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1
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Hamza RA, Mostafa I, Mohamed YS, Dora GA, Ateya AM, Abdelaal M, Fantoukh OI, Alqahtani A, Attia RA. Bioguided isolation of potential antitumor agents from the aerial parts of cultivated cardoon ( Cynara cardunculus var. altilis). Saudi Pharm J 2023; 31:125-134. [PMID: 36685304 PMCID: PMC9845127 DOI: 10.1016/j.jsps.2022.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 11/15/2022] [Indexed: 11/22/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of mortality worldwide; therefore, searching for an effective treatment for this illness is of great importance. In the present work, in vitro cytotoxic activity of the ethanol extract of the aerial parts of Cynara cardunculus L. against human liver carcinoma cells (Hep G2) was tested. Additionally, the antitumor activity of the extract was confirmed using chemically induced rat liver carcinogenesis with diethylnitrosamine (DEN). Moreover, bioguided fractionation and column chromatographic separation of the active compounds were carried out. The extract of C. cardunculus showed a promising cytotoxic activity according to the protocols of the National Cancer Institute. Bioguided chromatographic separation of the ethanol extract of C. cardunculus led to the isolation of seven secondary metabolites including two sesquiterpene lactones as the principal active components of the methylene chloride soluble fraction, grosheimin (IC50 = 7.49 µg/mL) and cynaropicrin (IC50 = 13.9 µg/mL). The compounds were characterized by different spectroscopic techniques such as EI-MS, IR and NMR. Additionally, in silico analysis of the two active compounds revealed their ability to bind with caspase-3 via hydrogen bonds interactions to initiate apoptosis of cancer cells. The results shed the light on the significance of C. cardunculus as a potential source of antitumor agents.
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Affiliation(s)
- Rasha A. Hamza
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt
| | - Islam Mostafa
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt
| | - Yasmin S. Mohamed
- Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Gamal A. Dora
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt
| | - Abdel-Monem Ateya
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt
| | - Mahmoud Abdelaal
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt
| | - Omer I. Fantoukh
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Abdulaziz Alqahtani
- Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Rasha A. Attia
- Department of Pharmacognosy, Faculty of Pharmacy, Zagazig University, 44519 Zagazig, Egypt
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2
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Delgado-Coello B, Navarro-Alvarez N, Mas-Oliva J. The Influence of Interdisciplinary Work towards Advancing Knowledge on Human Liver Physiology. Cells 2022; 11:3696. [PMID: 36429123 PMCID: PMC9688355 DOI: 10.3390/cells11223696] [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] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 11/11/2022] [Accepted: 11/13/2022] [Indexed: 11/23/2022] Open
Abstract
The knowledge accumulated throughout the years about liver regeneration has allowed a better understanding of normal liver physiology, by reconstructing the sequence of steps that this organ follows when it must rebuild itself after being injured. The scientific community has used several interdisciplinary approaches searching to improve liver regeneration and, therefore, human health. Here, we provide a brief history of the milestones that have advanced liver surgery, and review some of the new insights offered by the interdisciplinary work using animals, in vitro models, tissue engineering, or mathematical models to help advance the knowledge on liver regeneration. We also present several of the main approaches currently available aiming at providing liver support and overcoming organ shortage and we conclude with some of the challenges found in clinical practice and the ethical issues that have concomitantly emerged with the use of those approaches.
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Affiliation(s)
- Blanca Delgado-Coello
- Department of Structural Biology and Biochemistry, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Nalu Navarro-Alvarez
- Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City 14080, Mexico
- Departament of Molecular Biology, Universidad Panamericana School of Medicine, Mexico City 03920, Mexico
- Department of Surgery, University of Colorado Anschutz Medical Campus, Denver, CO 80045, USA
| | - Jaime Mas-Oliva
- Department of Structural Biology and Biochemistry, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
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3
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Park ES, Dezhbord M, Lee AR, Park BB, Kim KH. Dysregulation of Liver Regeneration by Hepatitis B Virus Infection: Impact on Development of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:cancers14153566. [PMID: 35892823 PMCID: PMC9329784 DOI: 10.3390/cancers14153566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/04/2023] Open
Abstract
The liver is unique in its ability to regenerate in response to damage. The complex process of liver regeneration consists of multiple interactive pathways. About 2 billion people worldwide have been infected with hepatitis B virus (HBV), and HBV causes 686,000 deaths each year due to its complications. Long-term infection with HBV, which causes chronic inflammation, leads to serious liver-related diseases, including cirrhosis and hepatocellular carcinoma. HBV infection has been reported to interfere with the critical mechanisms required for liver regeneration. In this review, the studies on liver tissue characteristics and liver regeneration mechanisms are summarized. Moreover, the inhibitory mechanisms of HBV infection in liver regeneration are investigated. Finally, the association between interrupted liver regeneration and hepatocarcinogenesis, which are both triggered by HBV infection, is outlined. Understanding the fundamental and complex liver regeneration process is expected to provide significant therapeutic advantages for HBV-associated hepatocellular carcinoma.
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Affiliation(s)
- Eun-Sook Park
- Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Seoul 05029, Korea; (E.-S.P.); (B.B.P.)
| | - Mehrangiz Dezhbord
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea; (M.D.); (A.R.L.)
| | - Ah Ram Lee
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea; (M.D.); (A.R.L.)
| | - Bo Bae Park
- Institute of Biomedical Science and Technology, School of Medicine, Konkuk University, Seoul 05029, Korea; (E.-S.P.); (B.B.P.)
| | - Kyun-Hwan Kim
- Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, Korea; (M.D.); (A.R.L.)
- Correspondence: ; Tel.: +82-31-299-6126
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4
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Zieglowski L, Kümmecke AM, Ernst L, Palme R, Weiskirchen R, Talbot SR, Tolba RH. Assessing the severity of laparotomy and partial hepatectomy in male rats-A multimodal approach. PLoS One 2021; 16:e0255175. [PMID: 34339407 PMCID: PMC8328343 DOI: 10.1371/journal.pone.0255175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 07/10/2021] [Indexed: 11/18/2022] Open
Abstract
This study assessed the postoperative severity after three different visceral surgical interventions in rats by using objective parameters pertaining to various disciplines. The objective was to evaluate whether the degree of severity increases with the invasiveness of the intervention and whether this is in accordance with the EU Directive 2010/63. 136 adult male WistarHan rats were assigned to three groups: Sham-laparotomy (Sham) [7 days post-surgical survival time]; 50% partial hepatectomy (PH); 70% PH [PH groups with 1, 3, or 7 days post-surgical survival times]. Post-surgical severity assessment was performed via several multimodal assessment tools: I) model-specific score sheet focusing on body weight, general condition, spontaneous behavior, and the animals' willingness to move as well as on wound healing; II) Open Field tests evaluating the total distance and velocity an animal moved within 10 minutes and its rearing behavior during the test; III) telemetric data analyzing heart rate and blood pressure; and IV) analysis of blood (AST, ALT, and hemogram) and fecal samples (fecal corticosterone metabolites). Significant differences among the experimental groups and models were observed. We demonstrated that the Open Field test can detect significant changes in severity levels. Sham-laparotomy and removal of 50% of the liver mass were associated with comparable severity (mild-moderate); the severity parameters returned to baseline levels within seven days. Removal of 70% of the liver tissue seemed to be associated with a moderate severity grade and entailed a longer recovery period (>7 days) for complete regeneration. We recommend the use of Open Field tests as part of multimodal objective severity assessment.
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Affiliation(s)
- Leonie Zieglowski
- Institute for Laboratory Animal Science & Experimental Surgery, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Anna Maria Kümmecke
- Institute for Laboratory Animal Science & Experimental Surgery, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Lisa Ernst
- Institute for Laboratory Animal Science & Experimental Surgery, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
| | - Rupert Palme
- Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Faculty of Medicine, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH Aachen University, Aachen, Germany
| | - Steven R. Talbot
- Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany
| | - René H. Tolba
- Institute for Laboratory Animal Science & Experimental Surgery, Faculty of Medicine, RWTH Aachen University, Aachen, Germany
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Hodge A, Andrewartha N, Lourensz D, Strauss R, Correia J, Goonetilleke M, Yeoh G, Lim R, Sievert W. Human Amnion Epithelial Cells Produce Soluble Factors that Enhance Liver Repair by Reducing Fibrosis While Maintaining Regeneration in a Model of Chronic Liver Injury. Cell Transplant 2021; 29:963689720950221. [PMID: 32813573 PMCID: PMC7563845 DOI: 10.1177/0963689720950221] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Human amnion epithelial cells (hAECs) exert potent antifibrotic and anti-inflammatory effects when transplanted into preclinical models of tissue fibrosis. These effects are mediated in part via the secretion of soluble factors by hAECs which modulate signaling pathways and affect cell types involved in inflammation and fibrosis. Based on these reports, we hypothesized that these soluble factors may also support liver regeneration during chronic liver injury. To test this, we characterized the effect of both hAECs and hAEC-conditioned medium (CM) on liver repair in a mouse model of carbon tetrachloride (CCl4)-induced fibrosis. Liver repair was assessed by liver fibrosis, hepatocyte proliferation, and the liver progenitor cell (LPC) response. We found that the administration of hAECs or hAEC-CM reduced liver injury and fibrosis, sustained hepatocyte proliferation, and reduced LPC numbers during chronic liver injury. Additionally, we undertook in vitro studies to document both the cell-cell and paracrine-mediated effects of hAECs on LPCs by investigating the effects of co-culturing the LPCs and hAECs and hAEC-CM on LPCs. We found little change in LPCs co-cultured with hAECs. In contrast, hAEC-CM enhances LPC proliferation and differentiation. These findings suggest that paracrine factors secreted by hAECs enhance liver repair by reducing fibrosis while promoting regeneration during chronic liver injury.
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Affiliation(s)
- Alexander Hodge
- Gastroenterology and Hepatology Unit, 2538Monash Health, Melbourne, Victoria, Australia.,Centre for Inflammatory Disease, School of Clinical Sciences, 2538Monash University, Melbourne, Victoria, Australia.,Both the authors contributed equally to this article
| | - Neil Andrewartha
- Centre for Medical Research, 102804Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.,School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia.,Both the authors contributed equally to this article
| | - Dinushka Lourensz
- Gastroenterology and Hepatology Unit, 2538Monash Health, Melbourne, Victoria, Australia.,Centre for Inflammatory Disease, School of Clinical Sciences, 2538Monash University, Melbourne, Victoria, Australia
| | - Robyn Strauss
- Centre for Medical Research, 102804Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.,School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - Jeanne Correia
- Gastroenterology and Hepatology Unit, 2538Monash Health, Melbourne, Victoria, Australia.,Centre for Inflammatory Disease, School of Clinical Sciences, 2538Monash University, Melbourne, Victoria, Australia
| | - Mihiri Goonetilleke
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, 2541Monash University, Melbourne, Victoria, Australia.,568369The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
| | - George Yeoh
- Centre for Medical Research, 102804Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.,School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia.,Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - Rebecca Lim
- Department of Obstetrics and Gynaecology, School of Clinical Sciences, 2541Monash University, Melbourne, Victoria, Australia.,568369The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
| | - William Sievert
- Gastroenterology and Hepatology Unit, 2538Monash Health, Melbourne, Victoria, Australia.,Centre for Inflammatory Disease, School of Clinical Sciences, 2538Monash University, Melbourne, Victoria, Australia
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6
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Hu ZG, Zhou Y, Lin CJ, Yuan GD, He SQ. Emerging recognition of the complement system in hepatic ischemia/reperfusion injury, liver regeneration and recovery (Review). Exp Ther Med 2021; 21:223. [PMID: 33603832 PMCID: PMC7851628 DOI: 10.3892/etm.2021.9654] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Accepted: 11/26/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatic ischemia/reperfusion injury (IRI) is a result of the ischemic cascade and may occur in the settings of liver trauma, resection and transplantation. Components of the complement system have been indicated to be mediators of hepatic IRI and regulators of liver regeneration. As such, their potential to mediate both beneficial and harmful effects render them key targets for therapy. In the present study, the mechanisms of complement mediating hepatic IRI were discussed with a focus on the different functions of complement in hepatic injury and liver recovery, and an explanation for this apparent paradox is provided, i.e. that the complement products C3a and C5a have an important role in liver damage; however, C3a and C5a are also necessary for liver regeneration. Furthermore, situated at the end of the complement activation cascade, the membrane attack complex is crucial in hepatic IRI and inhibiting the complex with a site-targeted murine complement inhibitor, complement receptor 2-CD59, may improve liver regeneration after partial hepatectomy, even when hepatectomy is combined with ischemia and reperfusion.
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Affiliation(s)
- Zhi-Gao Hu
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Yi Zhou
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Cheng-Jie Lin
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
- Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian 350005, P.R. China
| | - Guan-Dou Yuan
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Song-Qing He
- Division of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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7
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Lee J, Garcia V, Nambiar SM, Jiang H, Dai G. Pregnancy facilitates maternal liver regeneration after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 2020; 318:G772-G780. [PMID: 32003603 PMCID: PMC7191459 DOI: 10.1152/ajpgi.00125.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver resection induces robust liver regrowth or regeneration to compensate for the lost tissue mass. In a clinical setting, pregnant women may need liver resection without terminating pregnancy in some cases. However, how pregnancy affects maternal liver regeneration remains elusive. We performed 70% partial hepatectomy (PH) in nonpregnant mice and gestation day 14 mice, and histologically and molecularly compared their liver regrowth during the next 4 days. We found that compared with the nonpregnant state, pregnancy altered the molecular programs driving hepatocyte replication, indicated by enhanced activities of epidermal growth factor receptor and STAT5A, reduced activities of cMet and p70S6K, decreased production of IL-6, TNFα, and hepatocyte growth factor, suppressed cyclin D1 expression, increased cyclin A1 expression, and early activated cyclin A2 expression. As a result, pregnancy allowed the remnant hepatocytes to enter the cell cycle at least 12 h earlier, increased hepatic fat accumulation, and enhanced hepatocyte mitosis. Consequently, pregnancy ameliorated maternal liver regeneration following PH. In addition, a report showed that maternal liver regrowth after PH is driven mainly by hepatocyte hypertrophy rather than hyperplasia during the second half of gestation in young adult mice. In contrast, we demonstrate that maternal liver relies mainly on hepatocyte hyperplasia instead of hypertrophy to restore the lost mass after PH. Overall, we demonstrate that pregnancy facilitates maternal liver regeneration likely via triggering an early onset of hepatocyte replication, accumulating excessive liver fat, and promoting hepatocyte mitosis. The results from our current studies enable us to gain more insights into how maternal liver regeneration progresses during gestation.NEW & NOTEWORTHY We demonstrate that pregnancy may generate positive effects on maternal liver regeneration following partial hepatectomy, which are manifested by early entry of the cell cycle of remnant hepatocytes, increased hepatic fat accumulation, enhanced hepatocyte mitosis, and overall accelerated liver regrowth.
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Affiliation(s)
- Joonyong Lee
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Veronica Garcia
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Shashank Manohar Nambiar
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
| | - Huaizhou Jiang
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana,2School of Traditional Chinese Medicine, Anhui University of Chinese Medicine, Anhui, China
| | - Guoli Dai
- 1Department of Biology, Center for Developmental and Regenerative Biology, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana
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Regulation of liver regeneration by prostaglandin E 2 and thromboxane A 2 following partial hepatectomy in rats. Naunyn Schmiedebergs Arch Pharmacol 2020; 393:1437-1446. [PMID: 32162076 DOI: 10.1007/s00210-020-01848-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/02/2020] [Indexed: 12/17/2022]
Abstract
The implication of prostaglandin E2 (PGE2) and thromboxane A2 (TXA2) in the striking process of liver regeneration has been previously reported. However, their exact roles and downstream signals have not been utterly revealed. Therefore, the present study was conducted to explore whether inhibition of cyclooxygenase-2 (COX-2)-derived PGE2 by celecoxib and blocking of TXA2 action by seratrodast could alter the progression of liver regeneration after 70% partial hepatectomy (PHx) in rats. Celecoxib (20 mg/kg/day) and seratrodast (2 mg/kg/day) were given orally 1 h before PHx and then daily till the end of experiment (1, 3, or 7 days after the operation). Interestingly, celecoxib-treated rats showed a further increase in interleukin-6, p65 nuclear factor κB, and phosphorylated signal transducer and activator of transcription 3 as compared with PHx control rats. Furthermore, the liver contents of growth factors as well as β-catenin and cyclin D1protein expressions were also enhanced by celecoxib. Accordingly, celecoxib significantly improved hepatic proliferation as indicated by the increase in Ki67 expression and liver index. Contrariwise, seratrodast hindered the normal regeneration process and completely abolished the proliferative effect of celecoxib. In conclusion, TXA2 has a major role in liver regeneration that could greatly mediate the triggering effect of celecoxib on hepatocytes proliferation following PHx.
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Wang G, Guo X, Cheng L, Chu P, Chen M, Chen Y, Chang C. An integrated analysis of the circRNA-miRNA-mRNA network reveals novel insights into potential mechanisms of cell proliferation during liver regeneration. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2020; 47:3873-3884. [PMID: 31566012 DOI: 10.1080/21691401.2019.1669623] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cell proliferation constitutes the fundamental process and driving force behind regrowth during liver regeneration (LR). However, it remains unclear how competing endogenous RNA (ceRNA) networks affect hepatocyte proliferation and liver regeneration. Therefore, this study was designed to explore an LR-specific ceRNA network, which regulates cell proliferation. Based on the microarray data of mRNAs, and high-throughput sequencing data of miRNAs and circRNAs from regenerating livers, this study initially applied known 1484 LR associated mRNAs to perform GO analysis, and then selected 169 LR associated mRNAs involved in cell proliferation and the cell cycle. Subsequently, 188 interactive miRNA-mRNA pairs and 5206 circRNA-miRNA pairs, respectively, were predicted using bioinformatics methods. Next, in view of the differential expressions of these ceRNAs during LR, 26 miRNA-mRNA pairs and 71 circRNA-miRNA pairs were applied to generate a circRNA-miRNA-mRNA regulatory network, and only 14 triple interactive groups were obtained based on the predicted inverse interactions among ceRNAs. Finally, circ_19698/miR-423-5p axis was demonstrated to promote cell proliferation by modulating the expression of MYC, CCNA2, and CCND1 in rat BRL-3A cells. This study suggests a potential regulatory mechanism of cell proliferation in regenerating livers, as well as a novel pathway for modulating ceRNA networks to promote liver regeneration.
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Affiliation(s)
- Gaiping Wang
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Xueqiang Guo
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Liya Cheng
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Peipei Chu
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Meng Chen
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Yanhui Chen
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
| | - Cuifang Chang
- College of Life Science, Henan Normal University , Xinxiang , Henan , China.,State Key Laboratory Cultivation Base for Cell Differentiation Regulation , Xinxiang , Henan , China
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10
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Role of interleukin 6 in liver cell regeneration after hemi-hepatectomy, correlation with liver enzymes and flow cytometric study. Clin Exp Hepatol 2020; 6:42-48. [PMID: 32166123 PMCID: PMC7062121 DOI: 10.5114/ceh.2020.93055] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 11/25/2019] [Indexed: 02/07/2023] Open
Abstract
Aim of the study Liver regeneration after hemi-hepatectomy may be affected by several growth factors and cytokines. The aim is to evaluate the importance of interleukin 6 (IL-6) in the induction of liver cell regeneration and find correlations with other parameters such as liver enzymes, and DNA analysis by flow cytometric studies. Material and methods 80 adult male Sprague-Dawley rats were obtained and divided into two equal groups (n = 40 rats) to undergo 70% partial hepatectomy: group 1 - untreated (control) group; 40 rats not treated; and group 2 - treated group, 40 rats treated with IL-6 35 μg/100 gm body weight according to a lethality study for a period of 4 days, then hepatic resection was carried out according to the steps of Higgins and Anderson. Assessment of liver enzymes and bilirubin level was done. Flow cytometric study was done using a flow cytometer (FACSCalibur; Becton Dickinson) and DNA content was estimated with CellQuest software (Becton Dickinson). Results The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) were significantly higher in the untreated group of rats with liver resection. A higher value of bilirubin was observed in the treated group. Rat weight at sacrification was significantly lower in the group of rats treated with IL-6 than those without treatment, p < 0.001. Liver weight at sacrification was significantly higher in the group of rats treated with IL-6 (p < 0.001). The percentage of apoptotic cells with hypodiploid DNA content was determined from DNA histograms. Untreated rat resected liver showed a peak pattern that represented liver damage with high damage of 73.4%. Conclusions Interleukin 6 is of value in induction of liver cell regeneration after seventy percent hemi-hepatectomy as evident by increased liver cell mass, liver enzymes and flow cytometric analysis.
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11
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Adipose-Derived Stem Cell Transplantation Attenuates Inflammation and Promotes Liver Regeneration after Ischemia-Reperfusion and Hemihepatectomy in Swine. Stem Cells Int 2019; 2019:2489584. [PMID: 31827526 PMCID: PMC6885808 DOI: 10.1155/2019/2489584] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 09/17/2019] [Accepted: 10/23/2019] [Indexed: 02/07/2023] Open
Abstract
Aim To study the anti-inflammatory and liver regenerative effects of adipose-derived mesenchymal stem cells (ADSCs) on a porcine model of ischemia-reperfusion (IR) and hemihepatectomy. Methods Eighteen healthy Bama miniature pigs were randomly divided into the sham-operated (sham), untreated IR injury (IRI), and ADSC-transplanted (ADSC) groups. Hepatic IR was established by laparoscopic hemihepatectomy. ADSCs were transplanted directly into the liver parenchyma after the surgery. Hepatic inflammation and liver regeneration were evaluated by histopathological examination and assessment of relevant cytokines and other factors. Results ADSC transplantation successfully ameliorated the IRI-induced histopathological damage and the high levels of pro-inflammatory cytokines like IL-1β, IL-6, and TNF-α. In addition, the ADSCs enhanced the expression of the anti-inflammatory IL-10, regenerative factors including HGF, Cyclin D1, and proliferating cell nuclear antigen (PCNA), and angiogenic factors like VEGF, ANG-1, and ANG-2. Conclusions ADSCs attenuated the hepatic IRI-induced inflammatory response and promoted liver regeneration.
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12
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Lee GS, Yang HG, Kim JH, Ahn YM, Han MD, Kim WJ. Pine ( Pinus densiflora ) needle extract could promote the expression of PCNA and Ki-67 after partial hepatectomy in rat. Acta Cir Bras 2019; 34:e201900606. [PMID: 31432997 PMCID: PMC6705336 DOI: 10.1590/s0102-865020190060000006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Accepted: 05/12/2019] [Indexed: 12/16/2022] Open
Abstract
Purpose To investigate the effects of pine needle extract (PNE) on the expression of proliferating cell nuclear antigen (PCNA) and Ki-67 during liver regeneration induced by 70% partial hepatectomy (PH) in rat. Methods Forty-eight male rats (SD, 7 weeks) had surgery (70% PH). They were randomly divided into two groups. PH + PNE group was only provided PNE diluted in water (10%) for drinking and PH group was provided water from 5 days before surgery to the time of sacrifice. PNE was made by pressing and filtering. Animals were sacrificed at 12h, 24h, 36h, 60h, 84h, 168h after PH, respectively. The expressions of PCNA and Ki-67 were determined as proliferation indices. Results Immunohistochemistry turned out to increase the expression of PCNA and Ki-67. PCNA expression of PH+PNE group increased up to twice of that of PH group. Western blot also seemed to increase the PCNA expression. These results indicated the promotion of cell proliferation in liver tissue and hepatic regeneration. Conclusions Pine needle extract stimulates the expression of some mitotic proteins during liver regeneration induced by 70% PH in rats. It suggests that administration of pine needle extract could accelerate the liver regeneration after partial hepatectomy.
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Affiliation(s)
- Gyeong Seok Lee
- Department of Life Science and Biotechnology , Soonchunhyang University , Asan , Korea . Conception and design; acquisition, analysis and interpretation of data; technical procedures; histopathological examinations; statistics analysis; manuscript writing, final approval
| | - Hyeon Gung Yang
- Department of Life Science and Biotechnology , Soonchunhyang University , Asan , Korea . Conception and design; acquisition, analysis and interpretation of data; technical procedures; histopathological examinations; statistics analysis; manuscript preparation and writing, final approval
| | - Ji Hun Kim
- Department of Life Science and Biotechnology , Soonchunhyang University , Asan , Korea . Acquisition of data, manuscript preparation, final approval
| | - Young Mo Ahn
- PhD, Department of Life Science and Biotechnology , Soonchunhyang University , Asan , Korea . Acquisition of data, histopathological examinations, critical revision, final approval
| | - Man Deuk Han
- PhD, Professor, Department of Life Science and Biotechnology , Soonchunhyang University , Asan , Korea . Analysis and interpretation of data, histopathological examinations, critical revision, final approval
| | - Wan Jong Kim
- PhD, Professor, Department of Life Science and Biotechnology , Soonchunhyang University , Asan , Korea . Conception and design of the study, histopathological examinations, manuscript writing, critical revision, final approval
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13
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Ye S, Boeter JWB, Penning LC, Spee B, Schneeberger K. Hydrogels for Liver Tissue Engineering. Bioengineering (Basel) 2019; 6:E59. [PMID: 31284412 PMCID: PMC6784004 DOI: 10.3390/bioengineering6030059] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2019] [Revised: 06/28/2019] [Accepted: 07/03/2019] [Indexed: 12/14/2022] Open
Abstract
Bioengineered livers are promising in vitro models for drug testing, toxicological studies, and as disease models, and might in the future be an alternative for donor organs to treat end-stage liver diseases. Liver tissue engineering (LTE) aims to construct liver models that are physiologically relevant. To make bioengineered livers, the two most important ingredients are hepatic cells and supportive materials such as hydrogels. In the past decades, dozens of hydrogels have been developed to act as supportive materials, and some have been used for in vitro models and formed functional liver constructs. However, currently none of the used hydrogels are suitable for in vivo transplantation. Here, the histology of the human liver and its relationship with LTE is introduced. After that, significant characteristics of hydrogels are described focusing on LTE. Then, both natural and synthetic materials utilized in hydrogels for LTE are reviewed individually. Finally, a conclusion is drawn on a comparison of the different hydrogels and their characteristics and ideal hydrogels are proposed to promote LTE.
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Affiliation(s)
- Shicheng Ye
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Jochem W B Boeter
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Louis C Penning
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands
| | - Kerstin Schneeberger
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, 3584 CT Utrecht, The Netherlands.
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Verma BK, Subramaniam P, Vadigepalli R. Model-based virtual patient analysis of human liver regeneration predicts critical perioperative factors controlling the dynamic mode of response to resection. BMC SYSTEMS BIOLOGY 2019; 13:9. [PMID: 30651095 PMCID: PMC6335689 DOI: 10.1186/s12918-019-0678-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 01/02/2019] [Indexed: 11/10/2022]
Abstract
BACKGROUND Liver has the unique ability to regenerate following injury, with a wide range of variability of the regenerative response across individuals. Existing computational models of the liver regeneration are largely tuned based on rodent data and hence it is not clear how well these models capture the dynamics of human liver regeneration. Recent availability of human liver volumetry time series data has enabled new opportunities to tune the computational models for human-relevant time scales, and to predict factors that can significantly alter the dynamics of liver regeneration following a resection. METHODS We utilized a mathematical model that integrates signaling mechanisms and cellular functional state transitions. We tuned the model parameters to match the time scale of human liver regeneration using an elastic net based regularization approach for identifying optimal parameter values. We initially examined the effect of each parameter individually on the response mode (normal, suppressed, failure) and extent of recovery to identify critical parameters. We employed phase plane analysis to compute the threshold of resection. We mapped the distribution of the response modes and threshold of resection in a virtual patient cohort generated in silico via simultaneous variations in two most critical parameters. RESULTS Analysis of the responses to resection with individual parameter variations showed that the response mode and extent of recovery following resection were most sensitive to variations in two perioperative factors, metabolic load and cell death post partial hepatectomy. Phase plane analysis identified two steady states corresponding to recovery and failure, with a threshold of resection separating the two basins of attraction. The size of the basin of attraction for the recovery mode varied as a function of metabolic load and cell death sensitivity, leading to a change in the multiplicity of the system in response to changes in these two parameters. CONCLUSIONS Our results suggest that the response mode and threshold of failure are critically dependent on the metabolic load and cell death sensitivity parameters that are likely to be patient-specific. Interventions that modulate these critical perioperative factors may be helpful to drive the liver regenerative response process towards a complete recovery mode.
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Affiliation(s)
- Babita K Verma
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Chemical Engineering, Indian Institute of Technology-Madras, Chennai, India
| | | | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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15
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Hou CT, Chen YL, Lin CC, Chou CT, Lin KH, Lin PY, Hsu YL, Chen CB, Lin HC, Ko CJ, Wang SH, Weng LC, Hsieh CE. Portal venous velocity affects liver regeneration after right lobe living donor hepatectomy. PLoS One 2018; 13:e0204163. [PMID: 30222781 PMCID: PMC6141071 DOI: 10.1371/journal.pone.0204163] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 09/03/2018] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVES We investigated whether chronological changes in portal flow and clinical factors play a role in the liver regeneration (LR) process after right donor-hepatectomy. MATERIALS AND METHODS Participants in this prospective study comprised 58 donors who underwent right donor-hepatectomy during the period February 2014 to February 2015 at a single medical institution. LR was estimated using two equations: remnant left liver (RLL) growth (%) and liver volumetric recovery (LVR) (%). Donors were classified into an excellent regeneration (ER) group or a moderate regeneration (MR) group based on how their LR on postoperative day 7 compared to the median value. RESULTS Multivariate analysis revealed that low residual liver volume (OR = .569, 95% CI: .367- .882) and high portal venous velocity in the immediate postoperative period (OR = 1.220, 95% CI: 1.001-1.488) were significant predictors of LR using the RLL growth equation; high portal venous velocity in the immediate postoperative period (OR = 1.325, 95% CI: 1.081-1.622) was a significant predictor of LR using the LVR equation. Based on the two equations, long-term LR was significantly greater in the ER group than in the MR group (p < .001). CONCLUSION Portal venous velocity in the immediate postoperative period was an important factor in LR. The critical time for short-term LR is postoperative day 7; it is associated with long-term LR in donor-hepatectomy.
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Affiliation(s)
- Chen-Tai Hou
- Surgical Critical Unit, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Yao-Li Chen
- Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- * E-mail: (CEH); (YLC)
| | - Chia-Cheng Lin
- Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Chen-Te Chou
- Department of Radiology, Changhua Christian Hospital, Changhua, Taiwan
- Department of Biomedical Imaging and Radiological Science, National Yang-Ming Medical University, Taiper, Taiwan
| | - Kuo-Hua Lin
- Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Ping-Yi Lin
- Transplant Medicine & Surgery Research Centre, Changhua Christian Hospital, Changhua, Taiwan
| | - Ya-Lan Hsu
- Department of Nursing, Changhua Christian Hospital, Changhua, Taiwan
| | - Chia-Bang Chen
- Department of Radiology, Changhua Christian Hospital, Changhua, Taiwan
| | - Hui-Chuan Lin
- Department of Nursing, Hung Kuang University, Taichung, Taiwan
| | - Chih-Jan Ko
- Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan
| | - Su-Han Wang
- Department of Nursing, Changhua Christian Hospital, Changhua, Taiwan
| | - Li-Chueh Weng
- Department of Nursing, Graduate Institute of Clinical Medical Science, Chang Gung University, Taoyuan, Taiwan
| | - Chia-En Hsieh
- Department of Nursing, Changhua Christian Hospital, Changhua, Taiwan
- Graduate Institute of Clinical Medical Science, Chang Gung University, Taoyuan, Taiwan
- * E-mail: (CEH); (YLC)
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Aydemir TB, Cousins RJ. The Multiple Faces of the Metal Transporter ZIP14 (SLC39A14). J Nutr 2018; 148:174-184. [PMID: 29490098 PMCID: PMC6251594 DOI: 10.1093/jn/nxx041] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 11/07/2017] [Indexed: 12/14/2022] Open
Abstract
The SLC39A family of metal transporters was identified through homologies with the Zrt- and Irt-like (ZIP) proteins from yeast and plants. Of all the ZIP transporters, ZIP14 is arguably the most robustly characterized in terms of function at the integrative level. Mice with a global knockout of Zip14 are viable, thus providing the opportunity to conduct physiologic experiments. In mice, Zip14 expression is highly tissue specific, with the greatest abundance in the jejunum > liver > heart > kidney > white adipose tissue > skeletal muscle > spleen > pancreas. A unique feature of Zip14 is its upregulation by proinflammatory conditions, particularly increased interleukin 6 (IL-6) and nitric oxide. The transcription factors AP-1, ATF4, and ATF6α are involved in Zip14 regulation. ZIP14 does not appear to be zinc-regulated. The Zip14 knockout phenotype shows multiple sites of ZIP14 function, including the liver, adipose tissue, brain, pancreas, and bone. A prominent feature of the Zip14 ablation is a reduction in intestinal barrier function and onset of metabolic endotoxemia. Many aspects of the phenotype are accentuated with age and accompany increased circulating IL-6. Studies with 65Zn, 59Fe [nontransferrin-bound iron (NTBI)] and 54Mn show that ZIP14 transports these metals. At a steady state, the plasma concentrations of zinc, NTBI, and manganese are such that zinc ions are the major substrate available for ZIP14 at the cell surface. Upregulation of ZIP14 accounts for the hypozincemia and hepatic zinc accumulation associated with acute inflammation and sepsis and is required for liver regeneration and resistance to endoplasmic reticulum (ER) stress. Zip14 ablation in mice produces a defect in manganese excretion that leads to excess manganese accumulation in the brain that produces characteristics of Parkinsonism.
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Affiliation(s)
- Tolunay B Aydemir
- Food Science and Human Nutrition Department and Center for Nutritional
Sciences, College of Agricultural and Life Sciences, University of Florida, Gainesville,
FL,Address correspondence to TBA (e-mail: )
| | - Robert J Cousins
- Food Science and Human Nutrition Department and Center for Nutritional
Sciences, College of Agricultural and Life Sciences, University of Florida, Gainesville,
FL
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17
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Li X, Sun J, Fan X, Guan L, Li D, Zhou Y, Zeng X, Chen Y, Zhang H, Xu L, Jiang F, Huang M, Bi H. Schisandrol B promotes liver regeneration after partial hepatectomy in mice. Eur J Pharmacol 2018; 818:96-102. [DOI: 10.1016/j.ejphar.2017.10.044] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2017] [Revised: 10/20/2017] [Accepted: 10/20/2017] [Indexed: 01/20/2023]
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Gao H, Cao Y, Wan S, Liu J, Chen G, Li Z, Wang H, Li L. Upregulation of NM23-E2 accelerates the liver regeneration after 40% decreased-size liver transplantation in rats. J Surg Res 2017; 219:325-333. [PMID: 29078900 DOI: 10.1016/j.jss.2017.06.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 04/17/2017] [Accepted: 06/15/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Potential of liver regeneration after living-donor liver transplantation is closely associated with the recipient's prognosis, whereas exogenous gene might regulate the liver regeneration progress. NM23 is a multifunctional gene, which inhibits tumor metastasis and regulates cell proliferation, differentiation, development, and apoptosis; however, there is little research about NM23 in promoting liver cell proliferation. METHODS To investigate the effect of NM23-E2 on the liver cell proliferation, the NM23-E2 overexpression vector or negative control vector was transfected into BRL-3A cells and donor liver, respectively. NM23-E2, Cyclin D1, and PCNA expression levels in BRL-3A cells and liver tissues were detected by quantitative real-time polymerase chain reaction and Western blot analysis. Cell Counting Kit-8 was used to detect cell proliferation and flow cytometry for investigating cell cycle. The liver regeneration rate was determined by calculating (regenerated-liver weight of recipient - liver weight of donor/liver weight of donor) × 100%. RESULTS NM23-E2 overexpression increased the NM23-E2, Cyclin D1, and PCNA levels significantly in BRL-3A cells and liver tissues (P < 0.05). The number of S phase cells was more than that of negative control group, and cell proliferation rate was higher than that of the control group in BRL-3A cells markedly (P < 0.05). Moreover, the liver regeneration rate in the NM23-E2 overexpression group was also higher than that in negative control group on postoperative day 1, day 3, day 5, and day 7. CONCLUSIONS Overexpression of NM23-E2 can increase Cyclin D1 and PCNA expression, shorten cell cycle, and thereby promoting the proliferation of liver cells and accelerating the regeneration of liver after 40% decreased-size rat liver transplantation.
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Affiliation(s)
- Hongqiang Gao
- Department of Hepatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming City, Yunnan Province, PR China
| | - Yongmei Cao
- Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, PR China
| | - Shuo Wan
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical College, Zunyi City, Guzhou Province, PR China
| | - Jing Liu
- Department of Hepatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming City, Yunnan Province, PR China
| | - Gang Chen
- Department of Hepatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming City, Yunnan Province, PR China
| | - Zhiqiang Li
- Department of Hepatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming City, Yunnan Province, PR China
| | - Hailei Wang
- Department of Hepatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming City, Yunnan Province, PR China
| | - Li Li
- Department of Hepatobiliary Surgery, The Affiliated Calmette Hospital of Kunming Medical University, Kunming City, Yunnan Province, PR China.
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Xu Y, Navarro-Alvarez N, Yang C, Markmann JF, Dong J, Yeh H. A reliable scoring system after major liver resection in mice. J Surg Res 2016; 204:75-82. [PMID: 27451871 DOI: 10.1016/j.jss.2016.03.066] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 02/21/2016] [Accepted: 03/31/2016] [Indexed: 12/17/2022]
Abstract
BACKGROUND Posthepatectomy liver failure and its transplant counterpart, small-for-size syndrome, remain significant limitations for liver resections and segmental liver transplantation. Partial hepatectomy in mice is one of the most commonly used models to study liver regeneration, but blood and tissue sampling necessary to collect data can affect outcomes or even require euthanasia. We therefore developed a quantitative observational system to predict death from hepatectomy during the first 24 postoperative hours. MATERIALS AND METHODS A total of 100 female, 10 to 12-week-old C57BL/6 mice underwent two-thirds hepatectomy and were monitored for up to 7 d. Our scoring system was based on five categories, each assigned 0-2 points: activity level, body posture, fur condition, respiratory status, and eye appearance. Seventy-five mice were scored 6 h, 12 h, 24 h, 2 d, 3 d, 5 d, and 7 d after surgery. The remaining 25 mice were scored similarly, but underwent, in addition, blood sampling for serum alanine aminotransferase, total bilirubin, interleukin-6, tumor necrosis factor-alpha, or euthanasia with liver sampling for conventional hematoxylin-eosin and Ki-67 staining. RESULTS Retrospective analysis indicated that body condition scores ≤5 on two consecutive time points within the first 24 postoperative hours accurately predicted eventual death. Animals in the low scoring group also had significantly higher serum alanine aminotransferase, total bilirubin, interleukin-6, tumor necrosis factor-alpha, more hepatocyte necrosis in hematoxylin-eosin, and fewer Ki-67 positive hepatocytes. CONCLUSIONS Our scoring system accurately predicts survival, hepatocyte damage, liver regeneration, and systemic inflammation in a mouse hepatectomy model, within the first 24 hours of surgery. This could be useful in evaluating posthepatectomy interventions for their effect on survival and liver regeneration.
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Affiliation(s)
- Yinzhe Xu
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China; Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nalu Navarro-Alvarez
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Chao Yang
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - James F Markmann
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jiahong Dong
- Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing, China.
| | - Heidi Yeh
- Division of Transplantation, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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20
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Li X, Fan X, Li D, Zeng X, Zeng H, Wang Y, Zhou Y, Chen Y, Huang M, Bi H. Schisandra sphenanthera Extract Facilitates Liver Regeneration after Partial Hepatectomy in Mice. Drug Metab Dispos 2016; 44:647-52. [PMID: 26932815 DOI: 10.1124/dmd.115.068288] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 02/26/2016] [Indexed: 01/20/2023] Open
Abstract
Liver regeneration after surgical liver resection is crucial for the restoration of liver mass and the recovery of liver function.Schisandra sphenanthera extract (Wuzhi tablet, WZ) is a preparation of an extract from the dried ripe fruit of Schisandra sphenanthera Rehd. et Wils, a traditional hepatoprotective herb. Previously, we found that WZ could induce liver regeneration-related genes against acetaminophen-induced liver injury. However, whether WZ can directly facilitate liver regeneration after liver resection remains unknown. We investigated whether WZ has potential in promoting liver regeneration after a partial hepatectomy (PHX) in mice. Remnant livers were collected 1, 1.5, 2, 3, 5, 7, and 10 days after PHX. Hepatocyte proliferation was assessed using the Ki-67 labeling index. Western blot analysis was performed on proteins known to be involved in liver regeneration. The results demonstrated that WZ significantly increased the liver-to-body weight ratio of mice after PHX but had no effect on that of mice after a sham operation. Additionally, the peak hepatocyte proliferation was observed at 1.5 days in PHX/WZ-treated mice but at 2 days in PHX/saline-treated mice, as evidenced by the Ki-67 positive ratio. Furthermore, WZ significantly increased the protein expression of ligand-induced phosphorylation of epidermal growth factor receptor and up-regulated cyclin D1, cyclin D-dependent kinase 4, phosphorylated retinoblastoma, and proliferating cell nuclear antigen protein expression and down-regulated the expression of cell cycle inhibitors p21 and p27 in the regenerative process after PHX. These results demonstrate that WZ significantly facilitates hepatocyte proliferation and liver regeneration after PHX.
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Affiliation(s)
- Xi Li
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Xiaomei Fan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Dongshun Li
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Xuezhen Zeng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Hang Zeng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Yongtao Wang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Yawen Zhou
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Yixin Chen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Min Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
| | - Huichang Bi
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (X.L., D.L., X.Z., H.Z., Y.W., Y.Z., Y.C., M.H., H.B.); Shenzhen Bao'an Maternal and Child Health Hospital, Shenzhen (X.F.), People's Republic of China
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Valanejad L, Timchenko N. Akt-FoxO1 axis controls liver regeneration. Hepatology 2016; 63:1424-6. [PMID: 27100144 DOI: 10.1002/hep.28440] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2015] [Accepted: 12/25/2015] [Indexed: 01/10/2023]
Affiliation(s)
- Leila Valanejad
- Departments of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Nikolai Timchenko
- Departments of Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
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22
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Young LH, Periwal V. Metabolic scaling predicts posthepatectomy liver regeneration after accounting for hepatocyte hypertrophy. Liver Transpl 2016; 22:476-84. [PMID: 26709233 PMCID: PMC4809762 DOI: 10.1002/lt.24392] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 10/28/2015] [Accepted: 12/14/2015] [Indexed: 01/28/2023]
Abstract
We adapted a mathematical model of posthepatectomy liver regeneration using data from a subset of patients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study. The original model addressed changes in the number of quiescent, primed, and proliferating cells. Our adapted model takes into account hypertrophy of primed and replicating cells, and it is better able to predict liver volume. In addition, by building off the hypothesis that cell cycle parameters are approximately the same across all mammals, we found that changing only a single parameter characterizing metabolic load could model liver regeneration in 5 species of mammals. In conclusion, we improved a mathematical model of liver regeneration, predicted mammalian liver regeneration based on metabolism, and found correlations between model parameters and physiological measurements from liver donors.
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Affiliation(s)
- LeAnne H. Young
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Department of Health and Human Services; Bethesda MD
| | - Vipul Periwal
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Department of Health and Human Services; Bethesda MD
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Magalhães CR, Malafaia O, Torres OJM, Moreira LB, Tefil SCDSG, Pinherio MDR, Harada BA. Liver regeneration with l-glutamine supplemented diet: experimental study in rats. Rev Col Bras Cir 2016; 41:117-21. [PMID: 24918725 DOI: 10.1590/s0100-69912014000200008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2013] [Accepted: 02/08/2013] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE To assess liver regeneration in rats after 60% hepatectomy with and without supplementation of L-glutamine through liver weight changes, laboratory parameters and histological study. METHODS 36 male rats were divided into two groups: glutamine group and control group. Each group was subdivided into three subgroups, with death in 24h, 72h and seven days. The glutamine group received water and standard diet supplemented with L-glutamine, and the control recieved 0.9% saline. In all subgroups analysis of liver regeneration was made by the Kwon formula, study of liver function (AST, ALT, GGT, total bilirubin, indirect and indirect bilirubin and albumin) and analysis of cell mitosis by hematoxylin-eosin. RESULTS In both groups there was liver regeneration by weight gain. Gamma-GT increased significantly in the control group (p < 0.05); albumin increased in the glutamine group. The other indicators of liver function showed no significant differences. Histological analysis at 72h showed a higher number of mitoses in the glutamine group, with no differences in other subgroups. CONCLUSION Diet supplementation with L glutamine is beneficial for liver regeneration.
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Affiliation(s)
| | - Osvaldo Malafaia
- Medical Research Institute, Evangelical Faculty of Paraná, Evangelical University Hospital
| | | | | | | | | | - Bruna Ayumi Harada
- Hospital Universitário Evangélico de Curitiba, Faculdade Evangélica do Paraná, PR, Brasil
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Encapsulated Whole Bone Marrow Cells Improve Survival in Wistar Rats after 90% Partial Hepatectomy. Stem Cells Int 2015; 2016:4831524. [PMID: 26649048 PMCID: PMC4663362 DOI: 10.1155/2016/4831524] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 01/18/2015] [Accepted: 01/28/2015] [Indexed: 12/16/2022] Open
Abstract
Background and Aims. The use of bone marrow cells has been suggested as an alternative treatment for acute liver failure. In this study, we investigate the effect of encapsulated whole bone marrow cells in a liver failure model. Methods. Encapsulated cells or empty capsules were implanted in rats submitted to 90% partial hepatectomy. The survival rate was assessed. Another group was euthanized at 6, 12, 24, 48, and 72 hours after hepatectomy to study expression of cytokines and growth factors. Results. Whole bone marrow group showed a higher than 10 days survival rate compared to empty capsules group. Gene expression related to early phase of liver regeneration at 6 hours after hepatectomy was decreased in encapsulated cells group, whereas genes related to regeneration were increased at 12, 24, and 48 hours. Whole bone marrow group showed lower regeneration rate at 72 hours and higher expression and activity of caspase 3. In contrast, lysosomal-β-glucuronidase activity was elevated in empty capsules group. Conclusions. The results show that encapsulated whole bone marrow cells reduce the expression of genes involved in liver regeneration and increase those responsible for ending hepatocyte division. In addition, these cells favor apoptotic cell death and decrease necrosis, thus increasing survival.
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Feng G, Long Y, Peng J, Li Q, Cui Z. Transcriptomic characterization of the dorsal lobes after hepatectomy of the ventral lobe in zebrafish. BMC Genomics 2015; 16:979. [PMID: 26584608 PMCID: PMC4653908 DOI: 10.1186/s12864-015-2145-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/26/2015] [Indexed: 02/08/2023] Open
Abstract
Background The liver possesses an ability of compensatory growth after removing three of five lobes in mammals or one of three lobes in zebrafish. The reenter of hepatocytes into the cell cycle is one of the hallmarks for the initiation of liver compensatory growth, but cellular and molecular mechanisms underlying the activation of hepatocytes remain largely unknown. Results To better understand the process, transcriptional profiles of the remaining liver dorsal lobes in female zebrafish were generated with RNA-seq. About 44 million raw reads were obtained from three sequencing libraries and 71 % of raw reads were mapped to the reference genome of zebrafish. A total number of 5652 genes were differentially expressed in at least one of two time points during the compensatory growth of liver dorsal lobes and classified into different functional categories. A number of genes encoding angiogenesis-related growth factors/ligands and apoptosis-associated cytokines were strongly expressed at 6-h time point after the removal of the ventral lobe. Gene ontology enrichment analysis of genes up-regulated during early stages of liver compensatory growth revealed that small GTPase-mediated signal transduction, RNA processing and intracellular protein transport were the most highly overrepresented biological processes and SNARE interactions in vesicular transport, proteasome and basal transcription factors were the most highly enriched pathways. Moreover, 477 genes differently expressed during liver compensatory growth of both female zebrafish and mice were involved in the response to stimulus, DNA replication, metabolic processes of fatty acid, lipid and steroid, multicellular organismal homeostasis and extracellular matrix constituent secretion. Conclusions Multiple biological processes and signaling pathways are immediately activated in remaining dorsal lobes of female zebrafish right after removal of the ventral lobe and these findings provide crucial clues for further identification of cis-elements and trans-factors that are extensively involved in the initiation of liver compensatory growth. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-2145-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Guohui Feng
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Yong Long
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
| | - Jinrong Peng
- Zhejiang University, Hangzhou, 310058, Zhejiang, China.
| | - Qing Li
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
| | - Zongbin Cui
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
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Tissue Remodelling following Resection of Porcine Liver. BIOMED RESEARCH INTERNATIONAL 2015; 2015:248920. [PMID: 26240819 PMCID: PMC4512564 DOI: 10.1155/2015/248920] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Revised: 06/07/2015] [Accepted: 06/11/2015] [Indexed: 12/21/2022]
Abstract
AIM To study genes regulating the extracellular matrix (ECM) and investigate the tissue remodelling following liver resection in porcine. METHODS Four pigs with 60% partial hepatectomy- (PHx-) induced liver regeneration were studied over six weeks. Four pigs underwent sham surgery and another four pigs were used as controls of the normal liver growth. Liver biopsies were taken upon laparotomy, after three and six weeks. Gene expression profiles were obtained using porcine-specific oligonucleotide microarrays. Immunohistochemical staining was performed and a proliferative index was assessed. RESULTS More differentially expressed genes were associated with the regulation of ECM in the resection group compared to the sham and control groups. Secreted protein acidic and rich in cysteine (SPARC) and collagen 1, alpha 2 (COL1A2) were both upregulated in the early phase of liver regeneration, validated by immunopositive cells during the remodelling phase of liver regeneration. A broadened connective tissue was demonstrated by Masson's Trichrome staining, and an immunohistochemical staining against pan-Cytokeratin (pan-CK) demonstrated a distinct pattern of migrating cells, followed by proliferating cell nuclear antigen (PCNA) positive nuclei. CONCLUSIONS The present study demonstrates both a distinct pattern of PCNA positive nuclei and a deposition of ECM proteins in the remodelling phase of liver regeneration.
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Kornasiewicz O, Grąt M, Dudek K, Lewandowski Z, Gorski Z, Zieniewicz K, Krawczyk M. Serum levels of HGF, IL-6, and TGF-α after benign liver tumor resection. Adv Med Sci 2015; 60:173-177. [PMID: 25794904 DOI: 10.1016/j.advms.2015.01.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Revised: 01/27/2015] [Accepted: 01/29/2015] [Indexed: 12/21/2022]
Abstract
PURPOSE Literature is void of data on the relationship between pre- and postoperative levels of hepatocyte growth factor (HGF), interleukin 6 (IL-6), and tumor growth factor α (TGF-α) after liver resection performed for particular benign liver tumors. The purpose of this study was to assess whether there is a different degree of liver regeneration through the kinetics of HGF, IL-6, and TGF-α in 2 particular types of benign liver lesions. MATERIAL/METHODS The study included 9 patients diagnosed with hepatic hemangioma and 13 patients with focal nodular hyperplasia (FNH) who underwent liver resection. HGF, IL-6, and TGF-α were measured using enzyme-linked immunosorbent assay (ELISA) from blood serum drawn at 6 time points during an 8-day period. Statistical analysis was based on two-factor variance analysis with replicate measurements. RESULTS The HGF, IL-6, and TGF-α levels in patients who underwent FNH resection were not significantly different from the levels observed in hemangioma resection patients. Significant increases in HGF, IL-6, and TGF-α concentrations were observed only during the first 24h after resection in both groups of patients. CONCLUSIONS Obtained results suggest that the pre- and post-operative levels of HGF, IL-6, and TGF-α do not depend on the particular type of benign tumor. After resection of FNH and hemangioma tumors, the serum levels of HGF, IL-6, and TGF-α increased at similar rates during the first 24h, followed by significant declines back to pre-operative levels.
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Affiliation(s)
- Oskar Kornasiewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland.
| | - Michał Grąt
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Krzysztof Dudek
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | | | - Zuzanna Gorski
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Krzysztof Zieniewicz
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
| | - Marek Krawczyk
- Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Poland
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Szijártó A, Fülöp A. Triggered liver regeneration: from experimental model to clinical implications. Eur Surg Res 2015; 54:148-61. [PMID: 25592812 DOI: 10.1159/000368961] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 10/07/2014] [Indexed: 11/19/2022]
Abstract
BACKGROUND Major liver resection is the only therapeutic option for patients with malignant liver tumors. However, extended hepatectomy often leads to postoperative liver failure, mainly due to insufficient amounts of the remnant liver. Recently, selective portal vein occlusion (PVO) has been introduced to increase the remnant liver volume. This novel surgical technique initiated a progressive development in liver surgery, resulting in a significant increment in potential candidates for curative liver resection. SUMMARY The theoretical basis for this great advancement is formed by an understanding of the mechanisms of PVO-induced liver regeneration, mainly obtained from animal studies. The aim of this review is to give a comprehensive overview of the relevant animal models of PVO and to discuss the main characteristics of triggered liver regeneration, including the induced hemodynamic, morphological and functional alterations as well as the underlying molecular mechanisms, which might be of interest in both the laboratory and the clinic. Key Messages: Although basic research revealed the main characteristics of PVO-triggered liver regeneration within the last decades, several important issues regarding the regenerative process remain uncertain. To answer these open questions, additional well-designed animal experiments are needed in the future, which allow further refinement of this surgical technique.
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Affiliation(s)
- Attila Szijártó
- 1st Department of Surgery, Semmelweis University, Budapest, Hungary
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Baretta GAP, Gama Filho O, Toderke EL, Tolazzi ARD, Matias JEF. Effect of cyclosporine on liver regeneration in partial hepatectomized rats. Acta Cir Bras 2015; 30:54-9. [DOI: 10.1590/s0102-86502015001000007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2014] [Accepted: 12/30/2014] [Indexed: 11/22/2022] Open
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López ML, Kieling CO, Uribe Cruz C, Osvaldt A, Ochs de Muñoz G, Meurer L, Silla L, Matte U. Platelet increases survival in a model of 90% hepatectomy in rats. Liver Int 2014; 34:1049-56. [PMID: 24119092 DOI: 10.1111/liv.12326] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 08/29/2013] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Ninety per cent hepatectomy in rodents is a model for acute liver failure. It has been reported that platelets have a strong effect enhancing liver regeneration, because of the production of several growth factors such as serotonin. The aim of this study was to investigate the role of microencapsulated platelets on 90% hepatectomy in rats. METHODS Platelets (PLT) were microencapsulated in sodium alginate and implanted in the peritoneum of rats after 90% partial hepatectomy (PH). Control group received empty capsules (EC). Animals were euthanized at 6, 12, 24, 48 and 72 h post PH (n=9-12/group/time) to evaluate liver regeneration rate, mitotic index, liver content, serum and tissue levels of Interleukin 6 (IL-6) and serotonin and its receptor 5-hydroxytryptamine type 2B (5Ht2b). Survival rate in 10 days was evaluated in a different set of animals (n=20/group). RESULTS Platelets group showed the highest survival rate despite the lowest liver regeneration rate at any time point. Mitotic and BrdU index showed no difference between groups. However, the number of hepatocytes was higher and the internuclear distance was shorter for PLT group. Liver dry weight was similar in both groups indicating that water was the main responsible factor for the weight difference. Gene expression of IL-6 in the liver was significantly higher in EC group 6 h after PH, whereas 5Ht2b was up-regulated at 72 h in PLT group. CONCLUSIONS Platelets enhance survival of animals with 90% PH, probably by an early protective effect on hepatocytes and the increase in growth factor receptors.
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Affiliation(s)
- Mónica L López
- Gene Therapy Center, Hospital de Clínicas de Porto Alegre, Porto Alegre, do Rio Grande do Sul, Brazil; Post-Graduation Program on Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, do Rio Grande do Sul, Brazil
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Pagano D, Spada M, Parikh V, Tuzzolino F, Cintorino D, Maruzzelli L, Vizzini G, Luca A, Mularoni A, Grossi P, Gridelli B, Gruttadauria S. Liver regeneration after liver resection: Clinical aspects and correlation with infective complications. World J Gastroenterol 2014; 20:6953-6960. [PMID: 24944488 PMCID: PMC4051937 DOI: 10.3748/wjg.v20.i22.6953] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 01/23/2014] [Accepted: 03/13/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate whether early liver regeneration after resection in patients with hepatic tumors might be influenced by post-operative infective complications.
METHODS: A retrospective analysis of 27 liver resections for tumors performed in a single referral center from November 2004 to January 2010. Regeneration was evaluated by multidetector computed tomography at a mean follow-up of 43.85 d. The Clavien-Dindo classification was used to evaluate postoperative events in the first 6 mo after transplantation, and Centers for Disease Control and Prevention definitions were used for healthcare associated infections data. Generalized linear regression models with Gaussian family distribution and log link function were used to reveal the principal promoters of early liver regeneration.
RESULTS: Ten of the 27 patients (37%) underwent chemotherapy prior to surgery, with a statistically significant prevalence of patients with metastasis (P = 0.007). Eight patients (30%) underwent embolization, 3 with primary tumors, and 5 with secondary tumors. Twenty patients (74%) experienced complications, with 12 (60%) experiencing Clavien-Dindo Grade 3a to 5 complications. Regeneration ≥ 100% occurred in 10 (37%) patients. The predictors were smaller future remnant liver volume (-0.002; P < 0.001), and a greater spleen volume/future remnant liver volume ratio (0.499; P = 0.01). Patients with a resection of ≥ 5 Couinaud segments experienced greater early regeneration (P = 0.04). Nine patients experienced surgical site infections, and in 7 cases Clavien-Dindo Grade 3a to 4 complications were detected (P = 0.016). There were no significant differences between patients with primary or secondary tumors, and either onset or infections or severity of surgical complications.
CONCLUSION: Regardless of the onset of infective complications, future remnant liver and spleen volumes may be reliable predictors of early liver regeneration after hepatic resection on an otherwise healthy liver.
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Pagano D, Gruttadauria S. Impact of future remnant liver volume on post-hepatectomy regeneration in non-cirrhotic livers. Front Surg 2014; 1:10. [PMID: 25593935 PMCID: PMC4286982 DOI: 10.3389/fsurg.2014.00010] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2014] [Accepted: 04/02/2014] [Indexed: 02/06/2023] Open
Abstract
Objective: The purpose of the study is to detect if some parameters can be considered as predictors of liver regeneration in two different patient populations composed of in living donors for adult to adult living donor liver transplant and patients with hepatic malignancies within a single institution. Summary Background Data: Preoperative multi-detector computed tomography volumetry is an essential tool to assess the volume of the remnant liver. Methods: A retrospective analysis from an ongoing clinical study on 100 liver resections, between 2004 and 2010. Seventy patients were right lobe living donors for liver transplantation and 30 patients were resected for treatment of tumors. Pre-surgical factors such as age, weight, height, body mass index (BMI), original liver volume, future remnant liver volume (FRLV), spleen volume, liver function tests, creatinine, platelet count, steatosis, portal vein embolization, and number of resected segments were analyzed to evidence potential markers for liver regeneration. Results: Follow-up period did not influence the amount of liver regenerated: the linear regression evidenced that there is no correlation between percentage of liver regeneration and time of follow-up (p = 0.88). The pre-surgical variables that resulted markers of liver regeneration include higher preoperative values of BMI (p = 0.01), bilirubin (p = 0.04), glucose (p = 0.05), and gamma-glutamyl transpeptidase (p = 0.014); the most important association was revealed regarding the lower FRLV (p < 0.0001) and percentage of liver regeneration. The stepwise regression revealed a strong impact of FRLV (p < 0.0001) on the other predictor variables. Conclusion: Liver regeneration follows similar pathway in living donor and in patients resected for cancer. Small FRLV tends to regenerate more and faster, confirming that a larger resections may lead to a greater promotion of liver regeneration in patients with optimal conditions in terms of body habitus, preoperative liver function tests, and glucose level.
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Affiliation(s)
- Duilio Pagano
- Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), University of Pittsburgh Medical Center in Italy , Palermo , Italy
| | - Salvatore Gruttadauria
- Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT), University of Pittsburgh Medical Center in Italy , Palermo , Italy ; Department of Surgery, University of Pittsburgh , Pittsburgh, PA , USA
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How does a single cell know when the liver has reached its correct size? PLoS One 2014; 9:e93207. [PMID: 24690888 PMCID: PMC3972176 DOI: 10.1371/journal.pone.0093207] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Accepted: 03/02/2014] [Indexed: 01/19/2023] Open
Abstract
The liver is a multi-functional organ that regulates major physiological processes and that possesses a remarkable regeneration capacity. After loss of functional liver mass the liver grows back to its original, individual size through hepatocyte proliferation and apoptosis. How does a single hepatocyte 'know' when the organ has grown to its final size? This work considers the initial growth phase of liver regeneration after partial hepatectomy in which the mass is restored. There are strong and valid arguments that the trigger of proliferation after partial hepatectomy is mediated through the portal blood flow. It remains unclear, if either or both the concentration of metabolites in the blood or the shear stress are crucial to hepatocyte proliferation and liver size control. A cell-based mathematical model is developed that helps discriminate the effects of these two potential triggers. Analysis of the mathematical model shows that a metabolic load and a hemodynamical hypothesis imply different feedback mechanisms at the cellular scale. The predictions of the developed mathematical model are compared to experimental data in rats. The assumption that hepatocytes are able to buffer the metabolic load leads to a robustness against short-term fluctuations of the trigger which can not be achieved with a purely hemodynamical trigger.
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Shi JH, Scholz H, Huitfeldt HS, Line PD. The effect of hepatic progenitor cells on experimental hepatocellular carcinoma in the regenerating liver. Scand J Gastroenterol 2014; 49:99-108. [PMID: 24188385 DOI: 10.3109/00365521.2013.854406] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Liver regeneration following hepatectomy can stimulate the growth of hepatocellular carcinoma (HCC), and major hepatectomy can be associated with activation of hepatic progenitor cells (HPCs). The aim of this study was to evaluate how HPCs influence the malignant potential of tumor cells in vitro and HCC tumor growth after surgery in a rodent model. MATERIAL AND METHODS Hepatoma cells (JM1) were cultured with conditioned medium (CM) from syngeneic HPCs (WB-F344). Growth rate, resistance to Adriamycin, and expression patterns for invasiveness and stemness were compared with naïve JM1. Microscopic HCC tumors from naïve JM1 or JM1 cultured with CM were inoculated in Fischer 344 rats undergoing 70% hepatectomy with or without simultaneous infusion of WB-F344. Tumor growth and invasiveness-related factors were compared. Buffalo rats were induced with Morris hepatoma cells. Liver tissue from both in vivo models was examined with regard to activation of cells with progenitor-like phenotype. RESULTS Co-culture with CM resulted in an increased resistance to Adriamycin and enhanced expressions of α-FP, MMP9, ABCG2, CD133, and SOX2, as well as the activation of ERK, AKT, WNT, and TGF-β1 pathways. Tumor size and metastases were significantly higher in groups with co-cultured cells or HPCs infusion. After 70% hepatectomy and tumor implantation, cells positive for α-FP, CK19, and CD133 were found, thus suggesting a progenitor-like phenotype in the setting of epithelial-mesenchymal transition. CONCLUSION HPCs have a marked effect on HCC cells in vitro and appear to stimulate the growth and malignant potential of experimental HCC tumors.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters/genetics
- Animals
- Antibiotics, Antineoplastic/therapeutic use
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/secondary
- Cell Line, Tumor
- Cell Proliferation
- Coculture Techniques
- Cytokine Receptor Common beta Subunit/metabolism
- Doxorubicin/therapeutic use
- Drug Resistance, Neoplasm
- Epithelial-Mesenchymal Transition
- Gene Expression
- Hepatectomy
- Humans
- Liver/physiology
- Liver/surgery
- Liver Neoplasms, Experimental/metabolism
- Liver Neoplasms, Experimental/pathology
- Liver Regeneration
- MAP Kinase Signaling System
- Matrix Metalloproteinase 9/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- RNA, Messenger/metabolism
- Rats
- Rats, Inbred BUF
- Rats, Inbred F344
- SOXB1 Transcription Factors/genetics
- Stem Cells/metabolism
- Transforming Growth Factor beta1/metabolism
- Tumor Burden
- Wnt Signaling Pathway
- alpha-Fetoproteins/metabolism
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Affiliation(s)
- Ji-Hua Shi
- Department of Transplantation Medicine, Oslo University Hospital , Oslo , Norway
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Rychtrmoc D, Hubálková L, Víšková A, Libra A, Bunček M, Červinková Z. Transcriptome temporal and functional analysis of liver regeneration termination. Physiol Res 2013; 61:S77-92. [PMID: 23130906 DOI: 10.33549/physiolres.932393] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Decades of liver regeneration studies still left the termination phase least elucidated. However regeneration ending mechanisms are clinicaly relevant. We aimed to analyse the timing and transcriptional control of the latest phase of liver regeneration, both controversial. Male Wistar rats were subjected to 2/3 partial hepatectomy with recovery lasting from 1 to 14 days. Time-series microarray data were assessed by innovative combination of hierarchical clustering and principal component analysis and validated by real-time RT-PCR. Hierarchical clustering and principal component analysis in agreement distinguished three temporal phases of liver regeneration. We found 359 genes specifically altered during late phase regeneration. Gene enrichment analysis and manual review of microarray data suggested five pathways worth further study: PPAR signalling pathway; lipid metabolism; complement, coagulation and fibrinolytic cascades; ECM remodelling and xenobiotic biotransformation. Microarray findings pertinent for termination phase were substantiated by real-time RT-PCR. In conclusion, transcriptional profiling mapped late phase of liver regeneration beyond 5(th) day of recovery and revealed 5 pathways specifically acting at this time. Inclusion of longer post-surgery intervals brought improved coverage of regeneration time dynamics and is advisable for further works. Investigation into the workings of suggested pathways might prove helpful in preventing and managing liver tumours.
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Affiliation(s)
- D Rychtrmoc
- Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University in Prague, Hradec Králové, Czech Republic.
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Tralhão JG, Abrantes AM, Hoti E, Oliveiros B, Cardoso D, Faitot F, Carvalho C, Botelho MF, Castro-Sousa F. Hepatectomy and liver regeneration: from experimental research to clinical application. ANZ J Surg 2013; 84:665-71. [PMID: 23656467 DOI: 10.1111/ans.12201] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/24/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND The mechanisms and kinetics of hepatic growth have continuously been investigated. This study concerns liver regeneration in animal and patients who underwent partial hepatectomy evaluated by the hepatic extraction fraction (HEF) calculated through radioisotopic methods. METHODS Thirty normal Wistar rats were submitted to an 85% hepatectomy, and 95 patients with primary and secondary liver tumours were included. In animal study, the liver regeneration kinetics was assessed by HEF using 99mTc-mebrofenin, the ratio liver/bodyweight and by using bromodeoxyuridine deoxyribonucleic acid incorporation. In patient study, the liver regeneration was evaluated by calculation of HEF before surgery, 5 and 30 days after hepatectomy. RESULTS In animal, we verified a positive correlation between HEF kinetics and liver/bodyweight ratio or hepatocyte proliferation evaluated by bromodeoxyuridine deoxyribonucleic acid staining after 85% hepatectomy. In the clinical arm, no statistical differences of the HEF before hepatectomy, 5 and 30 days after hepatectomy, were observed. CONCLUSIONS Our results support the view that human liver regeneration commences early, is fast, non-anatomical and functionally complete 5 days after hepatectomy. The fast functional liver regeneration may have a high clinical impact particularly concerning the post-operative oncological therapeutic approaches.
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Affiliation(s)
- José G Tralhão
- Department of Surgery A, Coimbra University Hospital, Faculty of Medicine, University of Coimbra, Coimbra, Portugal; Biophysics Unit, IBILI, Faculty of Medicine, University of Coimbra, Portugal; Centre of Investigation on Environment, Genetics and Oncobiology (CIMAGO), Faculty of Medicine, Coimbra, Portugal
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Gao L, Utsumi T, Tashiro K, Liu B, Zhang D, Swenson ES, Iwakiri Y. Reticulon 4B (Nogo-B) facilitates hepatocyte proliferation and liver regeneration in mice. Hepatology 2013; 57:1992-2003. [PMID: 23299899 PMCID: PMC3628958 DOI: 10.1002/hep.26235] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2012] [Accepted: 11/28/2012] [Indexed: 12/20/2022]
Abstract
UNLABELLED Nogo-B, also known as reticulon 4B, promotes liver fibrosis and cirrhosis by facilitating the transforming growth factor β (TGF-β) signaling pathway in activated hepatic stellate cells. The aim of this study was to determine the role of Nogo-B in hepatocyte proliferation and liver regeneration. Partial hepatectomy (PHx, 70% resection) was performed in male wild-type (WT) and Nogo-A/B knockout mice (referred to as Nogo-B KO mice). Remnant livers were isolated 2 hours, 5 hours, and 1, 2, 3, 7, and 14 days after PHx. Hepatocyte proliferation was assessed by Ki67 labeling index. Quantitative real-time polymerase chain reaction was performed for genes known to be involved in liver regeneration. Hepatocytes isolated from WT and Nogo-B KO mice were used to examine the role of Nogo-B in interleukin-6 (IL-6), hepatocyte growth factor (HGF), epidermal growth factor (EGF), and TGF-β signaling. Nogo-B protein levels increased in the regenerating livers in a time-dependent manner after PHx. Specifically, Nogo-B expression in hepatocytes gradually spread from the periportal toward the central areas by 7 days after PHx, but receded notably by 14 days. Nogo-B facilitated IL-6/signal transducer and activator of transcription 3 signaling, increased HGF-induced but not EGF-induced hepatocyte proliferation, and tended to reduce TGF-β1-induced suppression of hepatocyte proliferation in cultured hepatocytes. Lack of Nogo-B significantly induced TGF-β1 and inhibitor of DNA binding expression 1 day after PHx and IL-6 and EGF expression 2 days after PHx. Lack of Nogo-B delayed hepatocyte proliferation but did not affect the liver-to-body ratio in the regenerative process. CONCLUSION Nogo-B expression in hepatocytes facilitates hepatocyte proliferation and liver regeneration.
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Affiliation(s)
- Lili Gao
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, U.S.A.,Department of Geriatric Gastroenterology, PLA General Hospital, Beijing, China
| | - Teruo Utsumi
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, U.S.A
| | - Keitaro Tashiro
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, U.S.A
| | - Bo Liu
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, U.S.A.,Department of Hepatobiliary Surgery, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Dahai Zhang
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, U.S.A
| | - E. Scott Swenson
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, U.S.A
| | - Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, U.S.A.,Corresponding author: Yasuko Iwakiri, Ph.D., 1080 LMP, 333 Cedar Street, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT 06520 U.S.A. , Phone #: 203-785-6204, Fax #: 203-785-7273
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Bönninghoff R, Schwenke K, Keese M, Magdeburg R, Bitter-Suermann H, Otto M, Hasenberg T, Post S, Sturm J. Effect of different liver resection methods on liver damage and regeneration factors VEGF and FGF-2 in mice. Can J Surg 2013; 55:389-93. [PMID: 22992401 DOI: 10.1503/cjs.007911] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Different approaches to study liver regeneration in murine models have been proposed. We investigated the effect of different liver resection models on liver damage and regeneration parameters in mice. METHODS We compared the technical aspect of the 2 most commonly used techniques of 50% and 70% liver resection. Liver damage, as determined by the change in serum alanine aminotransferase and aspartate aminotransferase, as well as the regeneration parameters VEGF and FGF-2 were analyzed at 6 time points. A postoperative vitality score was introduced. RESULTS Cholestasis was not observed for either technique. Both resection techniques resulted in full weight recovery of the liver after 240 hours, with no significant difference between sham and resection groups. Postoperative animal morbidity and total protein levels did not differ significantly for either method, indicating early and full functional recovery. However, comparing the mitogenic growth factors FGF-2 and VEGF, a significant increase in serum levels and, therefore, increased growth stimulus, was shown in the extended resection group. CONCLUSION Extended resection led to a greater response in growth factor expression. This finding is important since it shows that growth factor response differs acdording to the extent of resection. We have demonstrated the need to standardize murine hepatic resection models to adequately compare the resulting liver damage.
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Affiliation(s)
- Roderich Bönninghoff
- The Department of Surgery, Medical Faculty Mannheim, University Medical Centre Mannheim, Heidelberg University, Heidelberg, Germany
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Jia C, Dai C, Bu X, Peng S, Xu F, Xu Y, Zhao Y. Co-administration of prostaglandin E1 with somatostatin attenuates acute liver damage after massive hepatectomy in rats via inhibition of inflammatory responses, apoptosis and endoplasmic reticulum stress. Int J Mol Med 2012; 31:416-22. [PMID: 23242071 DOI: 10.3892/ijmm.2012.1213] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Accepted: 11/16/2012] [Indexed: 01/11/2023] Open
Abstract
Acute liver damage is considered to be the major cause of mortality after massive hepatectomy. Prostaglandin E1 (PGE1) and somatostatin (SST) have been shown to protect against hepatic injury of rats after partial hepatectomy. However, the precise mechanisms remain largely unknown. In this study, we examined the effects of PGE1, SST and the combination of these two drugs on acute liver damage of rats after 90% hepatectomy. We found that animal survival was improved when pretreated with PGE1 and SST. Portal venous pressure (PVP), serum alanine aminotransferase (ALT) and aspartate aminotransaminase (AST), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were all reduced after administration of PGE1 and SST. In addition, apoptosis was inhibited via upregulation of Bcl-2 and downregulation of Bax and caspase-3 in drug treatment groups. Furthermore, pretreatment with PGE1 and SST alleviated endoplasmic reticulum (ER) stress by induction of heat shock protein 70 (HSP70) and glucose-regulated protein 78 (GRP78), but suppression of transcription factor C/EBP homologous protein (CHOP). Our data suggest that administration of PGE1 and SST, particularly in combination, may prevent acute liver damage of rats after massive hepatectomy by inhibiting inflammatory responses, apoptosis and ER stress.
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Affiliation(s)
- Changjun Jia
- Department of Hepato-Biliary-Splenic Surgery, Shengjing Hospital, China Medical University, Shenyang, Liaoning 110004, P.R. China.
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Zinc transporter ZIP14 functions in hepatic zinc, iron and glucose homeostasis during the innate immune response (endotoxemia). PLoS One 2012; 7:e48679. [PMID: 23110240 PMCID: PMC3480510 DOI: 10.1371/journal.pone.0048679] [Citation(s) in RCA: 118] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Accepted: 09/28/2012] [Indexed: 12/16/2022] Open
Abstract
ZIP14 (slc39A14) is a zinc transporter induced in response to pro-inflammatory stimuli. ZIP14 induction accompanies the reduction in serum zinc (hypozincemia) of acute inflammation. ZIP14 can transport Zn2+ and non-transferrin-bound Fe2+ in vitro. Using a Zip14−/− mouse model we demonstrated that ZIP14 was essential for control of phosphatase PTP1B activity and phosphorylation of c-Met during liver regeneration. In the current studies, a global screening of ZIP transporter gene expression in response to LPS-induced endotoxemia was conducted. Following LPS, Zip14 was the most highly up-regulated Zip transcript in liver, but also in white adipose tissue and muscle. Using ZIP14−/− mice we show that ZIP14 contributes to zinc absorption from the gastrointestinal tract directly or indirectly as zinc absorption was decreased in the KOs. In contrast, Zip14−/− mice absorbed more iron. The Zip14 KO mice did not exhibit hypozincemia following LPS, but do have hypoferremia. Livers of Zip14−/− mice had increased transcript abundance for hepcidin, divalent metal transporter-1, ferritin and transferrin receptor-1 and greater accumulation of iron. The Zip14−/− phenotype included greater body fat, hypoglycemia and higher insulin levels, as well as increased liver glucose and greater phosphorylation of the insulin receptor and increased GLUT2, SREBP-1c and FASN expression. The Zip14 KO mice exhibited decreased circulating IL-6 with increased hepatic SOCS-3 following LPS, suggesting SOCS-3 inhibited insulin signaling which produced the hypoglycemia in this genotype. The results are consistent with ZIP14 ablation yielding abnormal labile zinc pools which lead to increased SOCS-3 production through G-coupled receptor activation and increased cAMP production as well as signaled by increased pSTAT3 via the IL-6 receptor, which inhibits IRS 1/2 phosphorylation. Our data show the role of ZIP14 in the hepatocyte is multi-functional since zinc and iron trafficking are altered in the Zip14−/− mice and their phenotype shows defects in glucose homeostasis.
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Martino RB, Coelho AMM, Kubrusly MS, Leitão R, Sampietre SN, Machado MCC, Bacchella T, D'Albuquerque LAC. Pentoxifylline improves liver regeneration through down-regulation of TNF-α synthesis and TGF-β1 gene expression. World J Gastrointest Surg 2012; 4:146-51. [PMID: 22816029 PMCID: PMC3400043 DOI: 10.4240/wjgs.v4.i6.146] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 06/20/2012] [Accepted: 06/23/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanism of pentoxifylline (PTX) improvement in liver regeneration.
RESULTS: Rats were randomized into 4 groups: Control rats; Sham - sham-operation rats; Saline - 70% hepatectomy plus saline solution; PTX - 70% hepatectomy plus PTX. At 2 and 6 h after hepatectomy, aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) serum and hepatic tissue levels were determined. Tumor growth factor (TGF)-β1 gene expression in liver tissue was evaluated 24 h after hepatectomy by quantitative reverse transcriptase polymerase chain reaction analysis. Proliferation was analyzed by mitotic index and proliferating cell nuclear antigen (PCNA) staining 48 h after hepatectomy.
RESULTS: TNF-α and IL-6 serum levels increased at 2 and 6 h after hepatectomy. At 2 h after hepatectomy serum PTX was reduced but not hepatic levels of TNF-α and IL-6. A decrease in liver TGF-β1 gene expression and an increase in mitotic index and PCNA after hepatectomy were observed in the PTX treatment group in comparison to the saline group.
CONCLUSION: PTX improves liver regeneration by a mechanism related to down regulation of TNF-α production and TGF-β1 gene expression.
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Affiliation(s)
- Rodrigo Bronze Martino
- Rodrigo Bronze Martino, Ana Maria Mendonça Coelho, Márcia Saldanha Kubrusly, Regina Leitão, Sandra Nassa Sampietre, Marcel Cerqueira Cesar Machado, Telesforo Bacchella, Luiz Augusto Carneiro D'Albuquerque, Department of Gastroenterology (LIM/37), and Department of Surgery, Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil
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Wu J, Li J, Salcedo R, Mivechi NF, Trinchieri G, Horuzsko A. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res 2012; 72:3977-86. [PMID: 22719066 DOI: 10.1158/0008-5472.can-12-0938] [Citation(s) in RCA: 195] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chronic inflammation drives liver cancer pathogenesis, invasion, and metastasis. Liver Kupffer cells have crucial roles in mediating the inflammatory processes that promote liver cancer, but the mechanistic basis for their contributions are not fully understood. Here we show that expression of the proinflammatory myeloid cell surface receptor TREM-1 expressed by Kupffer cells is a crucial factor in the development and progression of liver cancer. Deletion of the murine homolog Trem1 in mice attenuated hepatocellular carcinogenesis triggered by diethylnitrosamine (DEN). Trem1 deficiency attenuated Kupffer cell activation by downregulating transcription and protein expression of interleukin (IL)-6, IL-1β, TNF, CCL2, and CXCL10. In addition, Trem1 ablation diminished activation of the p38, extracellular regulated kinase 1/2, JNK, mitogen-activated protein kinase, and NF-κB signaling pathways in Kupffer cells, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type Kupffer cells to Trem1-deficient mice complemented these defects and reversed unresponsiveness to DEN-induced liver injury and malignant development. Together, our findings offer causal evidence that TREM-1 is a pivotal determinant of Kupffer cell activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer.
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Affiliation(s)
- Juan Wu
- Department of Medicine, Georgia Health Sciences University, Center for Molecular Chaperone/Radiobiology and Cancer Virology, Augusta, Georgia 30912, USA
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AYDEMIR TOLUNAYBEKER, SITREN HARRYS, COUSINS ROBERTJ. The zinc transporter Zip14 influences c-Met phosphorylation and hepatocyte proliferation during liver regeneration in mice. Gastroenterology 2012; 142:1536-46.e5. [PMID: 22374166 PMCID: PMC3635537 DOI: 10.1053/j.gastro.2012.02.046] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2011] [Revised: 02/10/2012] [Accepted: 02/14/2012] [Indexed: 01/16/2023]
Abstract
BACKGROUND & AIMS Zinc homeostasis in cells is maintained through tight regulation of zinc influx, efflux, and distribution to intracellular organelles by zinc transporters. The Zrt-Irt-like protein (ZIP) transporters facilitate zinc influx to the cytosol. Expression of the ZIP family member Zip14 can be induced by inflammatory cytokines, which also initiate liver regeneration. Hepatocyte proliferation is required for liver regeneration. Zinc regulates cell proliferation, tissue growth, and many mitogenic signaling pathways; we investigated its role in hepatocytes. METHODS Wild-type and Zip14(-/-) mice that underwent partial hepatectomy (70% of liver removed) were used as models of liver regeneration. We also analyzed AML12 hepatocytes that overexpressed Zip14. Proliferation was assessed with proliferating cell nuclear antigen, CD1, and Ki67 markers and along with assays of zinc content was related to protein tyrosine phosphatase 1B (PTP1B) and extracellular signal-regulated kinase 1/2 signaling. RESULTS Zip14 was up-regulated and hepatic zinc content increased during liver regeneration. Increased hepatic zinc inhibited activity of the phosphatase PTP1B and increased phosphorylation of c-Met, which promoted hepatocyte proliferation. AML12 cells that overexpressed Zip14 increased in zinc content and proliferation; PTP1B was inhibited and phosphorylation of c-Met increased. The increases in hepatic levels of zinc and hepatocyte proliferation that occurred following partial hepatectomy were not observed in Zip14(-/-) mice. CONCLUSIONS The transporter Zip14 mediates hepatic uptake of zinc during liver regeneration and for hepatocyte proliferation. These findings indicate that zinc transporter activity regulates liver tissue growth by sequestering zinc. Reagents that regulate ZIP14 activity might be developed as therapeutics to promote liver regeneration in patients with chronic liver disease.
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Weber CM, Martindale MQ, Tapscott SJ, Unguez GA. Activation of Pax7-positive cells in a non-contractile tissue contributes to regeneration of myogenic tissues in the electric fish S. macrurus. PLoS One 2012; 7:e36819. [PMID: 22685526 PMCID: PMC3365140 DOI: 10.1371/journal.pone.0036819] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2011] [Accepted: 04/15/2012] [Indexed: 11/19/2022] Open
Abstract
The ability to regenerate tissues is shared across many metazoan taxa, yet the type and extent to which multiple cellular mechanisms come into play can differ across species. For example, urodele amphibians can completely regenerate all lost tissues, including skeletal muscles after limb amputation. This remarkable ability of urodeles to restore entire limbs has been largely linked to a dedifferentiation-dependent mechanism of regeneration. However, whether cell dedifferentiation is the fundamental factor that triggers a robust regeneration capacity, and whether the loss or inhibition of this process explains the limited regeneration potential in other vertebrates is not known. Here, we studied the cellular mechanisms underlying the repetitive regeneration of myogenic tissues in the electric fish S. macrurus. Our in vivo microinjection studies of high molecular weight cell lineage tracers into single identified adult myogenic cells (muscle or noncontractile muscle-derived electrocytes) revealed no fragmentation or cellularization proximal to the amputation plane. In contrast, ultrastructural and immunolabeling studies verified the presence of myogenic stem cells that express the satellite cell marker Pax7 in mature muscle fibers and electrocytes of S. macrurus. These data provide the first example of Pax-7 positive muscle stem cells localized within a non-contractile electrogenic tissue. Moreover, upon amputation, Pax-7 positive cells underwent a robust replication and were detected exclusively in regions that give rise to myogenic cells and dorsal spinal cord components revealing a regeneration process in S. macrurus that is dependent on the activation of myogenic stem cells for the renewal of both skeletal muscle and the muscle-derived electric organ. These data are consistent with the emergent concept in vertebrate regeneration that different tissues provide a distinct progenitor cell population to the regeneration blastema, and these progenitor cells subsequently restore the original tissue.
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Affiliation(s)
- Christopher M. Weber
- Biology Department, New Mexico State University, Las Cruces, New Mexico, United States of America
| | - Mark Q. Martindale
- Kewalo Marine Lab, University of Hawaii, Honolulu, Hawaii, United States of America
| | - Stephen J. Tapscott
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Graciela A. Unguez
- Biology Department, New Mexico State University, Las Cruces, New Mexico, United States of America
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Taki-Eldin A, Zhou L, Xie HY, Zheng SS. Liver regeneration after liver transplantation. ACTA ACUST UNITED AC 2012; 48:139-53. [PMID: 22572792 DOI: 10.1159/000337865] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 02/07/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND/PURPOSE The liver has a remarkable capacity to regenerate after injury or resection. The aim of this review is to outline the mechanisms and factors affecting liver regeneration after liver transplantation. METHODS Relevant studies were reviewed using Medline, PubMed and Springer databases. RESULTS A variety of cytokines (such as interleukin-6 and tumor necrosis factor-α), growth factors (like hepatocyte growth factor and transforming growth factor-α) and cells are involved in liver regeneration. Several factors affect liver regeneration after transplantation such as ischemic injury, graft size, immunosuppression, steatosis, donor age and viral hepatitis. CONCLUSION Liver regeneration has been studied for many years. However, further research is essential to reveal the complex processes affecting liver regeneration, which may provide novel strategies in the management of liver transplantation recipients and donors.
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Affiliation(s)
- A Taki-Eldin
- Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Abshagen K, Eipel C, Vollmar B. A critical appraisal of the hemodynamic signal driving liver regeneration. Langenbecks Arch Surg 2012; 397:579-90. [PMID: 22311102 DOI: 10.1007/s00423-012-0913-0] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 01/20/2012] [Indexed: 12/25/2022]
Abstract
BACKGROUND Many aspects of the signaling mechanisms involved in the initiation of hepatic regeneration are under current investigation. Nevertheless, the actual mechanisms switching liver regeneration on and off are still unknown. Hemodynamic changes in the liver following partial hepatectomy have been suggested to be a primary stimulus in triggering liver regeneration. Most of the new knowledge about the impact of hemodynamic changes on liver regeneration is both conceptually important and directly relevant to clinical problems. PURPOSE The purpose of this review is therefore to exclusively address the hemodynamic signal driving the liver regeneration process.
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Affiliation(s)
- Kerstin Abshagen
- Institute for Experimental Surgery, University of Rostock, 18055 Rostock, Germany.
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47
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Zou Y, Bao Q, Kumar S, Hu M, Wang GY, Dai G. Four waves of hepatocyte proliferation linked with three waves of hepatic fat accumulation during partial hepatectomy-induced liver regeneration. PLoS One 2012; 7:e30675. [PMID: 22319576 PMCID: PMC3272022 DOI: 10.1371/journal.pone.0030675] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Accepted: 12/20/2011] [Indexed: 12/16/2022] Open
Abstract
UNLABELLED Partial hepatectomy (PH) triggers hepatocyte proliferation-mediated liver repair and is widely used to study the mechanisms governing liver regeneration in mice. However, the dynamics of the hepatocyte proliferative response to PH remain unclear. We found that PH-induced mouse liver regrowth was driven by four consecutive waves of hepatocyte replication. The first wave exhibited the highest magnitude followed by two moderate waves and one minor wave. Underlying this continuous hepatocyte replication was persistent activation of cell cycle components throughout the period of liver regeneration. Hepatocyte mitotic activity in the first three proliferative cycles showed a circadian rhythm manifested by three corresponding mitosis peaks, which were always observed at Zeitgeber time 0. The Bmal1-Clock/Wee1/Cdc2 pathway has been proposed by others to govern the circadian rhythm of hepatocyte mitosis during liver regeneration. However, we did not observe the correlations in the expression or phosphorylation of these proteins in regenerating livers. Notably, Bmal1 protein displayed frequent changes in hepatic distribution and cellular localization as the liver regrowth progressed. Further, three waves of hepatic fat accumulation occurred during hepatic regeneration. The first started before and lasted through the first round of hepatocyte proliferation, whereas the second and third occurred concomitantly with the second and third mitotic peaks, respectively. CONCLUSION PH-induced liver regeneration consists of four continuous waves of hepatocyte proliferation coupled with three waves of hepatic fat accumulation. Bmal1, Wee1, and Cdc2 may not form a pathway regulating the circadian rhythm of hepatocyte mitosis during liver regeneration.
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Affiliation(s)
- Yuhong Zou
- Department of Biology, Center for Regenerative Biology and Medicine, School of Science, Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, United States of America
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Russo FP, Parola M. Stem cells in liver failure. Best Pract Res Clin Gastroenterol 2012; 26:35-45. [PMID: 22482524 DOI: 10.1016/j.bpg.2012.01.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2011] [Accepted: 01/08/2012] [Indexed: 01/31/2023]
Abstract
Orthotopic liver transplantation (OLT) represents the only reliable therapeutic approach for acute liver failure (ALF), liver failure associated to end-stage chronic liver diseases (CLD) and non-metastatic liver cancer. The clinical impact of liver failure is relevant because of the still high ALF mortality and the increasing worldwide prevalence of cirrhosis that, in turn, is the main predisposing cause for hepatocellular carcinoma (HCC). Moreover, in the next decade because an increased number of patients reaching end-stage disease and requiring OLT may face a shortage of donor livers. This clinical scenario led several laboratories to explore the feasibility and efficiency of alternative approaches, involving cellular therapy, to counteract liver failure. The present chapter overviews results and concepts emerged from recent experimental and clinical studies in which adult or embryonic hepatocytes, hepatic stem/progenitor cells, induced pluripotent stem (iPS) cells as well as extrahepatic stem cells have been used as putative transplantable cell sources.
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Affiliation(s)
- Francesco P Russo
- Department of Surgical and Gastroenterological Sciences, Gastroenterology Unit, University of Padova, Padova, Italy.
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Tian J, Huang H, Hoffman B, Liebermann DA, Ledda-Columbano GM, Columbano A, Locker J. Gadd45β is an inducible coactivator of transcription that facilitates rapid liver growth in mice. J Clin Invest 2011; 121:4491-502. [PMID: 21965327 DOI: 10.1172/jci38760] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2011] [Accepted: 08/24/2011] [Indexed: 12/16/2022] Open
Abstract
The growth arrest and DNA damage-inducible 45 (Gadd45) proteins act in many cellular processes. In the liver, Gadd45b (encoding Gadd45β) is the gene most strongly induced early during both compensatory regeneration and drug-induced hyperplasia. The latter response is associated with the dramatic and rapid hepatocyte growth that follows administration of the xenobiotic TCPOBOP (1,4-bis[2-(3,5)-dichoropyridyloxy] benzene), a ligand of the nuclear receptor constitutive androstane receptor (CAR). Here, we have shown that Gadd45b-/- mice have intact proliferative responses following administration of a single dose of TCPOBOP, but marked growth delays. Moreover, early transcriptional stimulation of CAR target genes was weaker in Gadd45b-/- mice than in wild-type animals, and more genes were downregulated. Gadd45β was then found to have a direct role in transcription by physically binding to CAR, and TCPOBOP treatment caused both proteins to localize to a regulatory element for the CAR target gene cytochrome P450 2b10 (Cyp2b10). Further analysis defined separate Gadd45β domains that mediated binding to CAR and transcriptional activation. Although baseline hepatic expression of Gadd45b was broadly comparable to that of other coactivators, its 140-fold stimulation by TCPOBOP was striking and unique. The induction of Gadd45β is therefore a response that facilitates increased transcription, allowing rapid expansion of liver mass for protection against xenobiotic insults.
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Affiliation(s)
- Jianmin Tian
- Department of Pathology and Marion Bessin Liver Center, Albert Einstein College of Medicine, New York, New York, USA
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50
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Van Sweringen HL, Sakai N, Tevar AD, Burns JM, Edwards MJ, Lentsch AB. CXC chemokine signaling in the liver: impact on repair and regeneration. Hepatology 2011; 54:1445-53. [PMID: 21626524 PMCID: PMC3175305 DOI: 10.1002/hep.24457] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2011] [Accepted: 05/17/2011] [Indexed: 01/12/2023]
Abstract
The process of liver repair and regeneration following hepatic injury is complex and relies on a temporally coordinated integration of several key signaling pathways. Pathways activated by members of the CXC family of chemokines play important roles in the mechanisms of liver repair and regeneration through their effects on hepatocytes. However, little is known about the signaling pathways used by CXC chemokine receptors in hepatocytes. Here we review our current understanding of the pathways involved in both CXC chemokine receptor signaling in other cell types, most notably neutrophils, and similar pathways operant during hepatocyte proliferation/liver regeneration to formulate a basis for the function of CXC chemokine receptor signaling in hepatocytes.
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