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Ding H, Lv H, Sui M, Wang X, Sun Y, Tian M, Ma S, Xue Y, Zhang M, Wang X, Qi J, Wang L, Zhu Q. Interaction of neuropilin-1 and hepatocyte growth factor/C-Met pathway in liver fibrosis progression in hepatocyte-specific NRP-1 knockout mice. J Gastroenterol 2025:10.1007/s00535-025-02262-8. [PMID: 40419692 DOI: 10.1007/s00535-025-02262-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 04/29/2025] [Indexed: 05/28/2025]
Abstract
BACKGROUND Hepatocyte growth factor (HGF)/c-Met signaling critically influences liver fibrosis, but its interaction with neuropilin-1 (NRP-1) in hepatocytes remains unclear. We investigated the role of hepatocyte-specific NRP-1 deletion in liver fibrosis progression and its relationship with the HGF/c-Met pathway. METHODS Hepatocyte-specific NRP-1 knockout mice were generated using the Cre-lox system, and liver fibrosis was induced by carbon tetrachloride injections or a methionine- and choline-deficient diet. Fibrosis severity, hepatocyte injury, and cytokine secretion were evaluated via histology, biochemical assays, and molecular analyses in isolated hepatocytes. In vitro experiments were conducted in primary hepatocytes and Huh7 cells using lentiviral overexpression and knockdown of NRP-1. Chromatin immunoprecipitation and dual-luciferase reporter assays were performed to analyze transcription factor binding to the NRP-1 promoter. RESULTS Hepatocyte NRP-1 expression increased significantly during liver fibrosis and was positively correlated with HGF/c-Met expression and fibrosis severity. In vivo, NRP-1 inhibition reduced extracellular matrix accumulation and abnormal angiogenesis in Alb-Cre NRP-1f/f mice. In vitro, NRP-1 blockade inhibited c-Met activation and reduced transforming growth factor-beta and vascular endothelial growth factor secretion in hepatocytes. NRP-1 functioned as a co-receptor for HGF/c-Met, with HGF upregulating NRP-1 expression at transcript and protein levels. NRP-1 promoted fibrosis through the Met/extracellular signal-regulated kinase pathway. Furthermore, HGF increased retinoic acid receptor alpha expression, promoting NRP-1 transcription. CONCLUSIONS HGF-induced upregulation of hepatocyte NRP-1, mediated by RARA binding to its promoter, drives liver fibrosis through c-Met pathway activation, highlighting NRP-1 as a potential therapeutic target for liver fibrosis.
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Affiliation(s)
- Han Ding
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Huanran Lv
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Minghao Sui
- Department of Gastroenterology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Xinyu Wang
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Yanning Sun
- Urology Department, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Miaomiao Tian
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Shujun Ma
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Yuchan Xue
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Miao Zhang
- Department of Radiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Xin Wang
- Department of Ultrasound, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Jianni Qi
- Department of Key Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China
| | - Le Wang
- Department of Geriatrics, Department of Geriatric Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China.
| | - Qiang Zhu
- Department of Infectious Diseases, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Weiqi Road, Huaiyin District, Jinan City, Shandong Province, China.
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Abhinaya SV, Garg N, Sindwani G, Arora MK, Thapar S, Thomas S, Pamecha V, Sarin SK. Comparison of the effect of isoflurane and propofol on liver regeneration after donor hepatectomy - A randomized controlled trial. J Clin Anesth 2025; 104:111859. [PMID: 40347559 DOI: 10.1016/j.jclinane.2025.111859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 03/12/2025] [Accepted: 04/28/2025] [Indexed: 05/14/2025]
Abstract
BACKGROUND The biotransformation of inhalational anesthetic agents can result in production of hepatotoxic metabolites, which may potentially impair liver regeneration. Thus, isoflurane and propofol may have differential impacts on liver regeneration after donor hepatectomy. STUDY OBJECTIVE To compare the regeneration liver volume (RgLV) via computed tomography (CT) volumetry on post-operative day (POD) 14 in isoflurane and propofol groups. DESIGN Randomized controlled pilot trial. PATIENTS Sixty donors, who underwent donor hepatectomy. INTERVENTIONS Patients were randomized into isoflurane and propofol group using computer generated random number tables. In isoflurane group, anesthesia was maintained with isoflurane 1-2 % in air‑oxygen mixture. In propofol group, anesthesia was maintained with the target-controlled infusion (TCI) of propofol using a TCI system (Perfusor® Space- B. Braun) at a plasma target concentration of 3-6 μg.ml-1. BIS was recorded in all patients. MEASUREMENTS Liver CT volumetry was assessed at POD 14. MAIN RESULTS RgLV on POD14 was comparable in two groups [449.3(170) & 437.8 (177.8) cm3, [Mean Difference (MD) -11.904 95 % Confidence Interval(CI) -101.83, 78.03 respectively; p = 0.79]. CONCLUSION Administering propofol or isoflurane may not have differential effect on liver regeneration after donor hepatectomy.
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Affiliation(s)
- S V Abhinaya
- Department of Anaesthesia and Critical care, Institute of liver and biliary sciences, New Delhi, India
| | - Neha Garg
- Department of Anaesthesia, Institute of liver and biliary sciences, New Delhi, India.
| | - Gaurav Sindwani
- Department of Anaesthesia, Institute of liver and biliary sciences, New Delhi, India
| | - Mahesh Kumar Arora
- Department of Anaesthesia, Institute of liver and biliary sciences, New Delhi, India
| | - Shalini Thapar
- Department of Radiology, Institute of liver and biliary sciences, New Delhi, India
| | - Sherin Thomas
- Department of Biochemistry, Institute of liver and biliary sciences, New Delhi, India
| | - Viniyendra Pamecha
- Department of HPB Surgery, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Director and Chancellor, Institute of Liver and Biliary Sciences, New Delhi, India
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Vosough M, Shokouhian B, Sharbaf MA, Solhi R, Heidari Z, Seydi H, Hassan M, Devaraj E, Najimi M. Role of mitogens in normal and pathological liver regeneration. Hepatol Commun 2025; 9:e0692. [PMID: 40304568 PMCID: PMC12045551 DOI: 10.1097/hc9.0000000000000692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 01/31/2025] [Indexed: 05/02/2025] Open
Abstract
The liver has a unique ability to regenerate to meet the body's metabolic needs, even following acute or chronic injuries. The cellular and molecular mechanisms underlying normal liver regeneration have been well investigated to improve organ transplantation outcomes. Once liver regeneration is impaired, pathological regeneration occurs, and the underlying cellular and molecular mechanisms require further investigations. Nevertheless, a plethora of cytokines and growth factor-mediated pathways have been reported to modulate physiological and pathological liver regeneration. Regenerative mitogens play an essential role in hepatocyte proliferation. Accelerator mitogens in synergism with regenerative ones promote liver regeneration following hepatectomy. Finally, terminator mitogens restore the proliferating status of hepatocytes to a differentiated and quiescent state upon completion of regeneration. Chronic loss of hepatocytes, which can manifest in chronic liver disorders of any etiology, often has undesired structural consequences, including fibrosis, cirrhosis, and liver neoplasia due to the unregulated proliferation of remaining hepatocytes. In fact, any impairment in the physiological function of the terminator mitogens results in the progression of pathological liver regeneration. In the current review, we intend to highlight the updated cellular and molecular mechanisms involved in liver regeneration and discuss the impairments in central regulating mechanisms responsible for pathological liver regeneration.
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Affiliation(s)
- Massoud Vosough
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Bahare Shokouhian
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mohammad Amin Sharbaf
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Roya Solhi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Zahra Heidari
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Homeyra Seydi
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ezhilarasan Devaraj
- Department of Pharmacology, Hepatology and Molecular Medicine Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, India
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
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Zhang X, Li S, Hao L, Jia F, Yu F, Hu X. Influencing factors and mechanism of hepatocyte regeneration. J Transl Med 2025; 23:493. [PMID: 40307789 PMCID: PMC12042435 DOI: 10.1186/s12967-025-06278-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 02/20/2025] [Indexed: 05/02/2025] Open
Abstract
As a research hotspot in the field of regenerative medicine, hepatocyte regeneration has great potential in the treatment of liver diseases. This paper comprehensively summarizes the diverse sources of hepatocyte regeneration and its complex influencing factors, and deeply discusses the typical mechanism. According to the existing research, we observed that Wnt signaling pathway and Notch signaling pathway can play a synergistic role in the process of hepatocyte regeneration. So we further analyzed the crosstalk between Wnt and Notch signal pathway and the cross mechanism with TGF-β, YAP/TAZ pathway during regeneration. Despite the remarkable progress in the study of liver regeneration at the cellular and molecular levels, the comprehensive understanding of the fine regulation of influencing factors and the interaction between mechanisms still needs to be deepened. This paper aims to systematically analyze the interaction between influencing factors and classical mechanisms of hepatocyte regeneration by integrating multi-group data and advanced bioinformatics methods, so as to provide feasible ideas for the treatment of liver diseases and lay a solid theoretical foundation for the future development of regenerative medicine. It is believed that focusing on the rational development of innovative means such as inducing gene tendentiousness expression and anti-aging therapy, and in-depth analysis of the complex interactive network between hepatocyte regeneration mechanisms are expected to open up a new road for the development of more effective treatment strategies for liver diseases.
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Affiliation(s)
- Xiaoyi Zhang
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No.39, Shierqiao Road, Jinniu District, Chengdu, Sichuan, China
- Clinical Medical College of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Shenghao Li
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No.39, Shierqiao Road, Jinniu District, Chengdu, Sichuan, China
- Clinical Medical College of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Liyuan Hao
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No.39, Shierqiao Road, Jinniu District, Chengdu, Sichuan, China
- Clinical Medical College of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Fukang Jia
- Henan University of Traditional Chinese, Zhengzhou, China
| | - Fei Yu
- Chengdu University of Traditional Chinese Medicine, Chengdu, China
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No.39, Shierqiao Road, Jinniu District, Chengdu, Sichuan, China
- Clinical Medical College of Chengdu, University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaoyu Hu
- Chengdu University of Traditional Chinese Medicine, Chengdu, China.
- Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, No.39, Shierqiao Road, Jinniu District, Chengdu, Sichuan, China.
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Huang J, Chen H, Luo Z, Nie M, Wang J, Lu L, Zhao Y. Genetically Engineered Stromal Cell Exosomes from High-Throughput Herringbone Microfluidics. ACS NANO 2025; 19:10568-10577. [PMID: 40043164 DOI: 10.1021/acsnano.5c01773] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/19/2025]
Abstract
Stromal cell-derived exosomes have demonstrated their value in the field of biomedical engineering. However, the low production and specific requirements of different diseases limited the practical efficacy of these exosomes and restricted their wider applications. Here, we presented a method to culture genetically engineered mesenchymal stromal cells (MSC) that overexpressed the hepatocyte growth factor (HGF) in microfluidics and harvest mass HGF overexpressed exosomes for wound healing. The microfluidic chips were featured with herringbone grooves and micropillar arrays, where sufficient fluidic mechanical stimuli and efficient nutrient delivery were promoted by a turbulent vortex. It was demonstrated that the production of exosomes was much higher than by the traditional flask cell culture, along with higher HGF content. In addition, the MSCHGF-secreted exosomes were applied for wound healing in diabetic rat model, showing superior angiogenesis, cell migration, and immune modulation capabilities. These features indicated that the genetically engineered MSCHGF exosomes from high-throughput herringbone microfluidics possess great potential for wound healing and related biomedical applications.
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Affiliation(s)
- Junjie Huang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Hanxu Chen
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Zhiqiang Luo
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Min Nie
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Jinglin Wang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
| | - Ling Lu
- Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, Southeast University, Nanjing 210096, China
| | - Yuanjin Zhao
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China
- Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, Southeast University, Nanjing 210096, China
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Follert P, Große‐Segerath L, Lammert E. Blood flow-induced angiocrine signals promote organ growth and regeneration. Bioessays 2025; 47:e2400207. [PMID: 39529434 PMCID: PMC11755702 DOI: 10.1002/bies.202400207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 10/15/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024]
Abstract
Recently, we identified myeloid-derived growth factor (MYDGF) as a blood flow-induced angiocrine signal that promotes human and mouse hepatocyte proliferation and survival. Here, we review literature reporting changes in blood flow after partial organ resection in the liver, lung, and kidney, and we describe the angiocrine signals released by endothelial cells (ECs) upon blood flow alterations in these organs. While hepatocyte growth factor (HGF) and MYDGF are important angiocrine signals for liver regeneration, by now, angiocrine signals have also been reported to stimulate hyperplasia and/or hypertrophy during the regeneration of lungs and kidneys. In addition, angiocrine signals play a critical role in tumor growth. Understanding the mechano-elastic properties and flow-mediated alterations in the organ-specific microvasculature is crucial for therapeutic approaches to maintain organ health and initiate organ renewal.
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Affiliation(s)
- Paula Follert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
| | - Linda Große‐Segerath
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
- German Diabetes Center (DDZ)Leibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany
- German Center for Diabetes Research (DZD e.V.)NeuherbergGermany
| | - Eckhard Lammert
- Heinrich Heine University Düsseldorf, Faculty of Mathematics and Natural SciencesInstitute of Metabolic PhysiologyDüsseldorfGermany
- German Diabetes Center (DDZ)Leibniz Center for Diabetes Research at Heinrich Heine University DüsseldorfDüsseldorfGermany
- German Center for Diabetes Research (DZD e.V.)NeuherbergGermany
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Zhang S, Ma Y, Chen X, Wu S, Chen G. Circulating proliferative factors versus portal inflow redistribution: mechanistic insights of ALPPS-derived rapid liver regeneration. Front Oncol 2025; 14:1429564. [PMID: 39839786 PMCID: PMC11747645 DOI: 10.3389/fonc.2024.1429564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 12/10/2024] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) can induce accelerated regeneration of future liver remnant (FLR) and effectively reduce the occurrence of liver failure due to insufficient FLR after hepatectomy, thereby increasing the probability of radical resection for previously inoperable patients with liver cancer. However, the exact mechanism by which ALPPS accelerates liver regeneration remains elusive. METHODS A review of the literature was performed utilizing MEDLINE/PubMed and Web of Science databases in March of 2024. The key words "liver regeneration/hypertrophy", "portal vein ligation/embolization", "two-stage hepatectomy", "liver partition/split" and "future liver remnant" in combination with "mechanisms", "hemodynamics", "cytokines", "growth factors" or "collaterals" were searched in the title and/or abstract. The references of relevant articles were reviewed to identify additional eligible publications. RESULTS Previously, a widely accepted view is that the primary role of liver splitting in ALPPS stage 1 is to accelerate liver regeneration by promoting proliferative factor release, but increasing evidence in recent years reveal that not the circulating factors, but the portal hemodynamic alternations caused by liver parenchyma transection play a pivotal role in ALPPS-associated rapid liver hypertrophy. CONCLUSION Parenchyma transection-induced portal hemodynamic alternations are the main triggers or driving forces of accelerated liver regeneration following ALPPS. The release of circulating proliferative factors seems to be a secondary response to liver splitting and plays an auxiliary role in this process.
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Affiliation(s)
| | | | | | | | - Geng Chen
- Department of Hepatobiliary Surgery, Daping Hospital, Army Medical University, Chongqing, China
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Gao J, Lu Z, Liang W, Zhang J, Qin S, Huang J, Gong W, Xiang B. Safe Threshold Rate of Indocyanine Green Retention and Intervention of Nutrition Management After Hepatectomy. Nutr Cancer 2024; 77:372-379. [PMID: 39570005 DOI: 10.1080/01635581.2024.2431348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 11/12/2024] [Accepted: 11/13/2024] [Indexed: 11/22/2024]
Abstract
OBJECTIVE This study investigated the safe indocyanine green retention rate at the 15-minute (ICG-R15) threshold for hepatectomy and the effect of nutritional management on ICG-R15 and posthepatectomy liver failure (PHLF). METHODS A retrospective cohort study was conducted on 70 hepatectomy patients with chronic liver disease, divided into routine care and nutrition intervention groups. ICG-R15 was measured pre- and postoperatively, along with PHLF occurrence and other health metrics. RESULTS Seventy patients with chronic liver disease were divided into two groups: one received routine care, while the other followed a nutrition plan based on Omaha theory. The intervention group showed a significantly lower incidence of PHLF (15.8% vs 41.2%, p = 0.009) and clinically relevant PHLF (5.3% vs 19.6%, p = 0.031), along with shorter hospital stays (11.3 ± 6.4 days vs 21.5 ± 15.5 days, p = 0.012) and fewer complications (26.3% vs 47.1%, p = 0.020). The optimal ICG-R15 threshold for predicting PHLF was 4.5%, with 8.5% being critical. CONCLUSION ICG-R15 is a reliable predictor of PHLF, with 4.5% being safe and 8.5% critical. Nutritional management based on Omaha theory improves outcomes and quality of life. Further validation is needed.
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Affiliation(s)
- Junping Gao
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Zhan Lu
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Wanqiang Liang
- Department of General Surgery, Wuxiang Hospital of the Third Affiliated to, Guangxi Medical University, Nanning, China
| | - Jie Zhang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Shangdong Qin
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Juntao Huang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Wenfeng Gong
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
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Bedi O, Sapra V, Kumar M, Krishan P. Newer mitochondrial dynamics and their role of calcium signalling in liver regeneration. Mitochondrion 2024; 79:101969. [PMID: 39305943 DOI: 10.1016/j.mito.2024.101969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 09/09/2024] [Accepted: 09/18/2024] [Indexed: 11/18/2024]
Abstract
Liver regeneration is a crucial process involved in cellular proliferation, differentiation, and tissue repair. Calcium signaling impact key pathways like hepatocyte growth factor-Met-tyrosine kinase (HGF-Met) transduction pathway, the epidermal growth factor receptor (EGFR) signaling and Ca-mediated nuclear SKHep1 cell proliferation pathway. Intracellular hepatocyte calcium stores are considered as base for the induction of ca-mediated regeneration process. Calcium signaling interplays with HGF, TGF-β, and NF-κB signaling, influence stem cell behavior and triggers MAPK cascade. The mitochondria calcium is impacting on liver rejuvenation by regulating apoptosis and cell division. In conclusion, it is stated that calcium-signaling holds promise for therapeutic liver interventions.
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Affiliation(s)
- Onkar Bedi
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Vaibhav Sapra
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Manish Kumar
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Pawan Krishan
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
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Perry F, Johnson CN, Lahaye L, Santin E, Korver DR, Kogut MH, Arsenault RJ. Protected biofactors and antioxidants reduce the negative consequences of virus and cold challenge by modulating immunometabolism via changes in the interleukin-6 receptor signaling cascade in the liver. Poult Sci 2024; 103:104044. [PMID: 39043025 PMCID: PMC11325367 DOI: 10.1016/j.psj.2024.104044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/19/2024] [Accepted: 06/25/2024] [Indexed: 07/25/2024] Open
Abstract
Protected biofactors and antioxidants (PBA), and protected biofactors and antioxidants with protected organic acids and essential oils (PBA+POAEO) have been shown to have benefits in stressed or challenged birds. Here, we describe the immunometabolic changes observed in the liver of Ross 308 broilers during feed supplementation and brief physiological stress. These studied additives contain protected essential oils, organic acids, and vitamins which may have protective effects on the liver. Thus, we aimed to determine the signaling changes induced by these supplements and the resultant immunometabolic effects in the liver. All birds received a 2X dose of live bronchitis vaccine at d 0 and a 48-h cold challenge by reducing the temperature from 30 to 32°C, to 20 to 23°C on d 3 to 5. Control birds were fed a standard diet without supplementation. Liver samples were collected to evaluate the effects of these treatments on cytokine gene expression and protein phosphorylation via kinome peptide array. ANOVA was used for statistical analysis of the gene expression data (significance at a p-value of 0.05), and PIIKA2 was used for statistical evaluation and comparative analysis of the kinome peptide array data. At d 15, the kinome peptide array analysis and gene expression data showed stimulation of the interleukin 6 receptor (IL-6R) signal transduction for host protection via heightened immune response while inducing immune modulation and reducing inflammation in both supplement treated groups. Significant changes were observed via IL-6R signaling in the metabolic profiles of both groups compared to control and no significant differences when compared to each other. In the liver, these 2 feed additives induced immunometabolic changes predominantly via the IL-6 receptor family signaling cascade. Differences between the 2 treated groups were predominantly in the metabolic pathways, centered around the mTOR pathway and the proteins AMPK, mTOR and S6K, with a more anabolic phenotype following the addition of essential oils.
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Affiliation(s)
- F Perry
- Department of Animal and Food Sciences, University of Delaware, DE, USA
| | - C N Johnson
- USDA-ARS, Southern Plains Agricultural Research Center, College Station, TX, USA
| | - L Lahaye
- Jefo Nutrition Inc., Saint-Hyacinthe, Quebec, Canada
| | - E Santin
- I See Inside Institute, Curitiba, Paraná , Brazil
| | - D R Korver
- Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, AB, Canada
| | - M H Kogut
- USDA-ARS, Southern Plains Agricultural Research Center, College Station, TX, USA
| | - R J Arsenault
- Department of Animal and Food Sciences, University of Delaware, DE, USA.
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De Gasperi A, Petrò L, Amici O, Scaffidi I, Molinari P, Barbaglio C, Cibelli E, Penzo B, Roselli E, Brunetti A, Neganov M, Giacomoni A, Aseni P, Guffanti E. Major liver resections, perioperative issues and posthepatectomy liver failure: A comprehensive update for the anesthesiologist. World J Crit Care Med 2024; 13:92751. [PMID: 38855273 PMCID: PMC11155507 DOI: 10.5492/wjccm.v13.i2.92751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 03/15/2024] [Accepted: 05/07/2024] [Indexed: 06/03/2024] Open
Abstract
Significant advances in surgical techniques and relevant medium- and long-term outcomes over the past two decades have led to a substantial expansion in the indications for major liver resections. To support these outstanding results and to reduce perioperative complications, anesthesiologists must address and master key perioperative issues (preoperative assessment, proactive intraoperative anesthesia strategies, and implementation of the Enhanced Recovery After Surgery approach). Intensive care unit monitoring immediately following liver surgery remains a subject of active and often unresolved debate. Among postoperative complications, posthepatectomy liver failure (PHLF) occurs in different grades of severity (A-C) and frequency (9%-30%), and it is the main cause of 90-d postoperative mortality. PHLF, recently redefined with pragmatic clinical criteria and perioperative scores, can be predicted, prevented, or anticipated. This review highlights: (1) The systemic consequences of surgical manipulations anesthesiologists must respond to or prevent, to positively impact PHLF (a proactive approach); and (2) the maximal intensive treatment of PHLF, including artificial options, mainly based, so far, on Acute Liver Failure treatment(s), to buy time waiting for the recovery of the native liver or, when appropriate and in very selected cases, toward liver transplant. Such a clinical context requires a strong commitment to surgeons, anesthesiologists, and intensivists to work together, for a fruitful collaboration in a mandatory clinical continuum.
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Affiliation(s)
- Andrea De Gasperi
- Former Head, Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda ASST GOM Niguarda, Milan 20163, Italy
| | - Laura Petrò
- AR1, Ospedale Papa Giovanni 23, Bergamo 24100, Italy
| | - Ombretta Amici
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
| | - Ilenia Scaffidi
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
| | - Pietro Molinari
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
| | - Caterina Barbaglio
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
| | - Eva Cibelli
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
| | - Beatrice Penzo
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
| | - Elena Roselli
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
| | - Andrea Brunetti
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
| | - Maxim Neganov
- Anestesia e Terapia Intensiva Generale, Istituto Clinico Humanitas, Rozzano 20089, Italy
| | - Alessandro Giacomoni
- Chirurgia Oncologica Miniinvasiva, Grande Ospedale Metropolitano Niguarda ASST GOM Niguarda, Milan 20163, Italy
| | - Paolo Aseni
- Dipartimento di Medicina d’Urgenza ed Emergenza, Grande Ospedale Metropolitano Niguarda ASST GOM Niguarda, Milano 20163, MI, Italy
| | - Elena Guffanti
- Anesthesia and Critical Care Service 2, Grande Ospedale Metropolitano Niguarda AR2, ASST GOM Niguarda, Milan 20163, Italy
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12
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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13
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Nojima H, Shimizu H, Murakami T, Shuto K, Koda K. Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy. Cancers (Basel) 2024; 16:850. [PMID: 38473211 DOI: 10.3390/cancers16050850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/14/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases.
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Affiliation(s)
- Hiroyuki Nojima
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Hiroaki Shimizu
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Takashi Murakami
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Kiyohiko Shuto
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
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14
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Lopez-Lopez V, Linecker M, Caballero-Llanes A, Reese T, Oldhafer KJ, Hernandez-Alejandro R, Tun-Abraham M, Li J, Fard-Aghaie M, Petrowsky H, Brusadin R, Lopez-Conesa A, Ratti F, Aldrighetti L, Ramouz A, Mehrabi A, Autran Machado M, Ardiles V, De Santibañes E, Marichez A, Adam R, Truant S, Pruvot FR, Olthof PB, Van Gulick TM, Montalti R, Troisi RI, Kron P, Lodge P, Kambakamba P, Hoti E, Martinez-Caceres C, de la Peña-Moral J, Clavien PA, Robles-Campos R. Liver Histology Predicts Liver Regeneration and Outcome in ALPPS: Novel Findings From A Multicenter Study. Ann Surg 2024; 279:306-313. [PMID: 37487004 DOI: 10.1097/sla.0000000000006024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
BACKGROUND AND AIMS Alterations in liver histology influence the liver's capacity to regenerate, but the relevance of each of the different changes in rapid liver growth induction is unknown. This study aimed to analyze the influence of the degree of histological alterations during the first and second stages on the ability of the liver to regenerate. METHODS This cohort study included data obtained from the International ALPPS Registry between November 2011 and October 2020. Only patients with colorectal liver metastases were included in the study. We developed a histological risk score based on histological changes (stages 1 and 2) and a tumor pathology score based on the histological factors associated with poor tumor prognosis. RESULTS In total, 395 patients were included. The time to reach stage 2 was shorter in patients with a low histological risk stage 1 (13 vs 17 days, P ˂0.01), low histological risk stage 2 (13 vs 15 days, P <0.01), and low pathological tumor risk (13 vs 15 days, P <0.01). Regarding interval stage, there was a higher inverse correlation in high histological risk stage 1 group compared to low histological risk 1 group in relation with future liver remnant body weight ( r =-0.1 and r =-0.08, respectively), and future liver remnant ( r =-0.15 and r =-0.06, respectively). CONCLUSIONS ALPPS is associated with increased histological alterations in the liver parenchyma. It seems that the more histological alterations present and the higher the number of poor prognostic factors in the tumor histology, the longer the time to reach the second stage.
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Affiliation(s)
- Victor Lopez-Lopez
- Department of Surgery and Liver and Pancreas transplantation, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Michael Linecker
- Department of Surgery and Transplantation, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
| | - Albert Caballero-Llanes
- Department of Pathology, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Tim Reese
- Department of Surgery, Division of Liver, Bileduct and Pancreatic Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | - Karl J Oldhafer
- Department of Surgery, Division of Liver, Bileduct and Pancreatic Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | | | - Mauro Tun-Abraham
- Department of Surgery, Western University, London, Ontario, Canada
- Division of Transplantation/Hepatobiliary Surgery, Department of Surgery, University of Rochester, NY
| | - Jun Li
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mohammad Fard-Aghaie
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Henrik Petrowsky
- Department of Surgery and Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Zurich, Switzerland
| | - Roberto Brusadin
- Department of Surgery and Liver and Pancreas transplantation, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Asuncion Lopez-Conesa
- Department of Surgery and Liver and Pancreas transplantation, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Francesca Ratti
- Department of Surgery, Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, School of Medicine, Milan, Italy
| | - Luca Aldrighetti
- Department of Surgery, Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, School of Medicine, Milan, Italy
| | - Ali Ramouz
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Victoria Ardiles
- Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital Buenos Aires, Argentina
| | - Eduardo De Santibañes
- Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital Buenos Aires, Argentina
| | - Arthur Marichez
- Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France
| | - René Adam
- Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France
| | - Stéphanie Truant
- Department of Digestive Surgery and Transplantation, University Hospital, Lille, France
| | - Francois-René Pruvot
- Department of Digestive Surgery and Transplantation, University Hospital, Lille, France
| | - Pim B Olthof
- Department of Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Thomas M Van Gulick
- Department of Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Roberto Montalti
- Department of Clinical Medicine and Surgery, Federico II University Hospital Naples, Napoli, Italy
| | - Roberto I Troisi
- Department of Clinical Medicine and Surgery, Federico II University Hospital Naples, Napoli, Italy
| | - Philipp Kron
- HPB and Transplant Unit, St. James's University Hospital, Leeds, UK
| | - Peter Lodge
- HPB and Transplant Unit, St. James's University Hospital, Leeds, UK
| | - Patryk Kambakamba
- Department of Hepatobiliary Surgery and Liver Transplantation, St. Vincent's University Hospital, Dublin, Ireland
| | - Emir Hoti
- Department of Hepatobiliary Surgery and Liver Transplantation, St. Vincent's University Hospital, Dublin, Ireland
| | | | - Jesus de la Peña-Moral
- Department of Pathology, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Pierre-Alain Clavien
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ricardo Robles-Campos
- Department of Surgery and Liver and Pancreas transplantation, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
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15
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Zhang C, Sun C, Zhao Y, Ye B, Yu G. Signaling pathways of liver regeneration: Biological mechanisms and implications. iScience 2024; 27:108683. [PMID: 38155779 PMCID: PMC10753089 DOI: 10.1016/j.isci.2023.108683] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2023] Open
Abstract
The liver possesses a unique regenerative ability to restore its original mass, in this regard, partial hepatectomy (PHx) and partial liver transplantation (PLTx) can be executed smoothly and safely, which has important implications for the treatment of liver disease. Liver regeneration (LR) can be the very complicated procedure that involves multiple cytokines and transcription factors that interact with each other to activate different signaling pathways. Activation of these pathways can drive the LR process, which can be divided into three stages, namely, the initiation, progression, and termination stages. Therefore, it is important to investigate the pathways involved in LR to elucidate the mechanism of LR. This study reviews the latest research on the key signaling pathways in the different stages of LR.
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Affiliation(s)
- Chunyan Zhang
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Caifang Sun
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Yabin Zhao
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Bingyu Ye
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - GuoYing Yu
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
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16
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Ababneh SK, Siyam AA, Alqaraleh M, Al-Rawashde FA, Abbas MM, Ababneh S, Al-Othman N, Ababneh IK, Alkhatib AJ. Exploring the Role of Ki67 in the Liver of Diabetic Rats. Mater Sociomed 2024; 36:250-256. [PMID: 39963446 PMCID: PMC11830229 DOI: 10.5455/msm.2024.36.250-256] [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: 12/02/2024] [Accepted: 12/26/2024] [Indexed: 02/20/2025] Open
Abstract
Background Diabetes is not a single disease but rather, it is one aspect of metabolic syndrome. The pathologic aspects of diabetes involve cellular changes that need to be understood. Objective The main objective of this study was to explore the role of Ki67 in the liver of diabetic rats. Methods The study methodology involved the induction of diabetes in rats using Alloxan (120 mg/kg). A total of 20 albino rats were randomly assigned into two groups control group (N=10) and diabetes group (n=10). Diabetic group received the dose of alloxan, while the control group received similar dose of normal saline. Glucose level was monitored daily. After the end of the experiment (one -month period), all animals were terminated. Blood samples were taken to measure biochemical investigations including glucose, cholesterol, and triglycerides. Liver tissue was excised and washed with normal saline and fixed in buffered formalin (10%). Liver tissue was processed and stained by hematoxylin and eosin for routine histological examination and also stained by immunohistochemistry for Ki67 biomarker. Results The results revealed the efficacy of the diabetic model. All biochemical investigations were significantly higher in the diabetic group compared with that of control group (p<0.001). Histological studies showed the existence of morphological alterations in cells and fatty changes in the diabetic group compared with the control group. The expression of Ki67 was significantly higher in the diabetic group compared with that in the control group (p=0.011). Conclusion Taken together, diabetes has adverse effects on the spleen from a histological point of view, and from the expression of Ki67.
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Affiliation(s)
- Suha Khayri Ababneh
- Department of Allied Medical Sciences, Zarqa University College, Al-Balqa Applied University, Zarqa, Jordan
| | - Ali Abu Siyam
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Jadara University, Irbid, Jordan
| | - Moath Alqaraleh
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Balqa Applied University, Al-salt, Jordan
| | - Futoon Abedrabbu Al-Rawashde
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Balqa Applied University, Al-salt, Jordan
| | - Muna M. Abbas
- Department of Allied Medical Sciences, Zarqa University College, Al-Balqa Applied University, Zarqa, Jordan
| | - Sokiyna Ababneh
- Department of Allied Medical Sciences, Zarqa University College, Al-Balqa Applied University, Zarqa, Jordan
| | - Nihad Al-Othman
- Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, An-Najah National University, Palestine
| | - Islam Khayri Ababneh
- Nusaybah Al-Mazniyeh College for Midwifery, Nursing and Allied Medical Professions, Jordan
| | - Ahed J. Alkhatib
- Department of Legal Medicine, Toxicology and Forensic Medicine, Jordan University of Science and Technology, Jordan
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Nair DG, Weiskirchen R. Recent Advances in Liver Tissue Engineering as an Alternative and Complementary Approach for Liver Transplantation. Curr Issues Mol Biol 2023; 46:262-278. [PMID: 38248320 PMCID: PMC10814863 DOI: 10.3390/cimb46010018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 12/20/2023] [Accepted: 12/27/2023] [Indexed: 01/23/2024] Open
Abstract
Acute and chronic liver diseases cause significant morbidity and mortality worldwide, affecting millions of people. Liver transplantation is the primary intervention method, replacing a non-functional liver with a functional one. However, the field of liver transplantation faces challenges such as donor shortage, postoperative complications, immune rejection, and ethical problems. Consequently, there is an urgent need for alternative therapies that can complement traditional transplantation or serve as an alternative method. In this review, we explore the potential of liver tissue engineering as a supplementary approach to liver transplantation, offering benefits to patients with severe liver dysfunctions.
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Affiliation(s)
- Dileep G. Nair
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen, D-52074 Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), Rheinisch-Westfälische Technische Hochschule (RWTH) University Hospital Aachen, D-52074 Aachen, Germany
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18
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Mun SJ, Hong YH, Shin Y, Lee J, Cho HS, Kim DS, Chung KS, Son MJ. Efficient and reproducible generation of human induced pluripotent stem cell-derived expandable liver organoids for disease modeling. Sci Rep 2023; 13:22935. [PMID: 38129682 PMCID: PMC10739970 DOI: 10.1038/s41598-023-50250-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Accepted: 12/17/2023] [Indexed: 12/23/2023] Open
Abstract
Genetic liver disease modeling is difficult because it is challenging to access patient tissue samples and to develop practical and relevant model systems. Previously, we developed novel proliferative and functional liver organoids from pluripotent stem cells; however, the protocol requires improvement for standardization and reproducible mass production. Here, we improved the method such that it is suitable for scalable expansion and relatively homogenous production, resulting in an efficient and reproducible process. Moreover, three medium components critical for long-term expansion were defined. Detailed transcriptome analysis revealed that fibroblast growth factor signaling, the essential pathway for hepatocyte proliferation during liver regeneration, was mainly enriched in proliferative liver organoids. Short hairpin RNA-mediated knockdown of FGFR4 impaired the generation and proliferation of organoids. Finally, glycogen storage disease type Ia (GSD1a) patient-specific liver organoids were efficiently and reproducibly generated using the new protocol. They well maintained disease-specific phenotypes such as higher lipid and glycogen accumulation in the liver organoids and lactate secretion into the medium consistent with the main pathologic characteristics of patients with GSD1a. Therefore, our newly established liver organoid platform can provide scalable and practical personalized disease models and help to find new therapies for incurable liver diseases including genetic liver diseases.
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Affiliation(s)
- Seon Ju Mun
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Yeon-Hwa Hong
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Yongbo Shin
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea
| | - Jaeseo Lee
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Hyun-Soo Cho
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
- Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea
| | - Dae-Soo Kim
- Department of Bioinformatics, UST, 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea
- Department of Digital Biotech Innovation Center, KRIBB, 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea
| | - Kyung-Sook Chung
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea.
- Biomedical Translational Research Center, KRIBB, 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea.
| | - Myung Jin Son
- Stem Cell Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Gwahak-Ro, Yuseong-Gu, Daejeon, 34141, Republic of Korea.
- Department of Functional Genomics, Korea University of Science & Technology (UST), 217 Gajungro, Yuseong-Gu, Daejeon, 34113, Republic of Korea.
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19
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Almalla A, Elomaa L, Bechtella L, Daneshgar A, Yavvari P, Mahfouz Z, Tang P, Koksch B, Sauer I, Pagel K, Hillebrandt KH, Weinhart M. Papain-Based Solubilization of Decellularized Extracellular Matrix for the Preparation of Bioactive, Thermosensitive Pregels. Biomacromolecules 2023; 24:5620-5637. [PMID: 38009757 PMCID: PMC10716854 DOI: 10.1021/acs.biomac.3c00602] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 10/17/2023] [Accepted: 10/25/2023] [Indexed: 11/29/2023]
Abstract
Solubilized, gel-forming decellularized extracellular matrix (dECM) is used in a wide range of basic and translational research and due to its inherent bioactivity can promote structural and functional tissue remodeling. The animal-derived protease pepsin has become the standard proteolytic enzyme for the solubilization of almost all types of collagen-based dECM. In this study, pepsin was compared with papain, α-amylase, and collagenase for their potential to solubilize porcine liver dECM. Maximum preservation of bioactive components and native dECM properties was used as a decisive criterion for further application of the enzymes, with emphasis on minimal destruction of the protein structure and maintained capacity for physical thermogelation at neutral pH. The solubilized dECM digests, and/or their physically gelled hydrogels were characterized for their rheological properties, gelation kinetics, GAG content, proteomic composition, and growth factor profile. This study highlights papain as a plant-derived enzyme that can serve as a cost-effective alternative to animal-derived pepsin for the efficient solubilization of dECM. The resulting homogeneous papain-digested dECM preserved its thermally triggered gelation properties similar to pepsin digests, and the corresponding dECM hydrogels demonstrated their enhanced bioadhesiveness in single-cell force spectroscopy experiments with fibroblasts. The viability and proliferation of human HepaRG cells on dECM gels were similar to those on pure rat tail collagen type I gels. Papain is not only highly effective and economically attractive for dECM solubilization but also particularly interesting when digesting human-tissue-derived dECM for regenerative applications, where animal-derived materials are to be avoided.
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Affiliation(s)
- Ahed Almalla
- Institute
of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
| | - Laura Elomaa
- Institute
of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
| | - Leïla Bechtella
- Institute
of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
| | - Assal Daneshgar
- Experimental
Surgery, Department of Surgery, CCM|CVK, Charité − Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Prabhu Yavvari
- Institute
of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
| | - Zeinab Mahfouz
- Institute
of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
| | - Peter Tang
- Experimental
Surgery, Department of Surgery, CCM|CVK, Charité − Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Beate Koksch
- Institute
of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
| | - Igor Sauer
- Experimental
Surgery, Department of Surgery, CCM|CVK, Charité − Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Kevin Pagel
- Institute
of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
- Fritz
Haber Institute of the Max Planck Society, Faradayweg 4-6, 14195 Berlin, Germany
| | - Karl Herbert Hillebrandt
- Experimental
Surgery, Department of Surgery, CCM|CVK, Charité − Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin
Institute of Health at Charité − Universitätsmedizin
Berlin, BIH Biomedical Innovation Academy, BIH Charité, Clinician
Scientist Program, Charitéplatz
1, 10117 Berlin, Germany
| | - Marie Weinhart
- Institute
of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany
- Institute
of Physical Chemistry and Electrochemistry, Leibniz Universität
Hannover, 30167 Hannover, Germany
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20
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Oh KK, Choi I, Gupta H, Raja G, Sharma SP, Won SM, Jeong JJ, Lee SB, Cha MG, Kwon GH, Jeong MK, Min BH, Hyun JY, Eom JA, Park HJ, Yoon SJ, Choi MR, Kim DJ, Suk KT. New insight into gut microbiota-derived metabolites to enhance liver regeneration via network pharmacology study. ARTIFICIAL CELLS, NANOMEDICINE, AND BIOTECHNOLOGY 2023; 51:1-12. [PMID: 36562095 DOI: 10.1080/21691401.2022.2155661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/24/2022]
Abstract
We intended to identify favourable metabolite(s) and pharmacological mechanism(s) of gut microbiota (GM) for liver regeneration (LR) through network pharmacology. We utilized the gutMGene database to obtain metabolites of GM, and targets associated with metabolites as well as LR-related targets were identified using public databases. Furthermore, we performed a molecular docking assay on the active metabolite(s) and target(s) to verify the network pharmacological concept. We mined a total of 208 metabolites in the gutMGene database and selected 668 targets from the SEA (1,256 targets) and STP (947 targets) databases. Finally, 13 targets were identified between 61 targets and the gutMGene database (243 targets). Protein-protein interaction network analysis showed that AKT1 is a hub target correlated with 12 additional targets. In this study, we describe the potential microbe from the microbiota (E. coli), chemokine signalling pathway, AKT1 and myricetin that accelerate LR, providing scientific evidence for further clinical trials.
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Affiliation(s)
- Ki-Kwang Oh
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Ickwon Choi
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Haripriya Gupta
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Ganesan Raja
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Satya Priya Sharma
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Sung-Min Won
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Jin-Ju Jeong
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Su-Been Lee
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Min-Gi Cha
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Goo-Hyun Kwon
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Min-Kyo Jeong
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Byeong-Hyun Min
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Ji-Ye Hyun
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Jung-A Eom
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Hee-Jin Park
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Sang-Jun Yoon
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Mi-Ran Choi
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Dong Joon Kim
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
| | - Ki-Tae Suk
- Hallym University College of Medicine, Institute for Liver and Digestive Diseases, Chuncheon, Korea
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21
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Pan ES, Ermakova NN, Pershina OV, Pakhomova AV, Zhukova MA, Sandrikina LA, Kogai LV, Afanas'ev SA, Rebrova TY, Korepanov VA, Morozov SG, Kubitaev AA, Dygai AM, Skurikhin EG. Age-Related Features of the Early Period of Liver Regeneration after Partial Hepatectomy in Rats. Bull Exp Biol Med 2023; 176:150-155. [PMID: 38194075 DOI: 10.1007/s10517-024-05985-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Indexed: 01/10/2024]
Abstract
Regenerative processes in the liver were studied in 3-month-old (young) and 9-month-old (aged) male Wistar rats on day 1 after 30 and 70% hepatectomy. Regardless of the resected liver volume, shifts in the biochemical parameters of the serum in aged rats were more pronounced than in young animals. After 30% hepatectomy, no age differences in the rate of hepatic regeneration were found, while after 70% liver resection this parameter was higher in young rats. Hepatectomy in young rats led to recruitment of MSC, hepatocyte precursors, endothelial and epithelial progenitor cells into the liver parenchyma and increased fluidity of the plasma and mitochondrial membranes of hepatocytes. In aged rats, the recruitment of MSC, hepatocyte precursors, and endothelial progenitor cells into the injured liver was impaired and the rigidity of the mitochondrial membranes of hepatocytes increased.
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Affiliation(s)
- E S Pan
- E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.
| | - N N Ermakova
- E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - O V Pershina
- E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - A V Pakhomova
- E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - M A Zhukova
- E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - L A Sandrikina
- E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - L V Kogai
- E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - S A Afanas'ev
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - T Yu Rebrova
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - V A Korepanov
- Cardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - S G Morozov
- Research Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - A A Kubitaev
- Research Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - A M Dygai
- E. D. Goldberg Research Institute of Pharmacology and Regenerative Medicine, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
- Research Institute of General Pathology and Pathophysiology, Moscow, Russia
| | - E G Skurikhin
- Research Institute of General Pathology and Pathophysiology, Moscow, Russia
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22
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Jeong H, Lee C, Lee MJ, Jung Y. Therapeutic strategies to improve liver regeneration after hepatectomy. Exp Biol Med (Maywood) 2023; 248:1313-1318. [PMID: 37786387 PMCID: PMC10625346 DOI: 10.1177/15353702231191195] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/04/2023] Open
Abstract
Chronic liver disease is one of the most common diseases worldwide, and its prevalence is particularly high among adults aged 40-60 years; it takes a toll on productivity and causes significant economic burden. However, there are still no effective treatments that can fundamentally treat chronic liver disease. Although liver transplantation is considered the only effective treatment for chronic liver disease, it has limitations in that the pool of available donors is vastly insufficient for the number of potential recipients. Even if a patient undergoes liver transplantation, side effects such as immune rejection or bile duct complications could occur. In addition, impaired liver regeneration due to various causes, such as aging and metabolic disorders, may cause liver failure after liver resection, even leading to death. Therefore, further research on the liver regeneration process and therapeutic strategies to improve liver regeneration are needed. In this review, we describe the process of liver regeneration after hepatectomy, focusing on various cytokines and signaling pathways. In addition, we review treatment strategies that have been studied to date to improve liver regeneration, such as promotion of hepatocyte proliferation and metabolism and transplantation of mesenchymal stem cells. This review helps to understand the physiological processes involved in liver regeneration and provides basic knowledge for developing treatments for successful liver regeneration.
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Affiliation(s)
- Hayeong Jeong
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
| | - Chanbin Lee
- Institute of Systems Biology, College of Natural Science, Pusan National University, Pusan 46241, Korea
| | - Min Jae Lee
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, Pusan 46241, Korea
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23
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Maruyama M, Takaki H, Yamada N, Hirata Y, Yamakado K, Kitagaki H. Liver regeneration after portal vein embolization: comparison between absolute ethanol and N-butyl-cyanoacrylate in an in vivo rat model. Diagn Interv Radiol 2023; 29:621-627. [PMID: 36994506 PMCID: PMC10679635 DOI: 10.4274/dir.2022.211144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 05/25/2022] [Indexed: 01/15/2023]
Abstract
PURPOSE To compare the effects of absolute ethanol (ethanol) and N-butyl-cyanoacrylate (NBCA) on non-embolized liver lobe regeneration in a rat model. METHODS Twenty-seven Sprague-Dawley rats underwent portal vein embolization (PVE) using ethanol:lipiodol, 1:1 (ethanol group, n = 11, 40.74%), NBCA:lipiodol, 1:1 (NBCA group, n = 11, 40.74%), or sham treatment (sham group, n = 5, 18.52%). The non-embolized and embolized lobe-to-whole liver weight ratios 14 days after PVE were compared among the groups (n = 5, 18.52%). The expressions of CD68 and Ki-67 and embolized-lobe necrotic area percentages one day after PVE were compared between the ethanol (n = 3, 11.11%) and NBCA (n = 3, 11.11%) groups. RESULTS The non-embolized lobe-to-whole liver weight ratio after PVE was significantly higher in the NBCA group (n = 5, 33.33%) than in the ethanol group (n = 5, 33.33%) (84.28% ± 1.53% vs. 76.88% ± 4.12%, P = 0.029). The embolized lobe-to-whole liver weight ratio after PVE was significantly lower in the NBCA group than in the ethanol group (15.72% ± 1.53% vs. 23.12% ± 4.12%, P = 0.029). The proportions of CD68- and Ki-67-positive cells in the non-embolized lobe after PVE were significantly higher in the NBCA group (n = 30, 50%) than in the ethanol group (n = 30, 50%) [60 (48-79) vs. 55 (37-70), P = 0.003; 1 (0-2) vs. 1 (0-2), P = 0.004]. The embolized-lobe necrotic area percentage after PVE was significantly larger in the NBCA group (n = 30, 50%) than in the ethanol group (n = 30, 50%) [29.46 (12.56-83.90%) vs. 16.34 (3.22-32.0%), P < 0.001]. CONCLUSION PVE with NBCA induced a larger necrotic area in the embolized lobe and promoted greater non-embolized liver lobe regeneration compared with PVE with ethanol.
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Affiliation(s)
- Mitsunari Maruyama
- Department of Radiology, Shimane University Faculty of Medicine Enya-cho Izumo, Japan
| | - Haruyuki Takaki
- Department of Radiology, Hyogo College of Medicine, Hyogo, Japan
| | - Naoko Yamada
- Department of Pathology, Hyogo College of Medicine, Hyogo, Japan
| | - Yutaka Hirata
- Division of Physiome, Department of Physiology, Hyogo College of Medicine, Hyogo, Japan
| | | | - Hajime Kitagaki
- Department of Radiology, Shimane University Faculty of Medicine Enya-cho Izumo, Japan
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24
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Ballesteros-Pla C, Sánchez-Alonso MG, Pizarro-Delgado J, Zuccaro A, Sevillano J, Ramos-Álvarez MP. Pleiotrophin and metabolic disorders: insights into its role in metabolism. Front Endocrinol (Lausanne) 2023; 14:1225150. [PMID: 37484951 PMCID: PMC10360176 DOI: 10.3389/fendo.2023.1225150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 06/26/2023] [Indexed: 07/25/2023] Open
Abstract
Pleiotrophin (PTN) is a cytokine which has been for long studied at the level of the central nervous system, however few studies focus on its role in the peripheral organs. The main aim of this review is to summarize the state of the art of what is known up to date about pleiotrophin and its implications in the main metabolic organs. In summary, pleiotrophin promotes the proliferation of preadipocytes, pancreatic β cells, as well as cells during the mammary gland development. Moreover, this cytokine is important for the structural integrity of the liver and the neuromuscular junction in the skeletal muscle. From a metabolic point of view, pleiotrophin plays a key role in the maintenance of glucose and lipid as well as whole-body insulin homeostasis and favors oxidative metabolism in the skeletal muscle. All in all, this review proposes pleiotrophin as a druggable target to prevent from the development of insulin-resistance-related pathologies.
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25
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Deng Y, Zhao Z, Sheldon M, Zhao Y, Teng H, Martinez C, Zhang J, Lin C, Sun Y, Yao F, Zhu H, Ma L. LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.03.18.533289. [PMID: 36993315 PMCID: PMC10055204 DOI: 10.1101/2023.03.18.533289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro . In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3- CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage- induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver.
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26
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Luque LM, Carlevaro CM, Llamoza Torres CJ, Lomba E. Physics-based tissue simulator to model multicellular systems: A study of liver regeneration and hepatocellular carcinoma recurrence. PLoS Comput Biol 2023; 19:e1010920. [PMID: 36877741 PMCID: PMC10019748 DOI: 10.1371/journal.pcbi.1010920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/16/2023] [Accepted: 02/03/2023] [Indexed: 03/07/2023] Open
Abstract
We present a multiagent-based model that captures the interactions between different types of cells with their microenvironment, and enables the analysis of the emergent global behavior during tissue regeneration and tumor development. Using this model, we are able to reproduce the temporal dynamics of regular healthy cells and cancer cells, as well as the evolution of their three-dimensional spatial distributions. By tuning the system with the characteristics of the individual patients, our model reproduces a variety of spatial patterns of tissue regeneration and tumor growth, resembling those found in clinical imaging or biopsies. In order to calibrate and validate our model we study the process of liver regeneration after surgical hepatectomy in different degrees. In the clinical context, our model is able to predict the recurrence of a hepatocellular carcinoma after a 70% partial hepatectomy. The outcomes of our simulations are in agreement with experimental and clinical observations. By fitting the model parameters to specific patient factors, it might well become a useful platform for hypotheses testing in treatments protocols.
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Affiliation(s)
- Luciana Melina Luque
- Instituto de Física de Líquidos y Sistemas Biológicos - CONICET. La Plata, Argentina
- * E-mail: (LML); (CMC)
| | - Carlos Manuel Carlevaro
- Instituto de Física de Líquidos y Sistemas Biológicos - CONICET. La Plata, Argentina
- Departamento de Ingeniería Mecánica, Universidad Tecnológica Nacional, Facultad Regional La Plata, La Plata, Argentina
- * E-mail: (LML); (CMC)
| | | | - Enrique Lomba
- Instituto de Química Física Rocasolano - CSIC. Madrid, España
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27
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Li X, Li H, Zhu Y, Xu H, Tang S. PLT Counts as a Predictive Marker after Plasma Exchange in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure. J Clin Med 2023; 12:jcm12030851. [PMID: 36769497 PMCID: PMC9917441 DOI: 10.3390/jcm12030851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND AND OBJECTIVES The platelet (PLT) value in hepatitis B-related acute-on-chronic liver failure (HBV-ACLF) is not sufficiently understood. The present study aimed to evaluate the prognostic effect of PLT on the prediction of HBV-ACLF outcomes after plasma exchange (PE). METHODS HBV-ACLF patients treated with PE between January 2017 and August 2021 were followed up for at least 6 months. Cox regression was performed to develop the predictive model, and the model's performance was analyzed using the receiver operating characteristic curve (ROC). RESULTS A total of 170 patients were included. The overall survival rate within 180 days was 75.88%. Age, PLT, total bilirubin (TBil), and the iMELD scores were independent risk factors affecting the prognosis of HBV-ACLF patients after PE. According to the Cox regression results, the new model was calculated: R = 0.142 × iMELD-0.009 × PLT. The area under the curve (AUC) of the receiver operating characteristic curve (ROC) was 0.758 (95% CI 0.678-0.838), and patients with lower PLT-iMELD scores (<4.50) had a better prognosis (p < 0.001). CONCLUSION PLT is a valuable prognostic biomarker for HBV-ACLF patients after PE. The modified iMELD model incorporating PLT has a better sensitivity and efficacy in predicting the prognosis of patients.
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Affiliation(s)
- Xue Li
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu 610083, China
| | - Hao Li
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu 610083, China
| | - Yucui Zhu
- Clinic, The General Hospital of Western Theater Command, Chengdu 610083, China
| | - Huaqian Xu
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu 610083, China
| | - Shanhong Tang
- Department of Gastroenterology, The General Hospital of Western Theater Command, Chengdu 610083, China
- Correspondence: ; Tel.: +86-028-8657-1191
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28
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Di-Iacovo N, Pieroni S, Piobbico D, Castelli M, Scopetti D, Ferracchiato S, Della-Fazia MA, Servillo G. Liver Regeneration and Immunity: A Tale to Tell. Int J Mol Sci 2023; 24:1176. [PMID: 36674692 PMCID: PMC9864482 DOI: 10.3390/ijms24021176] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.
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Affiliation(s)
- Nicola Di-Iacovo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Stefania Pieroni
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Danilo Piobbico
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Marilena Castelli
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Damiano Scopetti
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Simona Ferracchiato
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Maria Agnese Della-Fazia
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Giuseppe Servillo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
- Centro Universitario di Ricerca sulla Genomica Funzionale (C.U.R.Ge.F.), University of Perugia, 06123 Perugia, Italy
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29
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Seidemann L, Prinz S, Scherbel JC, Götz C, Seehofer D, Damm G. Optimization of extracellular matrix for primary human hepatocyte cultures using mixed collagen-Matrigel matrices. EXCLI JOURNAL 2023; 22:12-34. [PMID: 36660192 PMCID: PMC9837384 DOI: 10.17179/excli2022-5459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/17/2022] [Indexed: 01/21/2023]
Abstract
Loss of differentiation of primary human hepatocytes (PHHs) ex vivo is a known problem of in vitro liver models. Culture optimizations using collagen type I and Matrigel reduce the dedifferentiation process but are not able to prevent it. While neither of these extracellular matrices (ECMs) on their own correspond to the authentic hepatic ECM, a combination of them could more closely resemble the in vivo situation. Our study aimed to systematically analyze the influence of mixed matrices composed of collagen type I and Matrigel on the maintenance and reestablishment of hepatic functions. Therefore, PHHs were cultured on mixed collagen-Matrigel matrices in monolayer and sandwich cultures and viability, metabolic capacity, differentiation markers, cellular arrangement and the cells' ability to repolarize and form functional bile canaliculi were assessed by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), functional assays and immunofluorescence microscopy. Our results show that mixed matrices were superior to pure matrices in maintaining metabolic capacity and hepatic differentiation. In contrast, Matrigel supplementation can impair the development of a proper hepatocytic polarization. Our systematic study helps to compose an optimized ECM to maintain and reestablish hepatic differentiation on cellular and multicellular levels in human liver models.
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Affiliation(s)
- Lena Seidemann
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Liebigstr. 20, 04103 Leipzig, Germany,Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
| | - Sarah Prinz
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Liebigstr. 20, 04103 Leipzig, Germany,Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
| | - Jan-Constantin Scherbel
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Liebigstr. 20, 04103 Leipzig, Germany,Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
| | - Christina Götz
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Liebigstr. 20, 04103 Leipzig, Germany,Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Liebigstr. 20, 04103 Leipzig, Germany,Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Liebigstr. 20, 04103 Leipzig, Germany,Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany,*To whom correspondence should be addressed: Georg Damm, Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, Liebigstr. 20, 04103 Leipzig, Germany; Tel.: +49-341-9739656, E-mail:
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30
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Pozzobon M, D’Agostino S, Roubelakis MG, Cargnoni A, Gramignoli R, Wolbank S, Gindraux F, Bollini S, Kerdjoudj H, Fenelon M, Di Pietro R, Basile M, Borutinskaitė V, Piva R, Schoeberlein A, Eissner G, Giebel B, Ponsaerts P. General consensus on multimodal functions and validation analysis of perinatal derivatives for regenerative medicine applications. Front Bioeng Biotechnol 2022; 10:961987. [PMID: 36263355 PMCID: PMC9574482 DOI: 10.3389/fbioe.2022.961987] [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: 06/05/2022] [Accepted: 07/01/2022] [Indexed: 11/26/2022] Open
Abstract
Perinatal tissues, such as placenta and umbilical cord contain a variety of somatic stem cell types, spanning from the largely used hematopoietic stem and progenitor cells to the most recently described broadly multipotent epithelial and stromal cells. As perinatal derivatives (PnD), several of these cell types and related products provide an interesting regenerative potential for a variety of diseases. Within COST SPRINT Action, we continue our review series, revising and summarizing the modalities of action and proposed medical approaches using PnD products: cells, secretome, extracellular vesicles, and decellularized tissues. Focusing on the brain, bone, skeletal muscle, heart, intestinal, liver, and lung pathologies, we discuss the importance of potency testing in validating PnD therapeutics, and critically evaluate the concept of PnD application in the field of tissue regeneration. Hereby we aim to shed light on the actual therapeutic properties of PnD, with an open eye for future clinical application. This review is part of a quadrinomial series on functional/potency assays for validation of PnD, spanning biological functions, such as immunomodulation, anti-microbial/anti-cancer, anti-inflammation, wound healing, angiogenesis, and regeneration.
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Affiliation(s)
- Michela Pozzobon
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Stefania D’Agostino
- Department of Women’s and Children’s Health, University of Padova, Padova, Italy
| | - Maria G. Roubelakis
- Laboratory of Biology, Medical School of Athens, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Cargnoni
- Centro di Ricerca E. Menni, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Susanne Wolbank
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, The Research Center in Cooperation with AUVA Trauma Research Center, Austrian Cluster for Tissue Regeneration, Vienna, Austria
| | - Florelle Gindraux
- Service de Chirurgie Orthopédique, Traumatologique et plastique, CHU Besançon, Laboratoire de Nanomédecine, Imagerie, Thérapeutique EA 4662, University Bourgogne Franche-Comté, Besançon, France
| | - Sveva Bollini
- Department of Experimental Medicine (DIMES), School of Medical and Pharmaceutical Sciences, University of Genova, Genova, Italy
| | - Halima Kerdjoudj
- University of Reims Champagne Ardenne, EA 4691 BIOS “Biomatériaux et Inflammation en Site Osseux”, UFR d’Odontologie, Reims, France
| | | | - Roberta Di Pietro
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Mariangela Basile
- Department of Medicine and Ageing Sciences, Section of Biomorphology, G. d'Annunzio University of Chieti-Pescara, Chieti, Italy
| | - Veronika Borutinskaitė
- Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, Vilnius, Lithuania
| | - Roberta Piva
- Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy
| | - Andreina Schoeberlein
- Department of Obstetrics and Feto-maternal Medicine, Inselspital, Bern University Hospital, Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
| | - Guenther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Bernd Giebel
- Institute for Transfusion Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerp, Belgium
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31
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De la Cruz Ku G, Aizpuru M, Hackl H, Ubl DS, Habermann EB, Pery R, Driedger M, Assinger A, Nagorney DM, Cleary SP, Smoot RL, Starlinger P. Hepatocellular carcinoma as predominant cancer subgroup accounting for sex differences in post-hepatectomy liver failure, morbidity and mortality. HPB (Oxford) 2022; 24:1453-1463. [PMID: 35293321 DOI: 10.1016/j.hpb.2022.02.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/11/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Experimental evidence suggests sex dependent differences in liver regeneration. Limited evidence is available examining sex differences in post-hepatectomy liver failure (PHLF) and postoperative outcomes. Our aim was to assess the influence of sex on the outcomes after liver resection. METHODS The hepatectomy targeted National Surgical Quality Improvement Program (NSQIP) database was assessed for associations between sex and outcomes. RESULTS A total of 13,401 patients underwent elective hepatic resection between 2014-2017. PHLF was highest among male patients with hepatocellular carcinoma (HCC) (OR = 2.81,95%CI:1.40-5.62). Male sex was independently associated with increased PHLF (OR = 1.47,95%CI:1.15-1.88), major complications (OR = 1.25,95%CI:1.08-1.45), mortality (OR = 1.61,95%CI:1.03-2.50), and if only major resections were assessed (OR = 1.38,95%CI:1.03-1.84). Diagnosis specific subgroup analyses revealed that effects of sex were predominantly HCC associated. CONCLUSIONS This is the largest series investigating the effects of gender on outcomes after hepatic resection. We documented that women undergoing liver resection have significantly lower risk of PHLF. This difference seemed influenced by the striking increase of PHLF in male HCC patients. These hypothesis suggest that sex might play a role in preoperative risk stratification.
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Affiliation(s)
- Gabriel De la Cruz Ku
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA; Universidad Cientifica del Sur, Lima, Peru
| | - Matthew Aizpuru
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Hubert Hackl
- Institute of Bioinformatics, Biocenter, Medical University of Innsbruck, Austria
| | - Daniel S Ubl
- Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery and Department of Health Services Research, Mayo Clinic, Rochester, USA
| | - Elizabeth B Habermann
- Mayo Clinic Robert D and Patricia E Kern Center for the Science of Health Care Delivery and Department of Health Services Research, Mayo Clinic, Rochester, USA
| | - Ron Pery
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Michael Driedger
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Alice Assinger
- Center of Physiology and Pharmacology, Institute of Vascular Biology and Thrombosis Research, Austria
| | - David M Nagorney
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Sean P Cleary
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Rory L Smoot
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
| | - Patrick Starlinger
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Surgery, Medical University of Vienna, General Hospital, Vienna, Austria.
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Dehlke K, Krause L, Tyufekchieva S, Murtha-Lemekhova A, Mayer P, Vlasov A, Klingmüller U, Mueller NS, Hoffmann K. Predicting liver regeneration following major resection. Sci Rep 2022; 12:13396. [PMID: 35927556 PMCID: PMC9352754 DOI: 10.1038/s41598-022-16968-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 07/19/2022] [Indexed: 11/09/2022] Open
Abstract
Breakdown of synthesis, excretion and detoxification defines liver failure. Post-hepatectomy liver failure (PHLF) is specific for liver resection and a rightfully feared complication due to high lethality and limited therapeutic success. Individual cytokine and growth factor profiles may represent potent predictive markers for recovery of liver function. We aimed to investigate these profiles in post-hepatectomy regeneration. This study combined a time-dependent cytokine and growth factor profiling dataset of a training (30 patients) and a validation (14 patients) cohorts undergoing major liver resection with statistical and predictive models identifying individual pathway signatures. 2319 associations were tested. Primary hepatocytes isolated from patient tissue samples were stimulated and their proliferation was analysed through DNA content assay. Common expression trajectories of cytokines and growth factors with strong correlation to PHLF, morbidity and mortality were identified despite highly individual perioperative dynamics. Especially, dynamics of EGF, HGF, and PLGF were associated with mortality. PLGF was additionally associated with PHLF and complications. A global association-network was calculated and validated to investigate interdependence of cytokines and growth factors with clinical attributes. Preoperative cytokine and growth factor signatures were identified allowing prediction of mortality following major liver resection by regression modelling. Proliferation analysis of corresponding primary human hepatocytes showed associations of individual regenerative potential with clinical outcome. Prediction of PHLF was possible on as early as first postoperative day (POD1) with AUC above 0.75. Prediction of PHLF and mortality is possible on POD1 with liquid-biopsy based risk profiling. Further utilization of these models would allow tailoring of interventional strategies according to individual profiles.
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Affiliation(s)
- Karolin Dehlke
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Linda Krause
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany
| | - Silvana Tyufekchieva
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Anastasia Murtha-Lemekhova
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Philipp Mayer
- Department of Diagnostic and Interventional Radiology, Ruprecht Karls University, 69120, Heidelberg, Germany
| | - Artyom Vlasov
- Division of Systems Biology of Signal Transduction, German Cancer Research Center, 69120, Heidelberg, Germany
| | - Ursula Klingmüller
- Division of Systems Biology of Signal Transduction, German Cancer Research Center, 69120, Heidelberg, Germany
| | - Nikola S Mueller
- Institute of Computational Biology, Helmholtz Center Munich, Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
| | - Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
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33
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Nehme A, Ghahramanpouri M, Ahmed I, Golsorkhi M, Thomas N, Munoz K, Abdipour A, Tang X, Wilson SM, Wasnik S, Baylink DJ. Combination therapy of insulin-like growth factor I and BTP-2 markedly improves lipopolysaccharide-induced liver injury in mice. FASEB J 2022; 36:e22444. [PMID: 35839071 DOI: 10.1096/fj.202200227rr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 06/14/2022] [Accepted: 06/27/2022] [Indexed: 01/06/2023]
Abstract
Acute liver injury is a common disease without effective therapy in humans. We sought to evaluate a combination therapy of insulin-like growth factor 1 (IGF-I) and BTP-2 in a mouse liver injury model induced by lipopolysaccharide (LPS). We chose this model because LPS is known to increase the expression of the transcription factors related to systemic inflammation (i.e., NFκB, CREB, AP1, IRF 3, and NFAT), which depends on calcium signaling. Notably, these transcription factors all have pleiotropic effects and account for the other observed changes in tissue damage parameters. Additionally, LPS is also known to increase the genes associated with a tissue injury (e.g., NGAL, SOD, caspase 3, and type 1 collagen) and systemic expression of pro-inflammatory cytokines. Finally, LPS compromises vascular integrity. Accordingly, IGF-I was selected because its serum levels were shown to decrease during systemic inflammation. BTP-2 was chosen because it was known to decrease cytosolic calcium, which is increased by LPS. This current study showed that IGF-I, BTP-2, or a combination therapy significantly altered and normalized all of the aforementioned LPS-induced gene changes. Additionally, our therapies reduced the vascular leakage caused by LPS, as evidenced by the Evans blue dye technique. Furthermore, histopathologic studies showed that IGF-I decreased the proportion of hepatocytes with ballooning degeneration. Finally, IGF-I also increased the expression of the hepatic growth factor (HGF) and the receptor for the epidermal growth factor (EGFR), markers of liver regeneration. Collectively, our data suggest that a combination of IGF-I and BTP-2 is a promising therapy for acute liver injury.
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Affiliation(s)
- Antoine Nehme
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA
| | - Mahdis Ghahramanpouri
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA
| | - Iqbal Ahmed
- Pathology and Laboratory Medicine, Loma Linda University, Loma Linda, California, USA
| | - Mohadese Golsorkhi
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA
| | | | - Kevin Munoz
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA
| | - Amir Abdipour
- Division of Nephrology, Loma Linda University Medical Center, Loma Linda, California, USA
| | - Xiaolei Tang
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA.,Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, New York, USA
| | - Sean M Wilson
- The Lawrence D. Longo, MD Center for Perinatal Biology, Department of Basic Sciences, Loma Linda University School of Medicine, Loma Linda, California, USA
| | - Samiksha Wasnik
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA
| | - David J Baylink
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, California, USA
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Wu J, Liu H, Wang H, Wang Y, Cheng Q, Zhao R, Gao H, Fang L, Zhu F, Xue B. iTRAQ-based quantitative proteomic analysis of the liver regeneration termination phase after partial hepatectomy in mice. J Proteomics 2022; 267:104688. [PMID: 35914716 DOI: 10.1016/j.jprot.2022.104688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/09/2022] [Accepted: 07/25/2022] [Indexed: 01/17/2023]
Abstract
Liver regeneration (LR) is an important biological process after liver injury. As the "brake" in the process of LR, the termination phase of LR not only suppresses the continuous increase in liver volume but also effectively promotes the recovery of liver function. However, the mechanisms underlying the termination phase of LR are still not clear. In our study, we used isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomic analysis to determine the protein expression profiles of livers in the termination phase of mouse LR after partial hepatectomy (PH). We found that the expression of 197 proteins increased gradually during LR; in addition, 187 proteins were upregulated and 264 proteins were downregulated specifically in the termination phase of LR. The GO analysis of the proteins revealed the upregulation of "cell-cell adhesion" and "translation" and the downregulation of the "oxidation-reduction process". The KEGG pathway analysis showed that "biosynthesis of antibiotics" and "ribosomes" were significantly upregulated, while "metabolic pathways" were significantly downregulated. These analyses indicated that the termination phase of LR mainly focuses on restoring cellular structure and function. Differentially expressed proteins such as SNX5 were also screened out from biological processes. SIGNIFICANCE: The key regulatory factors in the termination phase of LR were studied by iTRAQ-based proteomics to lay a foundation for further study of the molecular mechanism and biomarkers of the termination phase of LR. This study will guide the clinical perioperative management of patients after hepatectomy.
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Affiliation(s)
- Jing Wu
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
| | - He Liu
- General surgery Department, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Haiquan Wang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - Yuqi Wang
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Qi Cheng
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China
| | - Ruochen Zhao
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Hongliang Gao
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China
| | - Lei Fang
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing 210093, China.
| | - Feng Zhu
- General surgery Department, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
| | - Bin Xue
- Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing 211166, China.
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35
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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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36
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Zhao Y, Ye W, Wang YD, Chen WD. HGF/c-Met: A Key Promoter in Liver Regeneration. Front Pharmacol 2022; 13:808855. [PMID: 35370682 PMCID: PMC8968572 DOI: 10.3389/fphar.2022.808855] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 02/11/2022] [Indexed: 01/18/2023] Open
Abstract
Hepatocyte growth factor (HGF) is a peptide-containing multifunctional cytokine that acts on various epithelial cells to regulate cell growth, movement and morphogenesis, and tissue regeneration of injured organs. HGF is sequestered by heparin-like protein in its inactive form and is widespread in the extracellular matrix of most tissues. When the liver loses its average mass, volume, or physiological and biochemical functions due to various reasons, HGF binds to its specific receptor c-Met (cellular mesenchymal-epithelial transition) and transmits the signals into the cells, and triggers the intrinsic kinase activity of c-Met. The downstream cascades of HGF/c-Met include JAK/STAT3, PI3K/Akt/NF-κB, and Ras/Raf pathways, affecting cell proliferation, growth, and survival. HGF has important clinical significance for liver fibrosis, hepatocyte regeneration after inflammation, and liver regeneration after transplantation. And the development of HGF as a biological drug for regenerative therapy of diseases, that is, using recombinant human HGF protein to treat disorders in clinical trials, is underway. This review summarizes the recent findings of the HGF/c-Met signaling functions in liver regeneration.
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Affiliation(s)
- Yang Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation, The People's Hospital of Hebi, School of Medicine, Henan University, Kaifeng, China
| | - Wenling Ye
- Key Laboratory of Receptors-Mediated Gene Regulation, The People's Hospital of Hebi, School of Medicine, Henan University, Kaifeng, China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation, The People's Hospital of Hebi, School of Medicine, Henan University, Kaifeng, China
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37
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Extraembryonic Mesenchymal Stromal/Stem Cells in Liver Diseases: A Critical Revision of Promising Advanced Therapy Medicinal Products. Cells 2022; 11:cells11071074. [PMID: 35406638 PMCID: PMC8997603 DOI: 10.3390/cells11071074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/17/2022] [Accepted: 03/21/2022] [Indexed: 02/04/2023] Open
Abstract
Liver disorders have been increasing globally in recent years. These diseases are associated with high morbidity and mortality rates and impose high care costs on the health system. Acute liver failure, chronic and congenital liver diseases, as well as hepatocellular carcinoma have been limitedly treated by whole organ transplantation so far. But novel treatments for liver disorders using cell-based approaches have emerged in recent years. Extra-embryonic tissues, including umbilical cord, amnion membrane, and chorion plate, contain multipotent stem cells. The pre-sent manuscript discusses potential application of extraembryonic mesenchymal stromal/stem cells, focusing on the management of liver diseases. Extra-embryonic MSC are characterized by robust and constitutive anti-inflammatory and anti-fibrotic properties, indicating as therapeutic agents for inflammatory conditions such as liver fibrosis or advanced cirrhosis, as well as chronic inflammatory settings or deranged immune responses.
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38
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Current Surgical Management Strategies for Colorectal Cancer Liver Metastases. Cancers (Basel) 2022; 14:cancers14041063. [PMID: 35205811 PMCID: PMC8870224 DOI: 10.3390/cancers14041063] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/15/2022] [Accepted: 02/18/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Colorectal cancer is one of the most common cancer diagnoses in the world. At least half of patients diagnosed with colorectal cancer will develop metastatic disease, with most being identified in the liver. Surgical resection of colorectal liver metastases (CRLM) is potentially curative. Surgical resection of CRLM, however, remains underutilized despite the continued expansion of operative strategies available. This is likely due to differing views on resectability. Resectability is a surgical assessment, and the classification of CRLM as unresectable should only be made by an experienced hepatobiliary surgeon. Obtaining a surgical evaluation at the time of liver metastasis discovery may help mitigate the challenge of assessing resectability and the determination of potential operative time windows within current multimodal management strategies. The aim of this review is to help facilitate discussions surrounding resectability as well as the timing and sequencing of both surgical and non-surgical therapies. Abstract Colorectal cancer is the third most common cancer diagnosis in the world, and the second most common cause of cancer-related deaths. Despite significant progress in management strategies for colorectal cancer over the last several decades, metastatic disease remains difficult to treat and is often considered incurable. However, for patients with colorectal liver metastases (CRLM), surgical resection offers the best opportunity for survival, can be curative, and remains the gold standard. Unfortunately, surgical treatment options are underutilized. Misperceptions regarding resectable and unresectable CRLM likely play a role in this. The assessment of factors that impact resectability status like medical fitness, technical considerations, and disease biology can be difficult, necessitating careful multidisciplinary input and discussion. The identification of ideal operative time windows that align with the multimodal management of these patients can also be perplexing. For all patients with CRLM it may therefore be advantageous to obtain surgical evaluation at the time of discovering liver metastases to mitigate these challenges and minimize the risk of undertreatment. In this review we summarize current surgical management strategies for CRLM and discuss factors to be considered when determining resectability.
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Xie C, Zhang Z, Yang M, Cao C, Zhou Y, Zhu Z, Gong W, Xu C, Yan L, Hu Z, Ai L, Peng Y. Lactiplantibacillus plantarum AR113 Exhibit Accelerated Liver Regeneration by Regulating Gut Microbiota and Plasma Glycerophospholipid. Front Microbiol 2022; 12:800470. [PMID: 35154031 PMCID: PMC8834300 DOI: 10.3389/fmicb.2021.800470] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 11/29/2021] [Indexed: 12/11/2022] Open
Abstract
Emerging evidence indicates that probiotics have been proved to influence liver injury and regeneration. In the present study, the effects of Lactiplantibacillus plantarum AR113 on the liver regeneration were investigated in 70% partial hepatectomy (PHx) rats. Sprague-Dawley (SD) rats were gavaged with L. plantarum AR113 suspensions (1 × 1010 CFU/mL) both before and after partial hepatectomy. The results showed that L. plantarum AR113 administration 2 weeks before partial hepatectomy can accelerate liver regeneration by increased hepatocyte proliferation and tumor necrosis factor-α (TNF-α), hepatocyte growth factor (HGF), and transforming growth factor-β (TGF-β) expression. Probiotic administration enriched Lactobacillus and Bacteroides and depleted Flavonifractor and Acetatifactor in the gut microbiome. Meanwhile, L. plantarum AR113 showed decline of phosphatidylethanolamine (PE), phosphatidylcholine (PC), phosphatidyl serine (PS), and lysophosphatidyl choline (LysoPC) levels in the serum of the rats after the L. plantarum AR113 administration. Moreover, L. plantarum AR113 treated rats exhibited higher concentrations of L-leucine, L-isoleucine, mevalonic acid, and lower 7-oxo-8-amino-nonanoic acid in plasma than that in PHx. Spearman correlation analysis revealed a significant correlation between changes in gut microbiota composition and glycerophospholipid. These results indicate that L. plantarum AR113 is promising for accelerating liver regeneration and provide new insights regarding the correlations among the microbiome, the metabolome, and liver regeneration.
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Affiliation(s)
- Chunliang Xie
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Zhoumei Zhang
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Manyi Yang
- Department of Hepatobiliary and Pancreatic Surgery, NHC Key Laboratory of Nanobiological Technology, Xiangya Hospital, Central South University, Changsha, China
| | - Cha Cao
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Yingjun Zhou
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Zuohua Zhu
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Wenbing Gong
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Chao Xu
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Li Yan
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Zhenxiu Hu
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
| | - Lianzhong Ai
- Shanghai Engineering Research Center of Food Microbiology, School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China
- *Correspondence: Lianzhong Ai,
| | - Yuande Peng
- Institute of Bast Fiber Crops, Chinese Academy of Agricultural Sciences, Changsha, China
- Yuande Peng,
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Elkhalifa D, Rayan M, Negmeldin AT, Elhissi A, Khalil A. Chemically modified mRNA beyond COVID-19: Potential preventive and therapeutic applications for targeting chronic diseases. Biomed Pharmacother 2022; 145:112385. [PMID: 34915673 PMCID: PMC8552589 DOI: 10.1016/j.biopha.2021.112385] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/19/2021] [Accepted: 10/25/2021] [Indexed: 12/17/2022] Open
Abstract
Chemically modified mRNA represents a unique, efficient, and straightforward approach to produce a class of biopharmaceutical agents. It has been already approved as a vaccination-based method for targeting SARS-CoV-2 virus. The COVID-19 pandemic has highlighted the prospect of synthetic modified mRNA to efficiently and safely combat various diseases. Recently, various optimization advances have been adopted to overcome the limitations associated with conventional gene therapeutics leading to wide-ranging applications in different disease conditions. This review sheds light on emerging directions of chemically modified mRNAs to prevent and treat widespread chronic diseases, including metabolic disorders, cancer vaccination and immunotherapy, musculoskeletal disorders, respiratory conditions, cardiovascular diseases, and liver diseases.
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Affiliation(s)
- Dana Elkhalifa
- Department of Pharmacy, Aspetar Orthopedic and Sports Medicine Hospital, Doha, Qatar
| | - Menatallah Rayan
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar
| | - Ahmed T Negmeldin
- Department of Pharmaceutical Sciences, College of Pharmacy and Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Abdelbary Elhissi
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar; Office of the Vice President for Research and Graduate Studies, Qatar University, Doha, Qatar
| | - Ashraf Khalil
- Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, Doha, Qatar; Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, Doha, Qatar
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Abstract
The liver comprises both parenchymal and non-parenchymal cells with varying functions. Cirrhosis is often complicated by the development of portal hypertension and its associated complications. Hence, assessment of liver in cirrhosis should include assessment of its structural, function of both hepatic and non-hepatic tissue and haemodynamic assessment of portal hypertension. There is no single test that can evaluate all functions of liver and assess prevalence and severity of portal hypertension. Commonly available tests like serum bilirubin, liver enzymes (alanine [ALT] and aspartate aminotransferase [AST], serum alkaline phosphatase [ALP], gamma glutamyl transpeptidase [GGT]), serum albumin and prothrombin time for assessment of liver functions partly assess liver functions. quantitative liver functions like indocyanine clearance tests [ICG-K], methacetin breath test [MBT] were developed to assess dynamic status of liver but has its own limitation and availability. Imaging based assessment of liver by transient elastography, MRI based 99 mTc-coupled asialoglycoprotein mebrofenin scan help the clinician to assess liver function, functional volume of liver left after surgery and portal hypertension [PH]. Hepatic venous pressure gradient still remains the gold standard for the assessment of portal hypertension but is invasive and not available in all centres. Combinations of blood parameters in form of various indices like fibrosis score of 4 [FIB-4], Lok index, scores like model for end stage liver disease (MELD) and Child-Turcotte Pugh score are commonly used for assessing liver function in clinical practice.
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Key Words
- 99mTc-GSA, technetium-99m galactosyl human serum albumin
- ALP, alkaline phosphatase
- ALT, alanine aminotransferase
- ARFI, Acoustic Radiation Force Impulse
- AST, aspartate aminotransferase
- BUN, blood urea nitrogen
- CLD, chronic liver disease
- ESLD, end-stage liver disease
- FIB-4, fibrosis score of 4
- GGT, gamma glutamyl transpeptidase
- HVPG, Hepatic venous pressure gradient
- ICG-K, indocyanine clearance tests
- INR, International normalised ratio
- LFTs, liver function tests
- MBT, methacetin breath test
- NAFLD, non-alcoholic fatty liver disease
- PBS, primary biliary cholangitis
- PHT, portal hypertension
- PSC, primary Sclerosing cholangitis
- cirrhosis
- liver function tests
- portal hypertension
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Affiliation(s)
- Praveen Sharma
- Address for correspondence: Praveen Sharma, Associate Professor, Department of Gastroenterology, Sir Ganga Ram Hospital, New Delhi, India.
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Hai HH, Aw P, Teng TZJ, Shelat VG. Perioperative steroid administration reduces overall complications in patients undergoing liver resection: A meta-analysis. World J Gastrointest Surg 2021; 13:1079-1094. [PMID: 34621482 PMCID: PMC8462075 DOI: 10.4240/wjgs.v13.i9.1079] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/03/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatic resection (HR) results in an inflammatory response that can be modified by perioperative steroid administration. However, it remains to be determined if this response's attenuation translates to a reduction in complications. AIM To evaluate if perioperative administration of steroids reduces complications following HR. METHODS A systematic review of randomized controlled trials (RCTs) was conducted on PubMed, Embase, and Cochrane Central Register of Controlled Trials to evaluate the effect of perioperative steroid (compared to placebo or no intervention) use in patients undergoing HR. Clinical outcomes were extracted, and meta-analysis was performed. RESULTS 8 RCTs including 590 patients were included. Perioperative steroid administration was associated with significant reduction in postoperative complications [odds ratios: 0.58; 95% confidence intervals (CI): 0.35-0.97, P = 0.04]. There was also improvement in biochemical and inflammatory markers, including serum bilirubin on postoperative day 1 [MD: -0.27; 95%CI: (-0.47, -0.06), P = 0.01], C-reactive protein on postoperative day 3 [MD: -4.89; 95%CI: (-5.83, -3.95), P < 0.001], and interleukin-6 on postoperative day 1 [MD: -54.84; 95%CI: (-63.91, -45.76), P < 0.001]. CONCLUSION Perioperative steroids administration in HR may reduce overall complications, postoperative bilirubin, and inflammation. Further studies are needed to determine the optimal dose and duration and patient selection.
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Affiliation(s)
- Hao-Han Hai
- NUS Yong Loo Lin School of Medicine, Singapore 119228, Singapore
| | - Phoebe Aw
- NUS Yong Loo Lin School of Medicine, Singapore 119228, Singapore
| | | | - Vishal G Shelat
- NTU Lee Kong Chian School of Medicine, Singapore 308232, Singapore
- Department of General Surgery, Tan Tock Seng Hospital, Singapore 308433, Singapore
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Álvarez-Mercado AI, Caballeria-Casals A, Rojano-Alfonso C, Chávez-Reyes J, Micó-Carnero M, Sanchez-Gonzalez A, Casillas-Ramírez A, Gracia-Sancho J, Peralta C. Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection. Biomedicines 2021; 9:1158. [PMID: 34572344 PMCID: PMC8470173 DOI: 10.3390/biomedicines9091158] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body's required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors.
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Affiliation(s)
- Ana I. Álvarez-Mercado
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology, Biomedical Research Center, University of Granada, 18016 Armilla, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Albert Caballeria-Casals
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Carlos Rojano-Alfonso
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Jesús Chávez-Reyes
- Facultad de Medicina e Ingeniería en Sistemas Computacionales Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico; (J.C.-R.); (A.C.-R.)
| | - Marc Micó-Carnero
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Alfredo Sanchez-Gonzalez
- Teaching and Research Department, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
| | - Araní Casillas-Ramírez
- Facultad de Medicina e Ingeniería en Sistemas Computacionales Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico; (J.C.-R.); (A.C.-R.)
- Teaching and Research Department, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, 03036 Barcelona, Spain;
- Barcelona Hepatic Hemodynamic Laboratory, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
| | - Carmen Peralta
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
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Große-Segerath L, Lammert E. Role of vasodilation in liver regeneration and health. Biol Chem 2021; 402:1009-1019. [PMID: 33908220 DOI: 10.1515/hsz-2021-0155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 04/12/2021] [Indexed: 12/14/2022]
Abstract
Recently, we have shown that an enhanced blood flow through the liver triggers hepatocyte proliferation and thereby liver growth. In this review, we first explain the literature on hepatic blood flow and its changes after partial hepatectomy (PHx), before we present the different steps of liver regeneration that take place right after the initial hemodynamic changes induced by PHx. Those parts of the molecular mechanisms governing liver regeneration, which are directly associated with the hepatic vascular system, are subsequently reviewed. These include β1 integrin-dependent mechanotransduction in liver sinusoidal endothelial cells (LSECs), triggering mechanically-induced activation of the vascular endothelial growth factor receptor-3 (VEGFR3) and matrix metalloproteinase-9 (MMP9) as well as release of growth-promoting angiocrine signals. Finally, we speculate how advanced age and obesity negatively affect the hepatic vasculature and thus liver regeneration and health, and we conclude our review with some recent technical progress in the clinic that employs liver perfusion. In sum, the mechano-elastic properties and alterations of the hepatic vasculature are key to better understand and influence liver health, regeneration, and disease.
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Affiliation(s)
- Linda Große-Segerath
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
| | - Eckhard Lammert
- Institute of Metabolic Physiology, Heinrich Heine University, D-40225 Düsseldorf, Germany
- Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), Leibniz Center for Diabetes Research at Heinrich Heine University, D-40225 Düsseldorf, Germany
- German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum München, D-85764 Neuherberg, Germany
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Murtha-Lemekhova A, Fuchs J, Ghamarnejad O, Nikdad M, Probst P, Hoffmann K. Influence of cytokines, circulating markers and growth factors on liver regeneration and post-hepatectomy liver failure: a systematic review and meta-analysis. Sci Rep 2021; 11:13739. [PMID: 34215781 PMCID: PMC8253792 DOI: 10.1038/s41598-021-92888-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023] Open
Abstract
The pathophysiology of post-hepatectomy liver failure is not entirely understood but is rooted in the disruption of normal hepatocyte regeneration and homeostasis. Current investigations of post-hepatectomy liver failure and regeneration are focused on evaluation of circulating hepatic function parameters (transaminases, cholestasis, and coagulation parameters), volumetry and hepatic hemodynamics. However, identification of biochemical factors associated with regeneration and post hepatectomy liver failure is crucial for understanding the pathophysiology and identification of patients at risk. The objective of the present systematic review was to identify circulating factors associated with liver regeneration and post hepatectomy liver failure in patients undergoing hepatectomy. The quantitative analysis was intended if studies provided sufficient data. Electronic databases (MEDLINE via PubMed, Web of Knowledge, Cochrane Library and WHO International Clinical Trials Registry Platform) were searched for publications on cell signaling factors in liver regeneration and post-hepatectomy liver failure following liver resection in clinical setting. No date restriction was given. No language restriction was used. Studies were assessed using MINORS. This study was registered at PROSPERO (CRD42020165384) prior to data extraction. In total 1953 publications were evaluated for titles and abstracts after exclusion of duplicates. Full texts of 167 studies were further evaluated for inclusion. 26 articles were included in the review and 6 publications were included in the meta-analyses. High levels of serum hyaluronic acid even preoperatively are associated with PHLF but especially increased levels early after resection are predictive of PHLF with high sensitivity and specificity. Postoperative elevation of HA to levels between 100 and 500 ng/ml is increased the risk for PHLF ([OR] = 246.28, 95% [CI]: 11.82 to 5131.83; p = 0.0004) Inteleukin-6 levels show contradicting result in association with organ dysfunction. HGF positively correlates with liver regeneration. Overall, due to heterogeneity, scarcity, observational study design and largely retrospective analysis, the certainty of evidence, assessed with GRADE, is very low. High levels of serum hyaluronic acid show a strong association with PHLF and increased levels after resection are predictive of PHLF with high sensitivity and specificity, even on POD1. Interleukin-6 levels need to be studied further due to contradictive results in association with organ dysfunction. For HGF, no quantitative analysis could be made. Yet, most studies find positive correlation between high HGF levels and regeneration. Prospective studies investigating HGF and other growth factors, hyaluronic acid and interleukins 1 and 6 in correlation with liver regeneration measured sequentially through e.g. volumetry, and liver function parameters, preferably expanding the analysis to include dynamic liver function tests, are needed to sufficiently illustrate the connection between biomolecule levels and clinical outcomes.
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Affiliation(s)
- Anastasia Murtha-Lemekhova
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Juri Fuchs
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Mohammedsadegh Nikdad
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
| | - Pascal Probst
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany
- Study Center of the German Surgical Society (SDGC), Heidelberg University Hospital, Heidelberg, Germany
| | - Katrin Hoffmann
- Department of General, Visceral, and Transplantation Surgery, Ruprecht Karl University, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
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Lee GS, Jeong HY, Yang HG, Seo YR, Jung EG, Lee YS, Nam KW, Kim WJ. Astragaloside IV Suppresses Hepatic Proliferation in Regenerating Rat Liver after 70% Partial Hepatectomy via Down-Regulation of Cell Cycle Pathway and DNA Replication. Molecules 2021; 26:2895. [PMID: 34068164 PMCID: PMC8152973 DOI: 10.3390/molecules26102895] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 12/13/2022] Open
Abstract
Astragaloside IV (AS-IV) is one of the major bio-active ingredients of huang qi which is the dried root of Astragalus membranaceus (a traditional Chinese medicinal plant). The pharmacological effects of AS-IV, including anti-oxidative, anti-cancer, and anti-diabetic effects have been actively studied, however, the effects of AS-IV on liver regeneration have not yet been fully described. Thus, the aim of this study was to explore the effects of AS-IV on regenerating liver after 70% partial hepatectomy (PHx) in rats. Differentially expressed mRNAs, proliferative marker and growth factors were analyzed. AS-IV (10 mg/kg) was administrated orally 2 h before surgery. We found 20 core genes showed effects of AS-IV, many of which were involved with functions related to DNA replication during cell division. AS-IV down-regulates MAPK signaling, PI3/Akt signaling, and cell cycle pathway. Hepatocyte growth factor (HGF) and cyclin D1 expression were also decreased by AS-IV administration. Transforming growth factor β1 (TGFβ1, growth regulation signal) was slightly increased. In short, AS-IV down-regulated proliferative signals and genes related to DNA replication. In conclusion, AS-IV showed anti-proliferative activity in regenerating liver tissue after 70% PHx.
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Affiliation(s)
- Gyeong-Seok Lee
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Hee-Yeon Jeong
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Hyeon-Gung Yang
- Soonchunhyang Institute of Medi-bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Chungcheongnam-do, Korea;
| | - Young-Ran Seo
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Eui-Gil Jung
- Seoul Center, Korea Basic Science Institute, Seoul 02855, Korea;
| | - Yong-Seok Lee
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Kung-Woo Nam
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
| | - Wan-Jong Kim
- Department of Life Science and Biotechnology, College of Natural Sciences, Soonchunhyang University, Asan 31538, Chungcheongnam-do, Korea; (G.-S.L.); (H.-Y.J.); (Y.-R.S.); (Y.-S.L.); (K.-W.N.)
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F4/80 + Kupffer Cell-Derived Oncostatin M Sustains the Progression Phase of Liver Regeneration through Inhibition of TGF-β2 Pathway. Molecules 2021; 26:molecules26082231. [PMID: 33924385 PMCID: PMC8069260 DOI: 10.3390/molecules26082231] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/15/2021] [Accepted: 04/08/2021] [Indexed: 12/29/2022] Open
Abstract
The role of Kupffer cells (KCs) in liver regeneration is complicated and controversial. To investigate the distinct role of F4/80+ KCs at the different stages of the regeneration process, two-thirds partial hepatectomy (PHx) was performed in mice to induce physiological liver regeneration. In pre- or post-PHx, the clearance of KCs by intraperitoneal injection of the anti-F4/80 antibody (α-F4/80) was performed to study the distinct role of F4/80+ KCs during the regenerative process. In RNA sequencing of isolated F4/80+ KCs, the initiation phase was compared with the progression phase. Immunohistochemistry and immunofluorescence staining of Ki67, HNF-4α, CD-31, and F4/80 and Western blot of the TGF-β2 pathway were performed. Depletion of F4/80+ KCs in pre-PHx delayed the peak of hepatocyte proliferation from 48 h to 120 h, whereas depletion in post-PHx unexpectedly led to persistent inhibition of hepatocyte proliferation, indicating the distinct role of F4/80+ KCs in the initiation and progression phases of liver regeneration. F4/80+ KC depletion in post-PHx could significantly increase TGF-β2 serum levels, while TGF-βRI partially rescued the impaired proliferation of hepatocytes. Additionally, F4/80+ KC depletion in post-PHx significantly lowered the expression of oncostatin M (OSM), a key downstream mediator of interleukin-6, which is required for hepatocyte proliferation during liver regeneration. In vivo, recombinant OSM (r-OSM) treatment alleviated the inhibitory effect of α-F4/80 on the regenerative progression. Collectively, F4/80+ KCs release OSM to inhibit TGF-β2 activation, sustaining hepatocyte proliferation by releasing a proliferative brake.
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Herrero de la Parte B, González-Arribas M, Diaz-Sanz I, Palomares T, García-Alonso I. Partial hepatectomy enhances the growth of CC531 rat colorectal cancer cells both in vitro and in vivo. Sci Rep 2021; 11:5356. [PMID: 33686132 PMCID: PMC7970880 DOI: 10.1038/s41598-021-85082-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 02/25/2021] [Indexed: 12/13/2022] Open
Abstract
Partial hepatectomy (PHx) is the gold standard for the treatment of colorectal cancer liver metastases. However, after removing a substantial amount of hepatic tissue, growth factors are released to induce liver regeneration, which may promote the proliferation of liver micrometastases or circulating tumour cells still present in the patient. The aim of this study is to assess the effect of PHx on the growth of liver metastases induced by intrasplenic cell inoculation as well as on in vitro proliferation of the same cancer cell line. Liver tumours were induced in 18 WAG/RijHsd male rats, by seeding 250,000 syngeneic colorectal cancer cells (CC531) into the spleen. The left lateral lobe of the liver was mobilized and in half of the animals it was removed to achieve a 40% hepatectomy. Twenty-eight days after tumour induction, the animals were sacrificed and the liver was removed and sliced to assess the relative tumour surface area (RTSA%). CC531 cells were cultured in presence of foetal calf serum, non-hepatectomised (NRS) or hepatectomized rat serum (HRS), and their proliferation rate at 24, 48, and 72 h was measured. RTSA% was significantly higher in animals which had undergone PHx than in the controls (non-hepatectomised) (46.98 ± 8.76% vs. 18.73 ± 5.65%; p < 0.05). Analysing each lobe separately, this difference in favour of hepatectomized animals was relevant and statistically significant in the paramedian and caudate lobes. But in the right lobe the difference was scarce and not significant. In vitro, 2.5% HRS achieved stronger proliferative rates than the control cultures (10% FCS) or their equivalent of NRS. In this experimental model, a parallelism has been shown between the effect of PHx on the growth of colorectal cancer cells in the liver and the effect of the serum on those cells in vitro.
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Affiliation(s)
- Borja Herrero de la Parte
- Department of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940, Leioa, Vizcaya, Spain. .,Biocruces Bizkaia Health Research Institute, Plaza de Cruces s/n, 48903, Barakaldo, Spain.
| | - Mikel González-Arribas
- Department of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940, Leioa, Vizcaya, Spain
| | - Iñaki Diaz-Sanz
- Department of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940, Leioa, Vizcaya, Spain
| | - Teodoro Palomares
- Department of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940, Leioa, Vizcaya, Spain
| | - Ignacio García-Alonso
- Department of Surgery and Radiology and Physical Medicine, Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Barrio Sarriena s/n, 48940, Leioa, Vizcaya, Spain.,Biocruces Bizkaia Health Research Institute, Plaza de Cruces s/n, 48903, Barakaldo, Spain
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Zhang W, Wang L, Sun XH, Liu X, Xiao Y, Zhang J, Wang T, Chen H, Zhan YQ, Yu M, Ge CH, Li CY, Ren GM, Yin RH, Yang XM. Toll-like receptor 5-mediated signaling enhances liver regeneration in mice. Mil Med Res 2021; 8:16. [PMID: 33622404 PMCID: PMC7901072 DOI: 10.1186/s40779-021-00309-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 02/10/2021] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Toll-like receptor 5 (TLR5)-mediated pathways play critical roles in regulating the hepatic immune response and show hepatoprotective effects in mouse models of hepatic diseases. However, the role of TLR5 in experimental models of liver regeneration has not been reported. This study aimed to investigate the role of TLR5 in partial hepatectomy (PHx)-induced liver regeneration. METHODS We performed 2/3 PHx in wild-type (WT) mice, TLR5 knockout mice, or TLR5 agonist CBLB502 treated mice, as a model of liver regeneration. Bacterial flagellin content was measured with ELISA, and hepatic TLR5 expression was determined with quantitative PCR analyses and flow cytometry. To study the effects of TLR5 on hepatocyte proliferation, we analyzed bromodeoxyuridine (BrdU) incorporation and proliferating cell nuclear antigen (PCNA) expression with immunohistochemistry (IHC) staining. The effects of TLR5 during the priming phase of liver regeneration were examined with quantitative PCR analyses of immediate early gene mRNA levels, and with Western blotting analysis of hepatic NF-κB and STAT3 activation. Cytokine and growth factor production after PHx were detected with real-time PCR and cytometric bead array (CBA) assays. Oil Red O staining and hepatic lipid concentrations were analyzed to examine the effect of TLR5 on hepatic lipid accumulation after PHx. RESULTS The bacterial flagellin content in the serum and liver increased, and the hepatic TLR5 expression was significantly up-regulated in WT mice after PHx. TLR5-deficient mice exhibited diminished numbers of BrdU- and PCNA-positive cells, suppressed immediate early gene expression, and decreased cytokine and growth factor production. Moreover, PHx-induced hepatic NF-κB and STAT3 activation was inhibited in Tlr5-/- mice, as compared with WT mice. Consistently, the administration of CBLB502 significantly promoted PHx-mediated hepatocyte proliferation, which was correlated with enhanced production of proinflammatory cytokines and the recruitment of macrophages and neutrophils in the liver. Furthermore, Tlr5-/- mice displayed significantly lower hepatic lipid concentrations and smaller Oil Red O positive areas than those in control mice after PHx. CONCLUSION We reveal that TLR5 activation contributes to the initial events of liver regeneration after PHx. Our findings demonstrate that TLR5 signaling positively regulates liver regeneration and suggest the potential of TLR5 agonist to promote liver regeneration.
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Affiliation(s)
- Wen Zhang
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.,State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Lei Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xue-Hua Sun
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.,State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Xian Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Yang Xiao
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Jie Zhang
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China.,State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Ting Wang
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.,School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, Anhui Province, China
| | - Hui Chen
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Yi-Qun Zhan
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Miao Yu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Chang-Hui Ge
- Beijing Institute of Radiation Medicine, Beijing, 100850, China
| | - Chang-Yan Li
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China
| | - Guang-Ming Ren
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
| | - Rong-Hua Yin
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
| | - Xiao-Ming Yang
- Department of Pharmaceutical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072, China. .,State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, 102206, China.
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Mobed A, Shakouri SK, Dolati S. Biosensors: A novel approach to and recent discovery in detection of cytokines. Cytokine 2020; 136:155272. [PMID: 32916473 DOI: 10.1016/j.cyto.2020.155272] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 08/31/2020] [Indexed: 02/07/2023]
Abstract
Cytokines in tissues and physiological fluids can function as potentially suitable biomarkers. Cytokines are involved in stimulating different body responses including inflammatory response to external pathogens, regulating cell-to-cell communication, and maintaining tissue homeostasis. Consequently, cytokines are extensively used to monitor and predict disease progression and to track the outcome of patient treatment. The critical diagnosis of cytokine and chemokine biomarkers has been the focus of attention and it has been continuously directing the trajectory of related research to developing a novel sensing platform. Given the major challenges and constraints of the older identification methods including their high costs, low sensitivity, and high specificity, the development of biosensor technology as a simple and inexpensive tool with high sensitivity is quite attractive and interesting. The fundamental aim of this study is to present the state-of-the-art biosensor systems in order to detect different types of cytokines and to emphasize the role of these systems in the prevention, monitoring, and treatment of various cytokine-associated diseases.
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Affiliation(s)
- Ahmad Mobed
- Aging Research Institute, Faculty of Medicine, Tabriz University of Medical Sciences, Iran; Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran.
| | - Seyed Kazem Shakouri
- Aging Research Institute, Faculty of Medicine, Tabriz University of Medical Sciences, Iran; Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sanam Dolati
- Physical Medicine and Rehabilitation Research Center, Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran
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