocytes. Results: BA showed a high mean MMP7 multiplication score which was significantly different from the normal control and other non-BA pediatric cholestatic diseases including CC (p value < 0.001). The sensitivity, specificity, positive, and negative predictive values of MMP7 immunohistochemistry were 91.3%, 93.02%, 87.5%, and 95.2% respectively. Conclusion: MMP7 immunohistochemistry may be an adjunct to histomorphology in BA.
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Affiliation(s)
- Sandhya Biswal
- Department of Pathology, Kalinga Institute of Medical Sciences, Bhubaneswar, India
| | - Dipanwita Biswas
- Department of Pathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Suvendu Purkait
- Department of Pathology and Lab Medicine, AIIMS, Bhubaneswar, India
| | - Suvradeep Mitra
- Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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18
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Aldeiri B, Si T, Huang Z, Torner N, Ma Y, Davenport M, Hadzic N. Matrix Metalloproteinase-7 and Osteopontin Serum Levels as Biomarkers for Biliary Atresia. J Pediatr Gastroenterol Nutr 2023; 77:97-102. [PMID: 37326848 DOI: 10.1097/mpg.0000000000003792] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
OBJECTIVES Matrix metallopeptidase-7 (MMP-7) and osteopontin (OPN) are important components in the pathophysiology of fibrosis in biliary atresia (BA). There has been much recent interest in MMP-7 serum level in the diagnosis of BA. We aimed to assess the diagnostic accuracy and prognostic value of both MMP-7 and OPN in a Western BA study. METHODS Diagnostic value was assessed by comparison of serum MMP-7 and OPN levels in infants with BA and age-matched cholestatic controls. Prognostic value was assessed through subsequent clearance of jaundice (COJ) and need for liver transplantation (LT). RESULTS Serum was assessed from 32 BA and 27 controls. Median MMP-7 was higher in BA (96.4 vs 35 ng/mL; P < 0.0001) with an optimal cut-off value of 69 ng/mL. Sensitivity and specificity was 68% and 93%, respectively [negative predictive value (NPV) = 71%]. Similarly, median OPN was higher in BA (1952 vs 1457 ng/mL; P = 0.0001) and an optimal cut-off of 1611 ng/mL. Sensitivity and specificity was 84% and 78%, respectively (NPV = 81%). MMP-7 level correlated positively with Ishak liver fibrosis score (r = 0.27, P = 0.04). Neither MMP-7 (70 vs 100 ng/mL; P = 0.2) nor OPN (1969 vs 1939 ng/mL; P = 0.3) were predictive of COJ, or need for LT (99 vs 79 ng/mL; P = 0.7, and 1981 vs 1899 ng/mL; P = 0.2), respectively. CONCLUSIONS MMP-7 and OPN may have contributory value in the diagnosis of BA, but remain far of the "gold standard" role. Much more prospective data are required and collaborative multi-center initiatives should be the next logical steps.
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Affiliation(s)
- Bashar Aldeiri
- From the Department of Paediatric Surgery, King's College Hospital, Denmark Hill, London, UK
| | - Tengfei Si
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Zhenlin Huang
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Núria Torner
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Yun Ma
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Mark Davenport
- From the Department of Paediatric Surgery, King's College Hospital, Denmark Hill, London, UK
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Nedim Hadzic
- Institute of Liver Studies, King's College Hospital, London, UK
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Leung DH, Devaraj S, Goodrich NP, Chen X, Rajapakshe D, Ye W, Andreev V, Minard CG, Guffey D, Molleston JP, Bass LM, Karpen SJ, Kamath BM, Wang KS, Sundaram SS, Rosenthal P, McKiernan P, Loomes KM, Jensen MK, Horslen SP, Bezerra JA, Magee JC, Merion RM, Sokol RJ, Shneider BL, Alonso E, Bass L, Kelly S, Riordan M, Melin-Aldana H, Bezerra J, Bove K, Heubi J, Miethke A, Tiao G, Denlinger J, Chapman E, Sokol R, Feldman A, Mack C, Narkewicz M, Suchy F, Sundaram SS, Van Hove J, Garcia B, Kauma M, Kocher K, Steinbeiss M, Lovell M, Loomes KM, Piccoli D, Rand E, Russo P, Spinner N, Erlichman J, Stalford S, Pakstis D, King S, Squires R, Sindhi R, Venkat V, Bukauskas K, McKiernan P, Haberstroh L, Squires J, Rosenthal P, Bull L, Curry J, Langlois C, Kim G, Teckman J, Kociela V, Nagy R, Patel S, Cerkoski J, Molleston JP, Bozic M, Subbarao G, Klipsch A, Sawyers C, Cummings O, Horslen SP, Murray K, Hsu E, Cooper K, Young M, Finn L, Kamath BM, Ng V, Quammie C, Putra J, Sharma D, Parmar A, Guthery S, Jensen K, Rutherford A, Lowichik A, Book L, Meyers R, Hall T, et alLeung DH, Devaraj S, Goodrich NP, Chen X, Rajapakshe D, Ye W, Andreev V, Minard CG, Guffey D, Molleston JP, Bass LM, Karpen SJ, Kamath BM, Wang KS, Sundaram SS, Rosenthal P, McKiernan P, Loomes KM, Jensen MK, Horslen SP, Bezerra JA, Magee JC, Merion RM, Sokol RJ, Shneider BL, Alonso E, Bass L, Kelly S, Riordan M, Melin-Aldana H, Bezerra J, Bove K, Heubi J, Miethke A, Tiao G, Denlinger J, Chapman E, Sokol R, Feldman A, Mack C, Narkewicz M, Suchy F, Sundaram SS, Van Hove J, Garcia B, Kauma M, Kocher K, Steinbeiss M, Lovell M, Loomes KM, Piccoli D, Rand E, Russo P, Spinner N, Erlichman J, Stalford S, Pakstis D, King S, Squires R, Sindhi R, Venkat V, Bukauskas K, McKiernan P, Haberstroh L, Squires J, Rosenthal P, Bull L, Curry J, Langlois C, Kim G, Teckman J, Kociela V, Nagy R, Patel S, Cerkoski J, Molleston JP, Bozic M, Subbarao G, Klipsch A, Sawyers C, Cummings O, Horslen SP, Murray K, Hsu E, Cooper K, Young M, Finn L, Kamath BM, Ng V, Quammie C, Putra J, Sharma D, Parmar A, Guthery S, Jensen K, Rutherford A, Lowichik A, Book L, Meyers R, Hall T, Wang KS, Michail S, Thomas D, Goodhue C, Kohli R, Wang L, Soufi N, Thomas D, Karpen S, Gupta N, Romero R, Vos MB, Tory R, Berauer JP, Abramowsky C, McFall J, Shneider BL, Harpavat S, Hertel P, Leung D, Tessier M, Schady D, Cavallo L, Olvera D, Banks C, Tsai C, Thompson R, Doo E, Hoofnagle J, Sherker A, Torrance R, Hall S, Magee J, Merion R, Spino C, Ye W. Serum biomarkers correlated with liver stiffness assessed in a multicenter study of pediatric cholestatic liver disease. Hepatology 2023; 77:530-545. [PMID: 36069569 PMCID: PMC10151059 DOI: 10.1002/hep.32777] [Show More Authors] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 07/26/2022] [Accepted: 08/03/2022] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND AIMS Detailed investigation of the biological pathways leading to hepatic fibrosis and identification of liver fibrosis biomarkers may facilitate early interventions for pediatric cholestasis. APPROACH AND RESULTS A targeted enzyme-linked immunosorbent assay-based panel of nine biomarkers (lysyl oxidase, tissue inhibitor matrix metalloproteinase (MMP) 1, connective tissue growth factor [CTGF], IL-8, endoglin, periostin, Mac-2-binding protein, MMP-3, and MMP-7) was examined in children with biliary atresia (BA; n = 187), alpha-1 antitrypsin deficiency (A1AT; n = 78), and Alagille syndrome (ALGS; n = 65) and correlated with liver stiffness (LSM) and biochemical measures of liver disease. Median age and LSM were 9 years and 9.5 kPa. After adjusting for covariates, there were positive correlations among LSM and endoglin ( p = 0.04) and IL-8 ( p < 0.001) and MMP-7 ( p < 0.001) in participants with BA. The best prediction model for LSM in BA using clinical and lab measurements had an R2 = 0.437; adding IL-8 and MMP-7 improved R2 to 0.523 and 0.526 (both p < 0.0001). In participants with A1AT, CTGF and LSM were negatively correlated ( p = 0.004); adding CTGF to an LSM prediction model improved R2 from 0.524 to 0.577 ( p = 0.0033). Biomarkers did not correlate with LSM in ALGS. A significant number of biomarker/lab correlations were found in participants with BA but not those with A1AT or ALGS. CONCLUSIONS Endoglin, IL-8, and MMP-7 significantly correlate with increased LSM in children with BA, whereas CTGF inversely correlates with LSM in participants with A1AT; these biomarkers appear to enhance prediction of LSM beyond clinical tests. Future disease-specific investigations of change in these biomarkers over time and as predictors of clinical outcomes will be important.
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Affiliation(s)
- Daniel H Leung
- Division of Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Department of Pediatrics , Baylor College of Medicine , Houston , Texas , USA
| | - Sridevi Devaraj
- Department of Pathology and Immunology , Texas Children's Hospital, Baylor College of Medicine , Houston , Texas , USA
| | - Nathan P Goodrich
- Arbor Research Collaborative for Health , Ann Arbor , Michigan , USA
| | - Xinpu Chen
- Department of Pathology and Immunology , Texas Children's Hospital, Baylor College of Medicine , Houston , Texas , USA
| | - Deepthi Rajapakshe
- Department of Pathology and Immunology , Texas Children's Hospital, Baylor College of Medicine , Houston , Texas , USA
| | - Wen Ye
- Department of Biostatistics , University of Michigan , Ann Arbor , Michigan , USA
| | - Victor Andreev
- Arbor Research Collaborative for Health , Ann Arbor , Michigan , USA
| | - Charles G Minard
- Institute for Clinical and Translational Research , Baylor College of Medicine , Houston , Texas , USA
| | - Danielle Guffey
- Institute for Clinical and Translational Research , Baylor College of Medicine , Houston , Texas , USA
| | - Jean P Molleston
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics , Riley Hospital for Children , Indiana University , Indianapolis , Indiana , USA
| | - Lee M Bass
- Department of Pediatrics , Ann & Robert H. Lurie Children's Hospital of Chicago , Northwestern University Feinberg School of Medicine , Chicago , Illinois , USA
| | - Saul J Karpen
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Healthcare of Atlanta, Department of Pediatrics , Emory University School of Medicine , Atlanta , Georgia , USA
| | - Binita M Kamath
- Division of Gastroenterology, Hepatology and Nutrition , Hospital for Sick Children, University of Toronto , Toronto , Ontario , Canada
| | - Kasper S Wang
- Department of Pediatric Surgery , Children's Hospital Los Angeles , Los Angeles , California , USA
| | - Shikha S Sundaram
- Pediatric Gastroenterology, Hepatology and Nutrition , Children's Hospital Colorado, University of Colorado School of Medicine , Aurora , Colorado , USA
| | - Philip Rosenthal
- Department of Pediatrics , University of California, San Francisco , San Francisco , California , USA
| | - Patrick McKiernan
- Pediatric Gastroenterology, Hepatology and Nutrition , Children's Hospital of Pittsburgh , Pittsburg , Pennsylvania , USA
| | - Kathleen M Loomes
- Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics , The Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania , Philadelphia , Pennsylvania , USA
| | - M Kyle Jensen
- Pediatric Gastroenterology, Hepatology and Nutrition , University of Utah School of Medicine , Salt Lake City , Utah , USA
| | - Simon P Horslen
- Pediatric Gastroenterology, Hepatology and Nutrition , Seattle Children's Hospital, University of Washington School of Medicine , Seattle , Washington , USA
| | - Jorge A Bezerra
- Pediatric Gastroenterology, Hepatology and Nutrition , Cincinnati Children's Medical Center, University of Cincinnati School of Medicine , Cincinnati , Ohio , USA
| | - John C Magee
- University of Michigan Hospitals and Health Centers , Ann Arbor , Michigan , USA
| | - Robert M Merion
- Arbor Research Collaborative for Health , Ann Arbor , Michigan , USA
| | - Ronald J Sokol
- Pediatric Gastroenterology, Hepatology and Nutrition , Children's Hospital Colorado, University of Colorado School of Medicine , Aurora , Colorado , USA
| | - Benjamin L Shneider
- Division of Gastroenterology, Hepatology, and Nutrition, Texas Children's Hospital, Department of Pediatrics , Baylor College of Medicine , Houston , Texas , USA
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Saul SA, Chapin CA, Malladi P, Melin-Aldana H, Wechsler JB, Alonso EM, Taylor SA. RNA-Sequencing Analysis Identifies Etiology Specific Transcriptional Signatures in Neonatal Acute Liver Failure. J Pediatr 2023; 253:205-212.e2. [PMID: 36195310 PMCID: PMC10033333 DOI: 10.1016/j.jpeds.2022.09.044] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/18/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022]
Abstract
OBJECTIVE To assess hepatic transcriptional signatures in infants with gestational alloimmune liver disease (GALD) compared with other etiologies of neonatal acute liver failure (ALF) and older pediatric patients with ALF. STUDY DESIGN Neonates with ALF (international normalized ratio ≥2 within 30 days of life) and deceased neonates without liver disease (<30 days of age) with available liver tissue between 2010 and 2021 were identified at Ann & Robert H. Lurie Children's Hospital of Chicago. Clinical information, liver histology, and data from RNA-sequencing analysis was compared between neonates with GALD, non-GALD etiologies of neonatal ALF, and nondiseased neonatal liver. RESULTS Quantification of trichrome staining showed an increase in fibrosis in patients with GALD vs those with non-GALD neonatal ALF (P = .012); however, quantification of α-cytokeratin 19-positive ductules did not differ between groups (P = .244). Gene set enrichment analysis of RNA-sequencing data identified the pathways of complement activation, fibrosis, and organogenesis to be upregulated in patients with GALD with ALF. In contrast, patients with non-GALD causes of neonatal ALF had increased gene expression for interferon-driven immune pathways. Individual genes upregulated in GALD included matrix metallopeptidase 7, hepatocyte growth factor, and chemokine ligand 14. CONCLUSIONS We have identified distinct pathways that are significantly upregulated in patients with GALD and potential disease-specific diagnostic biomarkers. Future studies will aim to validate these findings and help identify GALD-specific diagnostic biomarkers to improve diagnostic accuracy and reduce GALD-associated patient mortality.
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Affiliation(s)
- Samantha A Saul
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Catherine A Chapin
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Padmini Malladi
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Hector Melin-Aldana
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Joshua B Wechsler
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Estella M Alonso
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL
| | - Sarah A Taylor
- Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.
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21
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Abstract
This article discusses current standard of care in neonatal biliary disease, particularly management of biliary atresia and choledochal cysts. It highlights surgical considerations, guidelines for adjuvant therapies, and promising therapeutic options that are under investigation.
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Affiliation(s)
- Sarah Mohamedaly
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, HSW 1652, Campus Box 0570, San Francisco, CA 94143-0570, USA
| | - Amar Nijagal
- Division of Pediatric Surgery, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, HSW 1652, Campus Box 0570, San Francisco, CA 94143-0570, USA; The Liver Center, University of California, San Francisco, CA, USA; The Pediatric Liver Center at UCSF Benioff Childrens' Hospitals, San Francisco, CA, USA.
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22
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Li Y, Yuan SL, Yin JY, Yang K, Zhou XG, Xie W, Wang Q. Differences of core genes in liver fibrosis and hepatocellular carcinoma: Evidence from integrated bioinformatics and immunohistochemical analysis. World J Gastrointest Oncol 2022; 14:1265-1280. [PMID: 36051101 PMCID: PMC9305567 DOI: 10.4251/wjgo.v14.i7.1265] [Citation(s) in RCA: 8] [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: 01/25/2022] [Revised: 05/18/2022] [Accepted: 06/26/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Liver fibrosis and hepatocellular carcinoma (HCC) are common adverse consequences of chronic liver injury. The interaction of various risk factors may cause them to happen. Identification of specific biomarkers is of great significance for understanding the occurrence, development mechanisms, and determining the novel tools for diagnosis and treatment of both liver fibrosis and HCC.
AIM To identify liver fibrosis-related core genes, we analyzed the differential expression pattern of core genes in liver fibrosis and HCC.
METHODS Gene expression profiles of three datasets, GSE14323, GSE36411, and GSE89377, obtained from the Gene Expression Omnibus (GEO) database, were analyzed, and differentially expressed genes (DEGs) between patients with liver cirrhosis and healthy controls were identified by screening via R software packages and online tool for Venn diagrams. The WebGestalt online tool was used to identify DEGs enriched in biological processes, molecular functions, cellular components, and Kyoto Encyclopedia of Genes and Genomes pathways. The protein–protein interactions of DEGs were visualized using Cytoscape with STRING. Next, the expression pattern of core genes was analyzed using Western blot and immunohistochemistry in a carbon tetrachloride (CCl4)-induced liver cirrhosis mouse model and in patient liver samples. Finally, Kaplan-Meier curves were constructed using the Kaplan-Meier plotter online server.
RESULTS Forty-five DEGs (43 upregulated and 2 downregulated genes) associated with liver cirrhosis were identified from three GEO datasets. Ten hub genes were identified, which were upregulated in liver cirrhosis. Western blot and immunohistochemical analyses of the three core genes, decorin (DCN), dermatopontin (DPT), and SRY-box transcription factor 9 (SOX9), revealed that they were highly expressed in the CCl4-induced liver cirrhosis mouse model. The expression levels of DCN and SOX 9 were positively correlated with the degree of fibrosis, and SOX 9 level in HCC patients was significantly higher than that in fibrosis patients. However, high expression of DPT was observed only in patients with liver fibrosis, and its expression in HCC was low. The gene expression profiling interactive analysis server (GEPIA) showed that SOX9 was significantly upregulated whereas DCN and DPT were significantly downregulated in patients with HCC. In addition, the Kaplan-Meier curves showed that HCC patients with higher SOX9 expression had significantly lower 5-year survival rate, while patients with higher expression of DCN or DPT had significantly higher 5-year survival rates.
CONCLUSION The expression levels of DCN, DPT, and SOX9 were positively correlated with the degree of liver fibrosis but showed different correlations with the 5-year survival rates of HCC patients.
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Affiliation(s)
- Yue Li
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Beijing 100015, China
| | - Shou-Li Yuan
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Beijing 100101, China
| | - Jing-Ya Yin
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Kun Yang
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Xin-Gang Zhou
- Department of Pathology, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Wen Xie
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
| | - Qi Wang
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China
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23
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Rohani P, Mirrahimi SB, Bashirirad H, Rahmani P, Kamran N, Alimadadi H, Hajipour M, Sohouli MH. Serum matrix metalloproteinase-7 levels in infants with cholestasis and biliary atresia. BMC Pediatr 2022; 22:351. [PMID: 35717157 PMCID: PMC9206322 DOI: 10.1186/s12887-022-03409-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 06/08/2022] [Indexed: 11/10/2022] Open
Abstract
Background The aim of this study was to evaluate the serum level of matrix metalloproteinase 7 (MMP7) in infants with cholestasis and the diagnostic values of this biomarker to differentiate biliary atresia (BA) from other causes of cholestasis. Methods This multi-center study is conducted during 2 years in Mofid children’s hospital and Children’s Medical Center, Pediatrics Center of Excellence Tehran, Iran. 54 infants with cholestasis were enrolled in this study with a control group consists of 41 healthy infants with the same age. Serum samples were taken from all these patients to assess serum levels of MMP7, Gamma-glutamyl Transferase (GGT). For each biomarker, we calculated the sensitivity and specificity and other statistical characteristics. Results There were 89 subjects, 22 patients with BA, 32 patients with non-BA cholestasis and 41 subjects as control group. The mean serum MMP7 levels in BA, non-BA cholestasis and control group was 15.91 ng/ml ± 6.64, 4.73 ng/ml ± 2.59 and 0.49 ng/ml ± 0.33, respectively. The best cut-off point is calculated 7.8 ng/ml for MMP7 and 434.5 U/L for GGT. The area under curve (AUC) for these two markers are 0.988 ± 0.008 and 0.854 ± 0.052, respectively. The sensitivity and specificity of MMP7 to differentiate biliary atresia from nonbiliary atresia cholestasis in our study was 95.5% and 94.5%, respectively. The sensitivity and specificity of GGT was 77.3% and 77.8%, respectively. These results show that the MMP7 has more sensitivity and specificity in differentiation. Conclusion MMP7 demonstrated good accuracy to differentiate biliary atresia from other causes of cholestasis.
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Affiliation(s)
- Pejman Rohani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyyed Bahador Mirrahimi
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Haleh Bashirirad
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Parisa Rahmani
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Niyoosha Kamran
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Hosein Alimadadi
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahmoud Hajipour
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Hassan Sohouli
- Pediatric Gastroenterology and Hepatology Research Center, Pediatrics Centre of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. .,Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. .,Department of Pediatrics, School of Medicine Childrens Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
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Meng N, Li Y, Jiang P, Bu X, Ding J, Wang Y, Zhou X, Yu F, Zhang Y, Zhang J, Xia L. A Comprehensive Pan-Cancer Analysis of the Tumorigenic Role of Matrix Metallopeptidase 7 (MMP7) Across Human Cancers. Front Oncol 2022; 12:916907. [PMID: 35785154 PMCID: PMC9248742 DOI: 10.3389/fonc.2022.916907] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/05/2022] [Indexed: 12/12/2022] Open
Abstract
Growing evidence has shown the oncogenic function of matrix metallopeptidase 7 (MMP7) in various tumors. However, no systemic pan-cancer analysis on the association between MMP7 and different cancers based on big clinical data is available. TIMER2, GEPIA2, UALCAN, cBioPortal, String, Metascape, and other web databases were searched in the present study. Generally, MMP7 expression is significantly upregulated in most The Cancer Genome Atlas (TCGA) cancer types compared to the paired normal controls, yet is downregulated in tumor tissues of invasive breast carcinoma (BRCA), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and skin cutaneous melanoma (SKCM). MMP7 protein expression is notably higher in the primary tumor tissues of colon cancer, lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC) than in normal tissues and is significantly lower in the primary tumor tissues of breast cancer, clear cell renal carcinoma, and ovarian cancer. Furthermore, MMP7 expression is strongly associated with pathological stages, clinical outcomes, tumor mutational burden (TMB), and microsatellite instability (TSI). Gene amplification was detected in most TCGA cancer types. In addition, the missense mutation is the primary type of MMP7 genetic alteration in tumors. Significant positive correlations between MMP7 expression and cancer-associated fibroblasts (CAFs) have been demonstrated in most TCGA cancers. MMP7 expression was also found to be positively correlated with infiltration of dendritic cells and macrophages in some specific tumor types. Functional enrichment analysis by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology (GO) methods revealed that RNA processing and DNA damage checkpoints might reveal the pathogenetic mechanisms of MMP7. This pan-cancer analysis provides a clear panorama for the tumorigenic roles of MMP7 across different cancer types. Moreover, MMP7 could be a potential drug therapeutic target in such cancers.
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Affiliation(s)
- Nana Meng
- Department of Ophthalmology, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
- Department of Ophthalmology, Zhenjiang Kangfu Eye Hospital, Zhenjiang, China
| | - Yaguang Li
- Department of Kidney Transplantation, Second Xiangya Hospital of Central South University, Changsha, China
| | - Pengcheng Jiang
- Department of General Surgery, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
| | - Xuefeng Bu
- Department of General Surgery, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
| | - Jifei Ding
- Department of Thoracic Surgery, Jiangsu Province Hospital on Integration of Chinese and Western Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China
| | - Yan Wang
- Department of Orthopedic, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
| | - Xiaodong Zhou
- Department of General Surgery, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
| | - Feng Yu
- Department of General Surgery, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
| | - Yongjun Zhang
- Department of General Surgery, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
| | - Jie Zhang
- Department of General Surgery, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
| | - Leizhou Xia
- Department of General Surgery, Affiliated People’s Hospital, Jiangsu University, Zhenjiang, China
- *Correspondence: Leizhou Xia,
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25
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Sakaguchi H, Konishi KI, Yasuda R, Sasaki H, Yoshimaru K, Tainaka T, Fukahori S, Sanada Y, Iwama I, Shoji H, Kinoshita M, Matsuura T, Fujishiro J, Uchida H, Nio M, Yamashita Y, Mizuochi T. Serum matrix metalloproteinase-7 in biliary atresia: A Japanese multicenter study. Hepatol Res 2022; 52:479-487. [PMID: 35106887 DOI: 10.1111/hepr.13753] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 01/12/2022] [Accepted: 01/26/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Biliary atresia (BA) is among the commonest indications for liver transplantation (LT) in children. We examined whether serum matrix metalloproteinase-7 (MMP-7) is useful for diagnosis of BA in Japanese infants, and whether serum MMP-7 concentrations before and after Kasai portoenterostomy (KP) predicted LT within a year. METHODS Subjects under 6 months old at eight pediatric centers in Japan were enrolled retrospectively, including patients with cholestasis and normal controls (NC) without liver disease. Patients with cholestasis were divided into groups representing BA versus cholestasis from other causes (non-BA). Serum samples were collected from patients with BA at diagnosis and 1 and 4 weeks after KP, as well as from non-BA and NC. RESULTS Serum MMP-7 concentrations were significantly higher in BA at diagnosis (median, 89.1 ng/ml) than in non-BA (11.0; p < 0.001) or NC (10.3; p < 0.001). Receiver operating characteristic (ROC) analysis of MMP-7 for BA versus non-BA yielded an area under the ROC curve of 0.99 (95% confidence interval, 0.96-1.00). An optimal cut-off value of 18.6 ng/ml for serum MMP-7 in diagnosing BA demonstrated sensitivity and specificity of 100% and 90%, respectively. Serum MMP-7 before and 1 week and 4 weeks after KP did not differ significantly between BA requiring only KP and BA requiring LT after KP. CONCLUSION Serum MMP-7 is a useful marker for diagnosis of BA in Japanese infants, but it could not predict LT within a year.
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Affiliation(s)
- Hirotaka Sakaguchi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Ken-Ichiro Konishi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan.,Department of Pediatric Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Yasuda
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Hideyuki Sasaki
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Koichiro Yoshimaru
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takahisa Tainaka
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Fukahori
- Department of Pediatric Surgery, Kurume University School of Medicine, Kurume, Japan
| | - Yukihiro Sanada
- Department of Surgery, Division of Gastroenterological, General and Transplant Surgery, Jichi Medical University, Shimotsuke, Japan
| | - Itaru Iwama
- Division of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama, Japan
| | - Hiromichi Shoji
- Department of Pediatrics, Juntendo University Faculty of Medicine, Tokyo, Japan
| | - Masahiro Kinoshita
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Toshiharu Matsuura
- Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Jun Fujishiro
- Department of Pediatric Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroo Uchida
- Department of Pediatric Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masaki Nio
- Department of Pediatric Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yushiro Yamashita
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
| | - Tatsuki Mizuochi
- Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
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26
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Liu F, Zhou J, Zhang X, Fang S, Liu R, Chen G, Luo Y, Zhang Z, Cheng Y, Wang L, Guo J, Zou Y. Whole-exome sequencing and functional validation reveals a rare missense variant in MMP7 confers ovarian endometriosis risk. Hum Mol Genet 2022; 31:2595-2605. [PMID: 35288736 DOI: 10.1093/hmg/ddac062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 11/13/2022] Open
Abstract
Prior studies have shown that genetic factors play important roles in ovarian endometriosis. Herein, we first analyzed the WES data from 158 patients with ovarian endometriosis and 385 local control women without endometriosis. Among which, a rare missense variant in the MMP7 (p.I79T, rs150338402) gene exhibited significant frequency difference. This rare variant was screened in an additional 1176 patients and 600 control women via direct DNA sequencing. Meanwhile, a total of 38 available clinical characteristics were collected. Our results showed 45 out of 1334 (3.37%) patients, while 15 out of 985 control women (1.52%) (P = 0.0076) harbored this rare variant, respectively. This rare variant was associated with clinical features such as follicle stimulating hormone (FSH, Padj = 0.0342), luteinizing hormone (LH, Padj = 0.0038), progesterone (PROG, Padj = 1.4e-7), testosterone (TESTO, Padj = 0.0923), total bilirubin (TBIL, Padj = 0.0699), carcinoembryonic antigen (CEA, Padj = 0.0665), and squamous cell carcinoma antigen (SCC, Padj = 0.0817), respectively. Functional assays showed this rare variant could promote cell migration, invasion, epithelial-mesenchymal transition (EMT), and increase the proteolytic protein activity of MMP7, implicating that the increased capacities of cell invasion, migration, and EMT might be mediated by enhanced proteolytic activity of MMP7 mutant. These results showed the MMP7 rare missense variant (p.I79T) played important roles in the pathogenesis of ovarian endometriosis. In conclusion, we identified for the first time, a significantly enriched MMP7 rare variant in ovarian endometriosis; this rare variant was closely associated with certain clinical features in ovarian endometriosis, thus, it could be a promising early diagnostic biomarker for this disease.
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Affiliation(s)
- Faying Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Central Laboratory, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Jiangyan Zhou
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Xiaoling Zhang
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Shufen Fang
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Rongfang Liu
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Department of Oncology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Ge Chen
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Central Laboratory, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Yong Luo
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Central Laboratory, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Ziyu Zhang
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Central Laboratory, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Yufen Cheng
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Liqun Wang
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Department of Reproductive Health, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Jiubai Guo
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Department of Gynecology, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
| | - Yang Zou
- Key Laboratory of Women's Reproductive Health of Jiangxi Province, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China.,Central Laboratory, Jiangxi Provincial Maternal and Child Health Hospital, Nanchang, Jiangxi 330006, China
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27
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Göteson A, Isgren A, Sparding T, Holmén-Larsson J, Jakobsson J, Pålsson E, Landén M. A serum proteomic study of two case-control cohorts identifies novel biomarkers for bipolar disorder. Transl Psychiatry 2022; 12:55. [PMID: 35136035 PMCID: PMC8826439 DOI: 10.1038/s41398-022-01819-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 12/12/2021] [Accepted: 01/17/2022] [Indexed: 01/08/2023] Open
Abstract
We set out to identify novel protein associations with potential as clinically viable biomarkers for bipolar disorder. To this end, we used proximity extension assay to analyze 201 unique proteins in blood serum from two independent cohorts comprising patients with bipolar disorder and healthy controls (total n = 493). We identified 32 proteins significantly associated with bipolar disorder in both case-control cohorts after adjusting for relevant covariates. Twenty-two findings are novel to bipolar disorder, but 10 proteins have previously been associated with bipolar disorder: chitinase-3-like protein 1, C-C motif chemokine 3 (CCL3), CCL4, CCL20, CCL25, interleukin 10, growth/differentiation factor-15, matrilysin (MMP-7), pro-adrenomedullin, and TNF-R1. Next, we estimated the variance in serum protein concentrations explained by psychiatric drugs and found that some case-control associations may have been driven by psychiatric drugs. The highest variance explained was observed between lithium use and MMP-7, and in post-hoc analyses and found that the serum concentration of MMP-7 was positively associated with serum lithium concentration, duration of lithium therapy, and inversely associated with estimated glomerular filtration rate in an interaction with lithium. This is noteworthy given that MMP-7 has been suggested as a mediator of renal tubulointerstitial fibrosis, which is characteristic of lithium-induced nephropathy. Finally, we used machine learning to evaluate the classification performance of the studied biomarkers but the average performance in unseen data was fair to moderate (area under the receiver operating curve = 0.72). Taken together, our serum biomarker findings provide novel insight to the etiopathology of bipolar disorder, and we present a suggestive biomarker for lithium-induced nephropathy.
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Affiliation(s)
- Andreas Göteson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
| | - Anniella Isgren
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Timea Sparding
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Jessica Holmén-Larsson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Joel Jakobsson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Erik Pålsson
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
| | - Mikael Landén
- Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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Associations between MRI T1 mapping, liver stiffness, quantitative MRCP, and laboratory biomarkers in children and young adults with autoimmune liver disease. Abdom Radiol (NY) 2022; 47:672-683. [PMID: 34932163 PMCID: PMC8847161 DOI: 10.1007/s00261-021-03378-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 12/02/2021] [Accepted: 12/03/2021] [Indexed: 12/15/2022]
Abstract
Purpose Define relationships between quantitative magnetic resonance imaging (MRI) metrics and clinical/laboratory data in a pediatric and young adult cohort with autoimmune liver disease (AILD). Materials and methods This prospective, cross-sectional study was institutional review board-approved. Patients enrolled in an institutional AILD registry were divided into groups: (1) autoimmune hepatitis (AIH) or (2) primary sclerosing cholangitis (PSC)/autoimmune sclerosing cholangitis (ASC). Participants underwent serum liver biochemistry testing and research MRI examinations, including 3D magnetic resonance cholangiopancreatography (MRCP), magnetic resonance elastography (MRE), and iron-corrected T1 mapping (cT1). MRCP + and LiverMultiScan (Perspectum Ltd., Oxford, UK) were used to post-process 3D MRCP and cT1 data. Multiple linear regression models were used to assess relationships. Results 58 patients, 35 male, median age 16 years were included; 30 in the AIH group, 28 in the PSC/ASC group. After statistical adjustments for patient age, sex, presence of inflammatory bowel disease (IBD), specific diagnosis (PSC/ASC vs. AIH), and time from diagnosis to MRI examination, left hepatic bile duct maximum diameter was a statistically significant predictor of whole liver mean cT1, cT1 interquartile range (IQR), and MRE liver stiffness (p = 0.01–0.04). Seven laboratory values were significant predictors of whole liver cT1 IQR (p < 0.0001–0.04). Eight laboratory values and right hepatic bile duct median and maximum diameter were significant predictors of liver stiffness (p < 0.0001–0.03). Conclusions Bile duct diameters and multiple laboratory biomarkers of liver disease are independent predictors of liver stiffness and cT1 IQR in pediatric patients with AILD. Supplementary Information The online version contains supplementary material available at 10.1007/s00261-021-03378-0.
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29
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Chen H, Zhang H, Wang Z. A ratiometric fluorescent probe based on peptide modified MnFe 2O 4 nanoparticles for matrix metalloproteinase-7 activity detection in vitro and in vivo. Analyst 2022; 147:1581-1588. [DOI: 10.1039/d2an00212d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
A peptide modified MnFe2O4 ratiometric fluorescent nanoprobe is developed for noninvasively visualizing the distribution of matrix metalloproteinase-7 in vitro and in vivo.
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Affiliation(s)
- Hongda Chen
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- School of Applied Chemical Engineering, University of Science and Technology of China, Road Baohe District, Hefei, Anhui, 230026, P. R. China
| | - Hua Zhang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
| | - Zhenxin Wang
- State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China
- School of Applied Chemical Engineering, University of Science and Technology of China, Road Baohe District, Hefei, Anhui, 230026, P. R. China
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30
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Kremastiotis G, Handa I, Jackson C, George S, Johnson J. Disparate effects of MMP and TIMP modulation on coronary atherosclerosis and associated myocardial fibrosis. Sci Rep 2021; 11:23081. [PMID: 34848763 PMCID: PMC8632906 DOI: 10.1038/s41598-021-02508-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 11/12/2021] [Indexed: 11/12/2022] Open
Abstract
Matrix metalloproteinase (MMP) activity is tightly regulated by the endogenous tissue inhibitors (TIMPs), and dysregulated activity contributes to extracellular matrix remodelling. Accordingly, MMP/TIMP balance is associated with atherosclerotic plaque progression and instability, alongside adverse post-infarction cardiac fibrosis and subsequent heart failure. Here, we demonstrate that prolonged high-fat feeding of apolipoprotein (Apo)e-deficient mice triggered the development of unstable coronary artery atherosclerosis alongside evidence of myocardial infarction and progressive sudden death. Accordingly, the contribution of select MMPs and TIMPs to the progression of both interrelated pathologies was examined in Apoe-deficient mice with concomitant deletion of Mmp7, Mmp9, Mmp12, or Timp1 and relevant wild-type controls after 36-weeks high-fat feeding. Mmp7 deficiency increased incidence of sudden death, while Mmp12 deficiency promoted survival, whereas Mmp9 or Timp1 deficiency had no effect. While all mice harboured coronary disease, atherosclerotic burden was reduced in Mmp7-deficient and Mmp12-deficient mice and increased in Timp1-deficient animals, compared to relevant controls. Significant differences in cardiac fibrosis were only observed in Mmp-7-deficient mice and Timp1-deficient animals, which was associated with reduced capillary number. Adopting therapeutic strategies in Apoe-deficient mice, TIMP-2 adenoviral-overexpression or administration (delayed or throughout) of a non-selective MMP inhibitor (RS-130830) had no effect on coronary atherosclerotic burden or cardiac fibrosis. Taken together, our findings emphasise the divergent roles of MMPs on coronary plaque progression and associated post-MI cardiac fibrosis, highlighting the need for selective therapeutic approaches to target unstable atherosclerosis alongside adverse cardiac remodelling while negating detrimental adverse effects on either pathology, with targeting of MMP-12 seeming a suitable target.
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Affiliation(s)
- Georgios Kremastiotis
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK
| | - Ishita Handa
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK
| | - Christopher Jackson
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK
| | - Sarah George
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK
| | - Jason Johnson
- Laboratory of Cardiovascular Pathology, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Bristol, BS2 8HW, England, UK.
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Tang X, Lv Y, Pu L, Ma J, Jin S, Xiang B. Matrix Metalloproteinase-7 as a Diagnostic Marker for Biliary Atresia: a Systematic Review and Meta-analysis. Indian J Surg 2021. [DOI: 10.1007/s12262-021-03107-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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32
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Enoksen ITT, Svistounov D, Norvik JV, Stefansson VTN, Solbu MD, Eriksen BO, Melsom T. Serum Matrix Metalloproteinase 7 and accelerated GFR decline in a general non-diabetic population. Nephrol Dial Transplant 2021; 37:1657-1667. [PMID: 34436577 PMCID: PMC9395374 DOI: 10.1093/ndt/gfab251] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Age-related reduction of glomerular filtration rate (GFR) is a major contributor to the global chronic kidney disease (CKD) epidemic. We investigated whether baseline serum levels of the pro-fibrotic matrix metalloproteinase 2 (MMP2), MMP7 and their inhibitor, tissue inhibitor of metalloproteinase 1 (TIMP1), which mediates fibrosis development in aging animals, were associated with GFR decline in a general nondiabetic population. METHODS In the Renal Iohexol Clearance Survey (RENIS), we measured GFR using iohexol clearance in 1627 subjects aged 50-64 without self-reported diabetes, kidney or cardiovascular disease. After a median of 5.6 years, 1324 had follow-up GFR measurements. Using linear mixed models and logistic regression analyses, we evaluated the association of MMP7, MMP2 and TIMP1 with the mean GFR decline rate, risk of accelerated GFR decline (defined as subjects with the 10% steepest GFR slopes: ≥1.8 ml/min/1.73 m2/year) and incident CKD (GFR <60 ml/min/1.73 m2 and/or urinary albumin to creatinine ratio (ACR) ≥3.0 mg/mmol). RESULTS Higher MMP7 levels (per SD increase of MMP7) were associated with steeper GFR decline rates (-0.23 ml/min/1.73m2/year [95% confidence interval, -0.34 to -0.12]) and increased risk of accelerated GFR decline and incident CKD, (odds ratios; 1.58 (1.30-1.93) and 1.45 (1.05-2.01), respectively, in a model adjusted for age, sex, baseline GFR, ACR and cardiovascular risk factors). MMP2 and TIMP1 showed no association with GFR decline or incident CKD. CONCLUSION The pro-fibrotic biomarker MMP7, but not MMP2 or TIMP1, is associated with increased risk of accelerated GFR decline and incident CKD in middle-aged persons from the general population.
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Affiliation(s)
| | - Dmitri Svistounov
- Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
| | - Jon V Norvik
- Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway.,Section of Nephrology, Clinic of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Vidar T N Stefansson
- Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway
| | - Marit D Solbu
- Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway.,Section of Nephrology, Clinic of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Bjørn O Eriksen
- Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway.,Section of Nephrology, Clinic of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
| | - Toralf Melsom
- Metabolic and Renal Research Group, UiT The Arctic University of Norway, Tromsø, Norway.,Section of Nephrology, Clinic of Internal Medicine, University Hospital of North Norway, Tromsø, Norway
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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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Liao HY, Da CM, Liao B, Zhang HH. Roles of matrix metalloproteinase-7 (MMP-7) in cancer. Clin Biochem 2021; 92:9-18. [PMID: 33713636 DOI: 10.1016/j.clinbiochem.2021.03.003] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 02/13/2021] [Accepted: 03/03/2021] [Indexed: 12/19/2022]
Abstract
Matrix metalloproteinase-7 (MMP-7) is a small proteolytic enzyme that secretes zinc and calcium endopeptidases. It can degrade a variety of extracellular matrix substrates and other substrates and plays important regulatory roles in many human pathophysiological processes. Since its discovery, MMP-7 has been recognized as a regulatory protein in wound healing, bone growth, and remodeling. Later, MMP-7 was reported to regulate the occurrence and development of cancers and mediate the proliferation, differentiation, metastasis, and invasion of several types of cancer cells via various mechanisms. Thus, matrix metalloproteinase-7 may be a promising tumor biomarker and therapeutic target. The expression of MMP-7 correlates with the clinical characteristics of cancer patients, and its expression profile is a new diagnostic and prognostic biomarker for a variety of human diseases. Hence, manipulating the expression or function of MMP-7 may be a potential treatment strategy for different diseases including cancers. This review summarizes the role played by MMP-7 in carcinogenesis of several human cancers, underlying mechanisms, and its clinical significance of the occurrence and development of cancers.
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Affiliation(s)
- Hai-Yang Liao
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
| | - Chao-Ming Da
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
| | - Bei Liao
- Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China; The First Clinical Medical College of Lanzhou University, 1 Donggang Road, Lanzhou 730000, PR China
| | - Hai-Hong Zhang
- The Second Clinical Medical College of Lanzhou University, 82 Cuiying Men, Lanzhou 730030, PR China; Orthopaedics Key Laboratory of Gansu Province, Lanzhou 730000, PR China.
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35
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Zhan Z, Jing Z, He B, Hosseini N, Westerhoff M, Choi EY, Garmire LX. Two-stage Cox-nnet: biologically interpretable neural-network model for prognosis prediction and its application in liver cancer survival using histopathology and transcriptomic data. NAR Genom Bioinform 2021; 3:lqab015. [PMID: 33778491 PMCID: PMC7985035 DOI: 10.1093/nargab/lqab015] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 02/01/2021] [Accepted: 02/24/2021] [Indexed: 12/11/2022] Open
Abstract
Pathological images are easily accessible data with the potential of prognostic biomarkers. Moreover, integration of heterogeneous data types from multi-modality, such as pathological image and gene expression data, is invaluable to help predicting cancer patient survival. However, the analytical challenges are significant. Here, we take the hepatocellular carcinoma (HCC) pathological image features extracted by CellProfiler, and apply them as the input for Cox-nnet, a neural network-based prognosis prediction model. We compare this model with the conventional Cox proportional hazards (Cox-PH) model, CoxBoost, Random Survival Forests and DeepSurv, using C-index and log-rank P-values. The results show that Cox-nnet is significantly more accurate than Cox-PH and Random Survival Forests models and comparable with CoxBoost and DeepSurv models, on pathological image features. Further, to integrate pathological image and gene expression data of the same patients, we innovatively construct a two-stage Cox-nnet model, and compare it with another complex neural-network model called PAGE-Net. The two-stage Cox-nnet complex model combining histopathology image and transcriptomic RNA-seq data achieves much better prognosis prediction, with a median C-index of 0.75 and log-rank P-value of 6e-7 in the testing datasets, compared to PAGE-Net (median C-index of 0.68 and log-rank P-value of 0.03). Imaging features present additional predictive information to gene expression features, as the combined model is more accurate than the model with gene expression alone (median C-index 0.70). Pathological image features are correlated with gene expression, as genes correlated to top imaging features present known associations with HCC patient survival and morphogenesis of liver tissue. This work proposes two-stage Cox-nnet, a new class of biologically relevant and interpretable models, to integrate multiple types of heterogenous data for survival prediction.
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Affiliation(s)
- Zhucheng Zhan
- School of Science and Engineering, Chinese University of Hong Kong, Shenzhen Campus, Shenzhen 518172, P.R. China
| | - Zheng Jing
- Department of Applied Statistics, University of Michigan, Ann Arbor, MI 48104, USA
| | - Bing He
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48104, USA
| | - Noshad Hosseini
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48104, USA
| | - Maria Westerhoff
- Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA
| | - Eun-Young Choi
- Department of Pathology, University of Michigan, Ann Arbor, MI 48104, USA
| | - Lana X Garmire
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48104, USA
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Martinez-Castillo M, Hernandez-Barragan A, Flores-Vasconcelos I, Galicia-Moreno M, Rosique-Oramas D, Perez-Hernandez JL, Higuera-De la Tijera F, Montalvo-Jave EE, Torre-Delgadillo A, Cordero-Perez P, Muñoz-Espinosa L, Kershenobich D, Gutierrez-Reyes G. Production and activity of matrix metalloproteinases during liver fibrosis progression of chronic hepatitis C patients. World J Hepatol 2021; 13:218-232. [PMID: 33708351 PMCID: PMC7934014 DOI: 10.4254/wjh.v13.i2.218] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/14/2020] [Accepted: 12/28/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Matrix metalloproteinases (MMPs) participate in the degradation of extracellular matrix compounds, maintaining the homeostasis between fibrogenesis and fibrolytic processes in the liver. However, there are few studies on the regulation of liver MMPs in fibrosis progression in humans. AIM To assess the production activity and regulation of matrix metalloproteinases in liver fibrosis stages in chronic hepatitis C (CHC). METHODS A prospective, cross-sectional, multicenter study was conducted. CHC patients were categorized in fibrosis grades through FibroTest ® and/or FibroScan ® . Serum MMP-2, -7, and -9 were determined by western blot and multiplex suspension array assays. Differences were validated by the Kruskal-Wallis and Mann-Whitney U tests. The Spearman correlation coefficient and area under the receiver operating characteristic curve were calculated. Collagenolytic and gelatinase activity was determined through the Azocoll substrate and zymogram test, whereas tissue inhibitor of metalloproteinase-1 production was determined by dot blot assays. RESULTS Serum concentrations of the MMPs evaluated were higher in CHC patients than in healthy subjects. MMP-7 distinguished early and advanced stages, with a correlation of 0.32 (P < 0.001), and the area under the receiver operating characteristic displayed moderate sensitivity and specificity for MMP-7 in F4 (area under the receiver operating characteristic, 0.705; 95% confidence interval: 0.605-0.805; P < 0.001). Collagenolytic activity was detected at F0 and F1, whereas gelatinase activity was not detected at any fibrosis stage. Tissue inhibitor of metalloproteinase-1 determination showed upregulation in F0 and F1 but downregulation in F2 (P < 0.001). CONCLUSION High concentrations of inactive MMPs were present in the serum of CHC patients, reflecting the impossibility to restrain liver fibrosis progression. MMPs could be good diagnostic candidates and therapeutic targets for improving novel strategies to reverse liver fibrosis in CHC.
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Affiliation(s)
- Moises Martinez-Castillo
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Abigail Hernandez-Barragan
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Ivonne Flores-Vasconcelos
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Marina Galicia-Moreno
- Department of Molecular Biology and Genomics, Institute of Molecular Biology in Medicine and Gene Therapy, Health Science University Center, University of Guadalajara, Guadalajara 06726, Mexico
| | - Dorothy Rosique-Oramas
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Jose Luis Perez-Hernandez
- Department of Gastroenterology, General Hospital of Mexico "Dr. Eduardo Liceaga," Mexico City 06726, Mexico
| | | | - Eduardo E Montalvo-Jave
- Department of General Surgery, General Hospital of Mexico "Dr. Eduardo Liceaga," School of Medicine, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico
| | - Aldo Torre-Delgadillo
- Hepatology and Liver Transplant, National Institute of Medical Sciences and Nutrition "Salvador Zubirán," Mexico City 06726, Mexico
| | - Paula Cordero-Perez
- University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo Leon, Monterrey 06726, Mexico
| | - Linda Muñoz-Espinosa
- University Hospital "Dr. José Eleuterio González," Autonomous University of Nuevo Leon, Monterrey 06726, Mexico
| | - David Kershenobich
- Hepatology and Liver Transplant, National Institute of Medical Sciences and Nutrition "Salvador Zubirán," Mexico City 06726, Mexico
| | - Gabriela Gutierrez-Reyes
- Liver, Pancreas and Motility Laboratory, Unit of Experimental Medicine, School of Medicine, General Hospital of Mexico, Universidad Nacional Autonoma de Mexico, Mexico City 06726, Mexico.
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Irvine KM, Okano S, Patel PJ, Horsfall LU, Williams S, Russell A, Powell EE. Serum matrix metalloproteinase 7 (MMP7) is a biomarker of fibrosis in patients with non-alcoholic fatty liver disease. Sci Rep 2021; 11:2858. [PMID: 33536476 PMCID: PMC7858627 DOI: 10.1038/s41598-021-82315-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 01/19/2021] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) affects 25% of the adult population globally. Since liver fibrosis is the most important predictor of liver-related complications in patients with NAFLD, identification of patients with advanced fibrosis among at-risk individuals is an important issue in clinical practice. Transient elastography is the best evaluated non-invasive method used in referral centres to assess liver fibrosis, however serum-based tests, such as the Enhanced Liver Fibrosis (ELF) score, have a practical advantage as first-line tests due to their wider availability and lower cost. We previously identified matrix metalloproteinase 7 (MMP7) as a serum biomarker of histological advanced fibrosis in a mixed-etiology patient cohort. In this study we aimed to determine the association between MMP7 and fibrosis, assessed by transient elastography, in patients with NAFLD. Serum MMP7 levels were measured in a cohort of 228 patients with NAFLD. Associations between MMP7, liver stiffness measurement (LSM), ELF score and clinical parameters were determined using logistic regression modelling. Serum MMP7 was associated with clinically significant fibrosis (LSM ≥ 8.2), independent of age, gender, BMI and diabetes. The addition of MMP7 significantly improved the diagnostic performance of the ELF test, particularly in patients over the age of 60. Combinations of serum biomarkers have the potential to improve the sensitivity and specificity of detection of advanced fibrosis in at-risk patients with NAFLD. We have demonstrated that serum MMP7 is independently associated with clinically significant fibrosis and improves the diagnostic performance of currently available tests in older patients.
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Affiliation(s)
- Katharine M Irvine
- Mater Research, The University of Queensland, Brisbane, Australia. .,Centre for Liver Disease Research, The University of Queensland, Brisbane, Australia.
| | - Satomi Okano
- Statistics Unit, QIMR-Berghofer Medical Research Institute, Brisbane, Australia
| | - Preya J Patel
- Centre for Liver Disease Research, The University of Queensland, Brisbane, Australia.,Institute for Liver and Digestive Health, University College London, London, UK
| | - Leigh U Horsfall
- Centre for Liver Disease Research, The University of Queensland, Brisbane, Australia.,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia
| | | | - Anthony Russell
- Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Australia.,Centre for Health Services Research, The University of Queensland, Brisbane, Australia
| | - Elizabeth E Powell
- Centre for Liver Disease Research, The University of Queensland, Brisbane, Australia. .,Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Brisbane, Australia.
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Nomden M, Beljaars L, Verkade HJ, Hulscher JBF, Olinga P. Current Concepts of Biliary Atresia and Matrix Metalloproteinase-7: A Review of Literature. Front Med (Lausanne) 2020; 7:617261. [PMID: 33409288 PMCID: PMC7779410 DOI: 10.3389/fmed.2020.617261] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 12/02/2020] [Indexed: 12/20/2022] Open
Abstract
Biliary atresia (BA) is a rare cholangiopathy of infancy in which the bile ducts obliterate, leading to profound cholestasis and liver fibrosis. BA is hypothesized to be caused by a viral insult that leads to over-activation of the immune system. Patients with BA are surgically treated with a Kasai portoenterostomy (KPE), which aims to restore bile flow from the liver to the intestines. After KPE, progressive liver fibrosis is often observed in BA patients, even despite surgical success and clearance of their jaundice. The innate immune response is involved during the initial damage to the cholangiocytes and further differentiation of the adaptive immune response into a T-helper 1 cell (Th1) response. Multiple studies have shown that there is continuing elevation of involved cytokines that can lead to the progressive liver fibrosis. However, the mechanism by which the progressive injury occurs is not fully elucidated. Recently, matrix metalloproteinase-7 (MMP-7) has been investigated to be used as a biomarker to diagnose BA. MMPs are involved in extracellular matrix (ECM) turnover, but also have non-ECM related functions. The role of MMP-7 and other MMPs in liver fibrosis is just starting to be elucidated. Multiple studies have shown that serum MMP-7 measurements are able to accurately diagnose BA in a cohort of cholestatic patients while hepatic MMP-7 expression correlated with BA-related liver fibrosis. While the mechanism by which MMP-7 can be involved in the pathophysiology of BA is unclear, MMP-7 has been investigated in other fibrotic pathologies such as renal and idiopathic pulmonary fibrosis. MMP-7 is involved in Wnt/β-catenin signaling, reducing cell-to-cell contact by shedding of E-cadherin, amplifying inflammation and fibrosis via osteopontin (OPN) and TNF-α while it also appears to play a role in induction of angiogenesis This review aims to describe the current understandings of the pathophysiology of BA. Subsequently, we describe how MMP-7 is involved in other pathologies, such as renal and pulmonary fibrosis. Then, we propose how MMP-7 can potentially be involved in BA. By doing this, we aim to describe the putative role of MMP-7 as a prognostic biomarker in BA and to provide possible new therapeutic and research targets that can be investigated in the future.
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Affiliation(s)
- Mark Nomden
- Divison of Pediatric Surgery, Department of Surgery, University of Groningen, Groningen, Netherlands
| | - Leonie Beljaars
- Division of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands
| | - Henkjan J Verkade
- Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Jan B F Hulscher
- Divison of Pediatric Surgery, Department of Surgery, University of Groningen, Groningen, Netherlands
| | - Peter Olinga
- Division of Pharmaceutical Technology and Biopharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands
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Watanabe E, Kawashima Y, Suda W, Kakihara T, Takazawa S, Nakajima D, Nakamura R, Nishi A, Suzuki K, Ohara O, Fujishiro J. Discovery of Candidate Stool Biomarker Proteins for Biliary Atresia Using Proteome Analysis by Data-Independent Acquisition Mass Spectrometry. Proteomes 2020; 8:proteomes8040036. [PMID: 33260872 PMCID: PMC7709124 DOI: 10.3390/proteomes8040036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 11/25/2020] [Indexed: 11/16/2022] Open
Abstract
Biliary atresia (BA) is a destructive inflammatory obliterative cholangiopathy of the neonate that affects various parts of the bile duct. If early diagnosis followed by Kasai portoenterostomy is not performed, progressive liver cirrhosis frequently leads to liver transplantation in the early stage of life. Therefore, prompt diagnosis is necessary for the rescue of BA patients. However, the prompt diagnosis of BA remains challenging because specific and reliable biomarkers for BA are currently unavailable. In this study, we discovered potential biomarkers for BA using deep proteome analysis by data-independent acquisition mass spectrometry (DIA–MS). Four patients with BA and three patients with neonatal cholestasis of other etiologies (non-BA) were recruited for stool proteome analysis. Among the 2110 host-derived proteins detected in their stools, 49 proteins were significantly higher in patients with BA and 54 proteins were significantly lower. These varying stool protein levels in infants with BA can provide potential biomarkers for BA. As demonstrated in this study, the deep proteome analysis of stools has great potential not only in detecting new stool biomarkers for BA but also in elucidating the pathophysiology of BA and other pediatric diseases, especially in the field of pediatric gastroenterology.
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Affiliation(s)
- Eiichiro Watanabe
- Department of Pediatric Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (E.W.); (T.K.); (K.S.)
| | - Yusuke Kawashima
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu 292-0818, Japan; (Y.K.); (D.N.); (R.N.); (O.O.)
| | - Wataru Suda
- Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan;
| | - Tomo Kakihara
- Department of Pediatric Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (E.W.); (T.K.); (K.S.)
| | - Shinya Takazawa
- Department of Surgery, Gunma Children’s Medical Center, Shibukawa 277-8577, Japan; (S.T.); (A.N.)
| | - Daisuke Nakajima
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu 292-0818, Japan; (Y.K.); (D.N.); (R.N.); (O.O.)
| | - Ren Nakamura
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu 292-0818, Japan; (Y.K.); (D.N.); (R.N.); (O.O.)
| | - Akira Nishi
- Department of Surgery, Gunma Children’s Medical Center, Shibukawa 277-8577, Japan; (S.T.); (A.N.)
| | - Kan Suzuki
- Department of Pediatric Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (E.W.); (T.K.); (K.S.)
| | - Osamu Ohara
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu 292-0818, Japan; (Y.K.); (D.N.); (R.N.); (O.O.)
| | - Jun Fujishiro
- Department of Pediatric Surgery, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; (E.W.); (T.K.); (K.S.)
- Correspondence: ; Tel.: +81-3-5800-8671; Fax: +81-3-5800-5104
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Lam S, Singh R, Dillman JR, Trout AT, Serai SD, Sharma D, Sheridan R, Su W, Fei L, Karns R, Haramija MM, Ridgway G, Goldfinger M, Squires JE, Denson LA, Hyams JS, Miethke AG. Serum Matrix Metalloproteinase 7 Is a Diagnostic Biomarker of Biliary Injury and Fibrosis in Pediatric Autoimmune Liver Disease. Hepatol Commun 2020; 4:1680-1693. [PMID: 33163837 PMCID: PMC7603534 DOI: 10.1002/hep4.1589] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/08/2020] [Accepted: 07/11/2020] [Indexed: 12/17/2022] Open
Abstract
In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy (P < 0.001). An sMMP7 concentration >23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for MMP7 (r = 0.70; P < 0.001). Using immunofluorescence, MMP7 was localized primarily to the cholangiocytes of patients with SC. In 46 subjects with liver biopsy available for blinded review, elevation in sMMP7 concentrations segregated with the presence of lymphocytic and neutrophilic cholangitis and periductal fibrosis and correlated with Ishak, Ludwig, and Nakanuma scoring systems. Liver stiffness measured by magnetic resonance elastography also correlated with sMMP7 concentrations (r = 0.56; P < 0.01). Using magnetic resonance cholangiopancreatography plus (MRCP+), sMMP7 in 34 patients correlated with the number of biliary dilatations (r = 0.54; P < 0.01) and strictures (r = 0.56; P < 0.01). MMP7 as a marker of biliary injury was validated in an independent cohort of children with ulcerative colitis. Higher sMMP7 concentrations also correlated with a history of SC-related complication. Conclusion: MMP7 is a promising biomarker for pediatric SC that diagnostically outperforms ALP and GGT. sMMP7 may directly reflect biliary injury and fibrosis, the main drivers of disease progression in SC.
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Affiliation(s)
- Simon Lam
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
- Section of Pediatric GastroenterologyDepartment of PediatricsAlberta Children’s HospitalUniversity of CalgaryCalgaryCanada
| | - Ruchi Singh
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Jonathan R. Dillman
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
- Department of RadiologyCincinnati Children's Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiOHUSA
| | - Andrew T. Trout
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
- Department of RadiologyCincinnati Children's Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiOHUSA
| | - Suraj D. Serai
- Department of RadiologyChildren’s Hospital of PhiladelphiaPhiladelphiaPAUSA
| | - Divya Sharma
- Division of PathologyUniversity of CincinnatiCincinnatiOHUSA
| | - Rachel Sheridan
- Department of PathologyDayton Children’s HospitalDaytonOHUSA
| | - Weizhe Su
- Division of Biostatistics and EpidemiologyCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Lin Fei
- Division of Biostatistics and EpidemiologyCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | - Rebekah Karns
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
| | | | - Ged Ridgway
- Perspectum Diagnostics Ltd.South San FranciscoCAUSA
| | | | | | - Lee A. Denson
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
| | - Jeffery S. Hyams
- Division of Digestive DiseasesHepatology, and NutritionConnecticut Children’s Hospital Medical CenterHartfordCTUSA
| | - Alexander G. Miethke
- Division of Gastroenterology, Hepatology and NutritionCincinnati Children's Hospital Medical CenterCincinnatiOHUSA
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOHUSA
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Masuzaki R, Kanda T, Sasaki R, Matsumoto N, Ogawa M, Matsuoka S, Karp SJ, Moriyama M. Noninvasive Assessment of Liver Fibrosis: Current and Future Clinical and Molecular Perspectives. Int J Mol Sci 2020; 21:4906. [PMID: 32664553 PMCID: PMC7402287 DOI: 10.3390/ijms21144906] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/29/2020] [Accepted: 07/09/2020] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis is one of the risk factors for hepatocellular carcinoma (HCC) development. The staging of liver fibrosis can be evaluated only via a liver biopsy, which is an invasive procedure. Noninvasive methods for the diagnosis of liver fibrosis can be divided into morphological tests such as elastography and serum biochemical tests. Transient elastography is reported to have excellent performance in the diagnosis of liver fibrosis and has been accepted as a useful tool for the prediction of HCC development and other clinical outcomes. Two-dimensional shear wave elastography is a new technique and provides a real-time stiffness image. Serum fibrosis markers have been studied based on the mechanism of fibrogenesis and fibrolysis. In the healthy liver, homeostasis of the extracellular matrix is maintained directly by enzymes called matrix metalloproteinases (MMPs) and their specific inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs and TIMPs could be useful serum biomarkers for liver fibrosis and promising candidates for the treatment of liver fibrosis. Further studies are required to establish liver fibrosis-specific markers based on further clinical and molecular research. In this review, we summarize noninvasive fibrosis tests and molecular mechanism of liver fibrosis in current daily clinical practice.
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Affiliation(s)
- Ryota Masuzaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Reina Sasaki
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Naoki Matsumoto
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Masahiro Ogawa
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Shunichi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
| | - Seth J. Karp
- Division of Liver Transplantation, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA;
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Itabashi-Ku, Tokyo 173-8610, Japan; (T.K.); (R.S.); (N.M.); (M.O.); (S.M.); (M.M.)
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Liu Z, Tan RJ, Liu Y. The Many Faces of Matrix Metalloproteinase-7 in Kidney Diseases. Biomolecules 2020; 10:960. [PMID: 32630493 PMCID: PMC7356035 DOI: 10.3390/biom10060960] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 06/19/2020] [Accepted: 06/22/2020] [Indexed: 12/11/2022] Open
Abstract
Matrix metalloproteinase-7 (MMP-7) is a secreted zinc-dependent endopeptidase that is implicated in regulating kidney homeostasis and diseases. MMP-7 is produced as an inactive zymogen, and proteolytic cleavage is required for its activation. MMP-7 is barely expressed in normal adult kidney but upregulated in acute kidney injury (AKI) and chronic kidney disease (CKD). The expression of MMP-7 is transcriptionally regulated by Wnt/β-catenin and other cues. As a secreted protein, MMP-7 is present and increased in the urine of patients, and its levels serve as a noninvasive biomarker for predicting AKI prognosis and monitoring CKD progression. Apart from degrading components of the extracellular matrix, MMP-7 also cleaves a wide range of substrates, such as E-cadherin, Fas ligand, and nephrin. As such, it plays an essential role in regulating many cellular processes, such as cell proliferation, apoptosis, epithelial-mesenchymal transition, and podocyte injury. The function of MMP-7 in kidney diseases is complex and context-dependent. It protects against AKI by priming tubular cells for survival and regeneration but promotes kidney fibrosis and CKD progression. MMP-7 also impairs podocyte integrity and induces proteinuria. In this review, we summarized recent advances in our understanding of the regulation, role, and mechanisms of MMP-7 in the pathogenesis of kidney diseases. We also discussed the potential of MMP-7 as a biomarker and therapeutic target in a clinical setting.
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Affiliation(s)
- Zhao Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China;
| | - Roderick J. Tan
- Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA;
| | - Youhua Liu
- State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China;
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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Geervliet E, Bansal R. Matrix Metalloproteinases as Potential Biomarkers and Therapeutic Targets in Liver Diseases. Cells 2020; 9:E1212. [PMID: 32414178 PMCID: PMC7290342 DOI: 10.3390/cells9051212] [Citation(s) in RCA: 98] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/06/2020] [Accepted: 05/13/2020] [Indexed: 01/18/2023] Open
Abstract
Chronic liver diseases, characterized by an excessive accumulation of extracellular matrix (ECM) resulting in scar tissue formation, are a growing health problem causing increasing morbidity and mortality worldwide. Currently, therapeutic options for tissue fibrosis are severely limited, and organ transplantation is the only treatment for the end-stage liver diseases. During liver damage, injured hepatocytes release proinflammatory factors resulting in the recruitment and activation of immune cells that activate quiescent hepatic stellate cells (HSCs). Upon activation, HSCs transdifferentiate into highly proliferative, migratory, contractile and ECM-producing myofibroblasts. The disrupted balance between ECM deposition and degradation leads to the formation of scar tissue referred to as fibrosis. This balance can be restored either by reducing ECM deposition (by inhibition of HSCs activation and proliferation) or enhancing ECM degradation (by increased expression of matrix metalloproteinases (MMPs)). MMPs play an important role in ECM remodeling and represent an interesting target for therapeutic drug discovery. In this review, we present the current knowledge about ECM remodeling and role of the different MMPs in liver diseases. MMP expression patterns in different stages of liver diseases have also been reviewed to determine their role as biomarkers. Finally, we highlight MMPs as promising therapeutic targets for the resolution of liver diseases.
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Affiliation(s)
| | - Ruchi Bansal
- Translational Liver Research, Department of Medical Cell BioPhysics, Technical Medical Centre, Faculty of Science and Technology, University of Twente, 7522 NB Enschede, The Netherlands;
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Zhong W, Wei X, Hao L, Lin TD, Yue R, Sun X, Guo W, Dong H, Li T, Ahmadi AR, Sun Z, Zhang Q, Zhao J, Zhou Z. Paneth Cell Dysfunction Mediates Alcohol-related Steatohepatitis Through Promoting Bacterial Translocation in Mice: Role of Zinc Deficiency. Hepatology 2020; 71:1575-1591. [PMID: 31520476 PMCID: PMC7069794 DOI: 10.1002/hep.30945] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 09/06/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Microbial dysbiosis is associated with alcohol-related hepatitis (AH), with the mechanisms yet to be elucidated. The present study aimed to determine the effects of alcohol and zinc deficiency on Paneth cell (PC) antimicrobial peptides, α-defensins, and to define the link between PC dysfunction and AH. APPROACH AND RESULTS Translocation of pathogen-associated molecular patterns (PAMPs) was determined in patients with severe AH and in a mouse model of alcoholic steatohepatitis. Microbial composition and PC function were examined in mice. The link between α-defensin dysfunction and AH was investigated in α-defensin-deficient mice. Synthetic human α-defensin 5 (HD5) was orally given to alcohol-fed mice to test the therapeutic potential. The role of zinc deficiency in α-defensin was evaluated in acute and chronic mouse models of zinc deprivation. Hepatic inflammation was associated with PAMP translocation and lipocalin-2 (LCN2) and chemokine (C-X-C motif) ligand 1 (CXCL1) elevation in patients with AH. Antibiotic treatment, lipopolysaccharide injection to mice, and in vitro experiments showed that PAMPs, but not alcohol, directly induced LCN2 and CXCL1. Chronic alcohol feeding caused systemic dysbiosis and PC α-defensin reduction in mice. Knockout of functional α-defensins synergistically affected alcohol-perturbed bacterial composition and the gut barrier and exaggerated PAMP translocation and liver damage. Administration of HD5 effectively altered cecal microbial composition, especially increased Akkermansia muciniphila, and reversed the alcohol-induced deleterious effects. Zinc-regulated PC homeostasis and α-defensins function at multiple levels, and dietary zinc deficiency exaggerated the deleterious effect of alcohol on PC bactericidal activity. CONCLUSIONS Taken together, the study suggests that alcohol-induced PC α-defensin dysfunction is mediated by zinc deficiency and involved in the pathogenesis of AH. HD5 administration may represent a promising therapeutic approach for treating AH.
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Affiliation(s)
- Wei Zhong
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081.,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081.,Corresponding authors: Wei Zhong, Phone: 704-250-5814, . Zhanxiang Zhou, Phone: 704-250-5800.
| | - Xiaoyuan Wei
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, USA 72701
| | - Liuyi Hao
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
| | - Tai-Du Lin
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081.,Department of Chemistry & Biochemistry, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
| | - Ruichao Yue
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
| | - Xinguo Sun
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
| | - Wei Guo
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
| | - Haibo Dong
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
| | - Tianjiao Li
- Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
| | - Ali R. Ahmadi
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 21205
| | - Qibin Zhang
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081.,Department of Chemistry & Biochemistry, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081
| | - Jiangchao Zhao
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR, USA 72701
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081.,Department of Nutrition, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC, USA 28081.,Corresponding authors: Wei Zhong, Phone: 704-250-5814, . Zhanxiang Zhou, Phone: 704-250-5800.
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Naim A, Baig MS. Matrix metalloproteinase-8 (MMP-8) regulates the activation of hepatic stellate cells (HSCs) through the ERK-mediated pathway. Mol Cell Biochem 2020; 467:107-116. [PMID: 32108279 DOI: 10.1007/s11010-020-03705-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2019] [Accepted: 02/15/2020] [Indexed: 12/11/2022]
Abstract
Hepatic stellate cells (HSCs) are known to play a key role in the progression of liver fibrosis by producing excessive extracellular matrix (ECM). Matrix metalloproteinases (MMPs) belong to a family of endopeptidases, which have a well-established role in the degradation of ECM. Our study suggests that, besides the degradation of the extracellular matrix, matrix metalloproteinase-8 (MMP-8) has a non-canonical role in activating the quiescent HSCs to myofibroblasts by regulating the expression of Col1A1 and αSMA. We have identified that MMP-8 secreted from macrophages as a response to LPS stimulation activates HSCs via ERK1/2-dependent pathway. In addition to this, we determined that MMP-8 may regulate the homodimerization of c-Jun in LX-2 cells, during the trans-differentiation process from quiescent HSC to activate myofibroblasts. Macrophage-released MMP-8 plays a master role in activating the dormant HSCs to activate myofibroblasts through the Erk-mediated pathway and Jun cellular translocation leading to liver fibrosis. Significance MMP-8 can be used as a therapeutic target against liver fibrosis.
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Affiliation(s)
- Adnan Naim
- Discipline of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, 453552, India
| | - Mirza S Baig
- Discipline of Biosciences and Biomedical Engineering (BSBE), Indian Institute of Technology Indore (IITI), Simrol, Indore, 453552, India.
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Jiang J, Wang J, Shen Z, Lu X, Chen G, Huang Y, Dong R, Zheng S. Serum MMP-7 in the Diagnosis of Biliary Atresia. Pediatrics 2019; 144:peds.2019-0902. [PMID: 31604829 DOI: 10.1542/peds.2019-0902] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/19/2019] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The overlapping features of biliary atresia (BA) and other neonatal cholestasis with alternative causes (non-BA) have posed challenges for diagnosis. Matrix metalloproteinase-7 (MMP-7) has been reported to be promising in diagnosing BA. We aimed to validate the diagnostic accuracy of MMP-7 for BA in a large population sample. METHODS We enrolled 288 patients with neonatal obstructive jaundice from March 2017 to October 2018. Serum MMP-7 levels were measured by using an enzyme-linked immunosorbent assay. Receiver operating characteristic curves were constructed, and decision curve analysis was done. A Pearson correlation coefficient test was conducted to assess the correlation between MMP-7 levels and other characteristics. RESULTS The median serum MMP-7 levels were 38.89 ng/mL (interquartile range: 22.96-56.46) for the BA group and 4.4 ng/mL (interquartile range: 2.73-6.56) for the non-BA group (P < .001). The area under the receiver operating characteristic curve value was 0.9829 for MMP-7, and the sensitivity, specificity, positive predictive value, and negative predictive value were 95.19%, 93.07%, 97.27%, and 91.43%, respectively, at a cutoff value of 10.37 ng/mL. When MMP-7 was combined with γ glutamyl transferase, the diagnostic accuracy was slightly improved without significance when compared with MMP-7 alone and had an area under the curve of 0.9880 (P = .08). Decision curve analysis also showed potential for MMP-7 to be used for clinical applications. A significant correlation was found with fibrosis stage from liver biopsy (R = 0.47; P < .001). CONCLUSIONS MMP-7 demonstrated good accuracy in diagnosing BA and holds promise for future clinical application. Furthermore, its correlation with liver fibrosis indicated its potential use as a therapeutic target or prognostic biomarker.
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Affiliation(s)
- Jingying Jiang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Junfeng Wang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Zhen Shen
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Xuexin Lu
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, 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 Defects, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
| | - Yanlei Huang
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai Key Laboratory of Birth Defects, 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 Defects, 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 Defects, and Key Laboratory of Neonatal Disease, Ministry of Health, Shanghai, China
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Ramachandran P, Balamurali D, Peter JJ, Kumar MM, Safwan M, Vij M, Rela M, Mahalingam S. RNA-seq reveals outcome-specific gene expression of MMP7 and PCK1 in biliary atresia. Mol Biol Rep 2019; 46:5123-5130. [PMID: 31342296 DOI: 10.1007/s11033-019-04969-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 07/04/2019] [Indexed: 12/25/2022]
Abstract
The disease phenotype in biliary atresia (BA) is caused by a fibro-inflammatory process leading to destruction of cholangiocytes, obstruction of ductular pathways and eventual progression to liver cirrhosis. The first line of management is a Kasai portoenterostomy (KPE) followed by liver transplantation (LT) in some children. Several factors have been postulated to affect the outcome of KPE and/or the subsequent progression of liver disease. However, no biomarkers have been identified in the liver for BA. We aimed to address this deficit. Whole transcriptome mRNA sequencing was performed for 29 samples (25 BA and 4 Controls) to identify the candidate genes predicting the prognosis of KPE. These results were further confirmed with quantitative Realtime PCR (qPCR). Analysis from RNA-sequencing data identified matrix metalloproteinase7 (MMP7) and phosphoenolpyruvate carboxykinase (PCK1) as potential determinants of the outcome of KPE. MMP7 expression was significantly elevated in patients who failed to clear jaundice after KPE as well as in patients with End Stage Liver Disease (ESLD). In contrast, PCK1 level was upregulated in patients who had successful KPE, while there was a significant down regulation in patients who failed KPE. MMP7 and PCK1 expression patterns had an inverse relation to the outcome of KPE and hence could potentially be used as biomarkers to predict KPE outcome and disease progression, enabling clinicians to design new treatment strategies for BA.
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Affiliation(s)
- Priya Ramachandran
- Department of Paediatric Surgery, Kanchi Kamakoti CHILDS Trust Hospital, CHILDS Trust Medical Research Foundation, Chennai, India
- Institute of Liver Disease & Transplantation, Gleneagles Global Health City, Chennai, India
- Dr. Rela Institute and Medical Centre, Chennai, India
| | - Deepak Balamurali
- National Cancer Tissue Biobank, Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - J John Peter
- National Cancer Tissue Biobank, Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - M Milner Kumar
- National Cancer Tissue Biobank, Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - Mohamed Safwan
- Institute of Liver Disease & Transplantation, Gleneagles Global Health City, Chennai, India
- Dr. Rela Institute and Medical Centre, Chennai, India
| | - Mukul Vij
- Dr. Rela Institute and Medical Centre, Chennai, India
- Department of Pathology, Gleneagles Global Health City, Chennai, India
| | - Mohamed Rela
- Institute of Liver Disease & Transplantation, Gleneagles Global Health City, Chennai, India
- Dr. Rela Institute and Medical Centre, Chennai, India
| | - Sundarasamy Mahalingam
- National Cancer Tissue Biobank, Laboratory of Molecular Cell Biology, Department of Biotechnology, Bhupat & Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 600036, India.
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Harpavat S. MMP-7: The Next Best Serum Biomarker for Biliary Atresia? J Pediatr 2019; 208:8-9. [PMID: 30857775 DOI: 10.1016/j.jpeds.2019.01.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 01/15/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Sanjiv Harpavat
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.
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Mazur F, Chandrawati R. Peptide-Mediated Liposome Fusion as a Tool for the Detection of Matrix Metalloproteinases. ACTA ACUST UNITED AC 2019; 3:e1800330. [PMID: 32627412 DOI: 10.1002/adbi.201800330] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Revised: 02/11/2019] [Indexed: 11/08/2022]
Abstract
Biological cells continue to inspire the development of technologies toward rapid, sensitive, and selective detection of analytes. Membrane fusion is a key biological event in living cells that involves a highly selective recognition mechanism controlled by different functional proteins. Herein, liposome-liposome fusion mediated by coiled-coil forming peptides JR2EC and JR2KC to mimic biological membrane fusion is reported. The liposome fusion event is monitored through fluorescence generation and this mechanism forms the basis of a detection assay for matrix metalloproteinases (MMPs), which are key homeostatic proteases. Using this approach, a limit of detection of 0.35 µg mL-1 MMP-7 in biological samples is obtained, and this assay does not require washing, separation, or amplification steps. The developed tool could be extended for the detection of other proteolytic enzymes of the MMP family (diagnostic or prognostic markers) and has the potential for screening of peptide libraries against a target of interest.
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Affiliation(s)
- Federico Mazur
- School of Chemical Engineering and Australian Centre for Nanomedicine (ACN), The University of New South Wales (UNSW Sydney), Sydney, NSW, 2052, Australia
| | - Rona Chandrawati
- School of Chemical Engineering and Australian Centre for Nanomedicine (ACN), The University of New South Wales (UNSW Sydney), Sydney, NSW, 2052, Australia
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Wu JF, Jeng YM, Chen HL, Ni YH, Hsu HY, Chang MH. Quantification of Serum Matrix Metallopeptide 7 Levels May Assist in the Diagnosis and Predict the Outcome for Patients with Biliary Atresia. J Pediatr 2019; 208:30-37.e1. [PMID: 30853207 DOI: 10.1016/j.jpeds.2018.12.006] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 11/09/2018] [Accepted: 12/04/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To assess the diagnostic and prognostic usefulness of the serum matrix metallopeptidase-7 (MMP-7) level for biliary atresia in infants with cholestasis after hepatoportoenterostomy. STUDY DESIGN We enrolled 100 infants with cholestasis (age, 43.56 ± 1.97 days; 62 males) with a direct bilirubin level of >1 mg/dL, of whom 36 (36%) were diagnosed with biliary atresisa. The MMP-7 levels in serum samples collected during the cholestasis workup and 6 months after hepatoportoenterostomy were assessed by enzyme-linked immunosorbent assay. We quantified liver fibrosis by Picro Sirius red staining of collagen in specimens from the 81 infants with cholestasis. RESULTS Infants with biliary atresisa had a significantly higher serum MMP-7 level than that of non-biliary atresisa infants with cholestasis of equivalent age (P < .0001). Receiver operating characteristic analysis showed that a serum MMP-7 level of >1.43 ng/mL was predictive of biliary atresisa in infants with cholestasis (diagnostic accuracy, 88%). There was a positive correlation between the serum MMP-7 level and the severity of liver fibrosis (P = .0002). Survival analysis showed that the frequency of liver transplantation was significantly higher in infants with biliary atresisa with a serum MMP-7 level of >10.30 ng/mL compared with a serum MMP-7 level of ≤10.30 ng/mL after hepatoportoenterostomy (hazard ratio, 4.22; P = .02). CONCLUSIONS The serum MMP-7 level, which reflects the severity of liver fibrosis and can be determined noninvasively, may facilitate the diagnosis of biliary atresisa among infants with cholestasis. Moreover, the serum MMP-7 level after hepatoportoenterostomy is associated with a need for liver transplantation in infants with biliary atresisa.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Ming Jeng
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Huey-Ling Chen
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Yen-Hsuan Ni
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan
| | - Hong-Yuan Hsu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan; Department of Hepatitis Research Center, National Taiwan University Hospital, Taipei, Taiwan.
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