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Zhan X, Bai Y, Zhu Q, Gao Y, Li F, Bu Q, Zhu Z, Rao Z, Zhou H. Macrophage ATG16L1 promotes liver regeneration after partial hepatectomy. JHEP Rep 2025; 7:101330. [PMID: 40290519 PMCID: PMC12023798 DOI: 10.1016/j.jhepr.2025.101330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 01/10/2025] [Accepted: 01/15/2025] [Indexed: 04/30/2025] Open
Abstract
Background & Aims Autophagy plays an important role in liver regeneration. However, most studies are limited to hepatocytes, and the function and mechanism of macrophage autophagy in liver regeneration remain unclear. This study investigated the role of the essential autophagy gene encoding autophagy-related 16-like 1 (ATG16L1), which regulates the macrophage phenotype in liver regeneration. Methods We generated FloxP-Atg16l1 (Atg16l1 FL/FL ), Lyz2-Cre Atg16l1 knockout (KO) (Atg16l1 M-KO ), and myeloid-specific Atg16l1-overexpression-knock-in (Atg16l1 OE ) mice. These mice were subjected to 70% partial hepatectomy to demonstrate the role of ATG16L1 in macrophages during liver regeneration. Results ATG16L1 expression was significantly upregulated in macrophages during the early stages of liver regeneration. ATG16L1 deletion in macrophages substantially delayed liver regeneration in mice and caused a marked imbalance in Ly6Chi and Ly6Clo macrophage proportions in the liver. RNA-sequencing analysis revealed that, compared with macrophages isolated from Atg16l1 FL/FL mice, those from Atg16l1 M-KO mice exhibited significant downregulation of genes associated with oxidative phosphorylation and upregulation of proinflammatory gene expression. Mechanistically, ATG16L1 loss impaired mitophagy in macrophages, leading to the accumulation of mitochondrial damage and a metabolic shift that promoted proinflammatory macrophage polarization. ATG16L1 deficiency not only promoted macrophage mitochondrial (mt)DNA release and cyclic GMP-AMP synthase-stimulator of interferon genes (STING) activation, but also suppressed STING degradation. Sustained STING hyperactivation and subsequent increased release of downstream interferons further contributed to the inhibition of liver regeneration. Notably, pharmacological activation or genetic overexpression of ATG16L1 significantly enhanced liver regeneration in mice. Conclusions ATG16L1 has a pivotal role in liver regeneration by affecting the phenotype and function of macrophages. Thus, targeting ATG16L1 in macrophages could present a novel strategy for promoting liver regeneration. Impact and implications The autophagy-related gene ATG16L1 mediates mitophagy, facilitating the clearance of damaged mitochondria in macrophages following partial hepatectomy and maintaining a reparative macrophage phenotype. ATG16L1 deficiency triggers excessive STING activation and inhibits its degradation, thereby suppressing liver regeneration. Thus, targeting ATG16L1 in macrophages could represent a novel strategy to promote liver regeneration.
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Affiliation(s)
- Xinyu Zhan
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Yan Bai
- Department of Anesthesiology, Jiangsu Province People's Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, 210029, China
| | - Qing Zhu
- Department of Anesthesiology, Jiangsu Province People's Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, 210029, China
| | - Yiyun Gao
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Fan Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Qingfa Bu
- Department of General Surgery, Nanjing BenQ Medical Center, The Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zeyu Zhu
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
| | - Zhuqing Rao
- Department of Anesthesiology, Jiangsu Province People's Hospital and Nanjing Medical University First Affiliated Hospital, Nanjing, 210029, China
| | - Haoming Zhou
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
- Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, 210029, China
- NHC Key Laboratory of Living Donor Liver Transplantation (Nanjing Medical University), Nanjing, 210029, China
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Fuchs J, Rabaux-Eygasier L, Husson T, Fouquet V, Guerin F, Hery G, Branchereau S. Too Big to Fail: Volumetric Analyses and Incidence of Posthepatectomy Liver Failure in 125 Major Hepatectomies in Children. Ann Surg 2025; 281:476-484. [PMID: 39584774 DOI: 10.1097/sla.0000000000006595] [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: 11/26/2024]
Abstract
OBJECTIVE To assess the incidence of posthepatectomy liver failure (PHLF) and the role of the future liver remnant (FLR) in children undergoing major hepatectomy. BACKGROUND Incidence and risk factors of PHLF in children are unclear, with no validated definition for this age group. Consequently, the role of the FLR in pediatric hepatectomy and evidence-based preoperative guidelines remains undefined. METHODS All pediatric patients undergoing major hepatectomy at a tertiary care center over a 10-year study period were analyzed. Preoperative imaging was used for volumetry. The incidence of PHLF was assessed by applying predefined definitions, and the prognostic impact of the FLR on PHLF and complications was evaluated. RESULTS A total of 125 children underwent major hepatectomy, including 35 trisectionectomies. There was a strong correlation between imaging-based measured total liver volume (TLV) and calculated standard liver volume ( r = 0.728, P < 0.001). The median TLV-to-body weight (BW) ratio was 3.4%, and the median FLR/BW ratio was 1.5%. The median FLR-to-TLV ratio was 44% (range: 18%-97%). No clinically relevant PHLF occurred. FLR/TLV and FLR/BW ratios had low predictive value for postoperative liver dysfunction and morbidity. CONCLUSIONS This is the largest reported single-center series of pediatric major hepatectomies. PHLF is exceedingly rare in children. The liver volume-to-BW ratio is higher in children compared with adults, and the FLR is sufficient even in extreme resections with <20% of the liver remnant. These findings strongly question the use of asociating liver partition and portal vein ligation for staged hepatectomy, portal vein embolization, or transplantation based on suspected insufficient liver remnants in children.
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Affiliation(s)
- Juri Fuchs
- Department of Pediatric Surgery, Hôpital Kremlin-Bicêtre, APHP, University of Paris-Saclay, Paris, France
- Department of General, Visceral, Pediatric and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany
| | - Lucas Rabaux-Eygasier
- Department of Pediatric Surgery, Hôpital Kremlin-Bicêtre, APHP, University of Paris-Saclay, Paris, France
- Department of Hepato-Biliary-Pancreatic Surgery, and Liver Transplantation, Hôpital Paul Brousse, APHP, University of Paris-Saclay, Paris, France
| | - Thomas Husson
- Department of Hepato-Biliary-Pancreatic Surgery, and Liver Transplantation, Hôpital Paul Brousse, APHP, University of Paris-Saclay, Paris, France
| | - Virginie Fouquet
- Department of Pediatric Surgery, Hôpital Kremlin-Bicêtre, APHP, University of Paris-Saclay, Paris, France
| | - Florent Guerin
- Department of Pediatric Surgery, Hôpital Kremlin-Bicêtre, APHP, University of Paris-Saclay, Paris, France
| | - Geraldine Hery
- Department of Pediatric Surgery, Hôpital Kremlin-Bicêtre, APHP, University of Paris-Saclay, Paris, France
| | - Sophie Branchereau
- Department of Pediatric Surgery, Hôpital Kremlin-Bicêtre, APHP, University of Paris-Saclay, Paris, France
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [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: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Rossetti GG, Dommann N, Karamichali A, Dionellis VS, Asensio Aldave A, Yarahmadov T, Rodriguez-Carballo E, Keogh A, Candinas D, Stroka D, Halazonetis TD. In vivo DNA replication dynamics unveil aging-dependent replication stress. Cell 2024; 187:6220-6234.e13. [PMID: 39293447 DOI: 10.1016/j.cell.2024.08.034] [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: 05/11/2023] [Revised: 03/16/2024] [Accepted: 08/19/2024] [Indexed: 09/20/2024]
Abstract
The genome duplication program is affected by multiple factors in vivo, including developmental cues, genotoxic stress, and aging. Here, we monitored DNA replication initiation dynamics in regenerating livers of young and old mice after partial hepatectomy to investigate the impact of aging. In young mice, the origin firing sites were well defined; the majority were located 10-50 kb upstream or downstream of expressed genes, and their position on the genome was conserved in human cells. Old mice displayed the same replication initiation sites, but origin firing was inefficient and accompanied by a replication stress response. Inhibitors of the ATR checkpoint kinase fully restored origin firing efficiency in the old mice but at the expense of an inflammatory response and without significantly enhancing the fraction of hepatocytes entering the cell cycle. These findings unveil aging-dependent replication stress and a crucial role of ATR in mitigating the stress-associated inflammation, a hallmark of aging.
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Affiliation(s)
- Giacomo G Rossetti
- Department of Molecular and Cellular Biology, University of Geneva, Geneva 1205, Switzerland
| | - Noëlle Dommann
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Angeliki Karamichali
- Department of Molecular and Cellular Biology, University of Geneva, Geneva 1205, Switzerland
| | - Vasilis S Dionellis
- Department of Molecular and Cellular Biology, University of Geneva, Geneva 1205, Switzerland
| | - Ainhoa Asensio Aldave
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Tural Yarahmadov
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
| | | | - Adrian Keogh
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
| | - Daniel Candinas
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Deborah Stroka
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland.
| | - Thanos D Halazonetis
- Department of Molecular and Cellular Biology, University of Geneva, Geneva 1205, Switzerland.
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Jiang M, Zheng Z, Wang X, Chen Y, Qu J, Ding Q, Zhang W, Liu YS, Yang J, Tang W, Hou Y, He J, Wang L, Huang P, Li LC, He Z, Gao Q, Lu Q, Wei L, Wang YJ, Ju Z, Fan JG, Ruan XZ, Guan Y, Liu GH, Pei G, Li J, Wang Y. A biomarker framework for liver aging: the Aging Biomarker Consortium consensus statement. LIFE MEDICINE 2024; 3:lnae004. [PMID: 39872390 PMCID: PMC11749002 DOI: 10.1093/lifemedi/lnae004] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Accepted: 01/29/2024] [Indexed: 01/11/2025]
Abstract
In human aging, liver aging per se not only increases susceptibility to liver diseases but also increases vulnerability of other organs given its central role in regulating metabolism. Total liver function tends to be well maintained in the healthy elderly, so liver aging is generally difficult to identify early. In response to this critical challenge, the Aging Biomarker Consortium of China has formulated an expert consensus on biomarkers of liver aging by synthesizing the latest scientific literature, comprising insights from both scientists and clinicians. This consensus provides a comprehensive assessment of biomarkers associated with liver aging and presents a systematic framework to characterize these into three dimensions: functional, imaging, and humoral. For the functional domain, we highlight biomarkers associated with cholesterol metabolism and liver-related coagulation function. For the imaging domain, we note that hepatic steatosis and liver blood flow can serve as measurable biomarkers for liver aging. Finally, in the humoral domain, we pinpoint hepatokines and enzymatic alterations worthy of attention. The aim of this expert consensus is to establish a foundation for assessing the extent of liver aging and identify early signs of liver aging-related diseases, thereby improving liver health and the healthy life expectancy of the elderly population.
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Affiliation(s)
| | - Mengmeng Jiang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhuozhao Zheng
- Department of Radiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Xuan Wang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yanhao Chen
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jing Qu
- State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
| | - Qiurong Ding
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Weiqi Zhang
- CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing 100101, China
| | - You-Shuo Liu
- Department of Geriatrics, the Second Xiangya Hospital, and the Institute of Aging and Geriatrics, Central South University, Changsha 410011, China
| | - Jichun Yang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Center for Non-coding RNA Medicine, Peking University Health Science Center, Beijing 100191, China
| | - Weiqing Tang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, China
| | - Yunlong Hou
- Yiling Pharmaceutical Academician Workstation, Shijiazhuang 050035, China
| | - Jinhan He
- Department of Pharmacy, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Lin Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Pengyu Huang
- State Key Laboratory of Advanced Medical Materials and Devices, Engineering Research Center of Pulmonary and Critical Care Medicine Technology and Device (Ministry of Education), Institute of Biomedical Engineering, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, China
| | - Lin-Chen Li
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200092, China
| | - Qiang Gao
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qian Lu
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Lai Wei
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
| | - Yan-Jiang Wang
- Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing 400042, China
| | - Zhenyu Ju
- Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, Guangzhou 510632, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Xiong Zhong Ruan
- Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China
| | - Youfei Guan
- Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Gang Pei
- Collaborative Innovation Center for Brain Science, School of Life Science and Technology, Tongji University, Shanghai 200092, China
| | - Jian Li
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology of National Health Commission, Beijing 100730, China
| | - Yunfang Wang
- Hepatopancreatobiliary Center, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Clinical Translational Science Center, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing 102218, China
- Key Laboratory of Digital Intelligence Hepatology (Ministry of Education), School of Clinical Medicine, Tsinghua University, Beijing 102218, China
- Research Unit of Precision Hepatobiliary Surgery Paradigm, Chinese Academy of Medical Sciences, Beijing 102218, China
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He Y, Wang S, Liu S, Qin D, Liu Z, Wang L, Chen X, Zhang L. MSL1 Promotes Liver Regeneration by Driving Phase Separation of STAT3 and Histone H4 and Enhancing Their Acetylation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2301094. [PMID: 37279389 PMCID: PMC10427353 DOI: 10.1002/advs.202301094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 04/25/2023] [Indexed: 06/08/2023]
Abstract
Male-specific lethal 1 (MSL1) is critical for the formation of MSL histone acetyltransferase complex which acetylates histone H4 Lys16 (H4K16ac) to activate gene expression. However, the role of MSL1 in liver regeneration is poorly understood. Here, this work identifies MSL1 as a key regulator of STAT3 and histone H4 (H4) in hepatocytes. MSL1 forms condensates with STAT3 or H4 through liquid-liquid phase separation to enrich acetyl-coenzyme A (Ac-CoA), and Ac-CoA in turn enhances MSL1 condensate formation, synergetically promoting the acetylation of STAT3 K685 and H4K16, thus stimulating liver regeneration after partial hepatectomy (PH). Additionally, increasing Ac-CoA level can enhance STAT3 and H4 acetylation, thus promoting liver regeneration in aged mice. The results demonstrate that MSL1 condensate-mediated STAT3 and H4 acetylation play an important role in liver regeneration. Thus, promoting the phase separation of MSL1 and increasing Ac-CoA level may be a novel therapeutic strategy for acute liver diseases and transplantation.
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Affiliation(s)
- Yucheng He
- College of Veterinary Medicine/Bio‐medical CenterHuazhong Agricultural UniversityWuhanHubei430070China
| | - Shichao Wang
- College of Veterinary Medicine/Bio‐medical CenterHuazhong Agricultural UniversityWuhanHubei430070China
| | - Shenghui Liu
- College of Veterinary Medicine/Bio‐medical CenterHuazhong Agricultural UniversityWuhanHubei430070China
| | - Dan Qin
- College of Veterinary Medicine/Bio‐medical CenterHuazhong Agricultural UniversityWuhanHubei430070China
| | - Zhangmei Liu
- College of Veterinary Medicine/Bio‐medical CenterHuazhong Agricultural UniversityWuhanHubei430070China
| | - Liqiang Wang
- Department of NephrologyChinese PLA General HospitalChinese PLA Institute of NephrologyState Key Laboratory of Kidney DiseasesNational Clinical Research Center for Kidney Diseases28th Fuxing RoadBeijing100853China
| | - Xiangmei Chen
- Department of NephrologyChinese PLA General HospitalChinese PLA Institute of NephrologyState Key Laboratory of Kidney DiseasesNational Clinical Research Center for Kidney Diseases28th Fuxing RoadBeijing100853China
| | - Lisheng Zhang
- College of Veterinary Medicine/Bio‐medical CenterHuazhong Agricultural UniversityWuhanHubei430070China
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Sim JH, Kwon HM, Kim KW, Ko YS, Jun IG, Kim SH, Kim KS, Moon YJ, Song JG, Hwang GS. Associations of sarcopenia with graft failure and mortality in patients undergoing living donor liver transplantation. Liver Transpl 2022; 28:1345-1355. [PMID: 35243771 DOI: 10.1002/lt.26447] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/08/2022] [Accepted: 02/28/2022] [Indexed: 01/13/2023]
Abstract
Recent studies have reported that sarcopenia influences morbidity and mortality in surgical patients. However, few studies have investigated the associations of sarcopenia with short-term and long-term graft failure in recipients after living donor liver transplantation (LDLT). In this study, we investigated the associations between sarcopenia and graft failure/mortality in patients undergoing LDLT. We retrospectively examined 2816 recipients who underwent LDLT between January 2008 and January 2018. Cox regression analysis was performed to evaluate the associations between sarcopenia and graft failure/mortality in recipients at 60 days, 180 days, and 1 year and overall. Sarcopenia in the recipient was significantly associated with 60-day graft failure (adjusted hazard ratio [HR], 1.98; 95% confidence interval [CI], 1.09-3.61; p = 0.03), 180-day graft failure (HR, 1.85; 95% CI, 1.19-2.88; p = 0.01), 1-year graft failure (HR, 1.45; 95% CI, 1.01-2.17; p = 0.05), and overall graft failure (HR, 1.42; 95% CI, 1.08-1.87; p = 0.01). In addition, recipient sarcopenia was associated with 180-day mortality (HR, 1.88; 95% CI, 1.17-3.01; p = 0.01), 1-year mortality (HR, 1.53; 95% CI, 1.01-2.29; p = 0.04), and overall mortality (HR, 1.43; 95% CI, 1.08-1.90; p = 0.01). Preoperative sarcopenia was associated with high rates of graft failure and mortality in LDLT recipients. Therefore, preoperative sarcopenia may be a strong predictor of the surgical prognosis in LDLT recipients.
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Affiliation(s)
- Ji-Hoon Sim
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hye-Mee Kwon
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyung-Won Kim
- Department of Radiology, Asan Image Metrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - You-Sun Ko
- Department of Radiology, Asan Image Metrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - In-Gu Jun
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung-Hoon Kim
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Kyoung-Sun Kim
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young-Jin Moon
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jun-Gol Song
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Gyu-Sam Hwang
- Department of Anesthesiology and Pain Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Liver Regeneration: Changes in Oxidative Stress, Immune System, Cytokines, and Epigenetic Modifications Associated with Aging. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9018811. [PMID: 35936214 PMCID: PMC9352489 DOI: 10.1155/2022/9018811] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/25/2022] [Accepted: 06/29/2022] [Indexed: 01/10/2023]
Abstract
The regenerative capacity of the liver decreases with increase in age. In recent years, studies in mice have found that the regenerative capacity of the liver is associated with changes in the immune system of the liver, cytokines in the body, aging-related epigenetic modifications in the cell, and intracellular signaling pathways. In the immune system of the aging liver, monocytes and macrophages play an important role in tissue repair. During tissue repair, monocytes and macrophages undergo a series of functional and phenotypic changes to initiate and maintain tissue repair. Studies have discovered that knocking out macrophages in the liver during the repair phase results in significant impairment of liver regeneration. Furthermore, as the body ages, the secretion and function of cytokines undergo a series of changes. For example, the levels of interleukin-6, transforming growth factor-alpha, hepatocyte growth factor, and vascular endothelial growth factor undergo changes that alter hepatocyte regulation, thereby affecting its proliferation. In addition, body aging is accompanied by cellular aging, which leads to changes in gene expression and epigenetic modifications. Additionally, this in turn causes alterations in cell function, morphology, and division and affects the regenerative capacity of the liver. As the body ages, the activity of associated functional proteins, such as CCAAT-enhancer-binding proteins, p53, and switch/sucrose nonfermentable complex, changes in the liver, leading to alterations in several signaling pathways, such as the Hippo, PI3K-Akt, mTOR, and STAT3 pathways. Therefore, in recent years, research on aging and liver regeneration has primarily focused on the immune system, signaling pathways, epigenetic changes of senescent cells, and cytokine secretion in the liver. Hence, this review details the roles of these influencing factors in liver regeneration and impact of aging-related factors.
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Lee O, Kim JM, Kim SJ, Rhu J, Choi GS, Joh JW. Healthy Spouses can be Considered as Living Liver Donors. World J Surg 2022; 46:1474-1484. [PMID: 35316397 DOI: 10.1007/s00268-022-06518-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2022] [Indexed: 11/26/2022]
Abstract
BACKGROUND Spousal donors have gradually been accepted as an alternative living liver donors to alleviate the organ shortage and prevent donations from children. No information is available regarding the effects of spousal donation on donor safety and recipient outcomes. Our purpose in this study was to determine how spousal liver grafts in living donor liver transplantation (LDLT) affect donor safety and recipient outcomes compared with those of LDLT from children. METHODS We retrospectively analyzed 656 patients, including spouses and children, who underwent a right or extended right hepatectomy for living liver donation between January 2009 and December 2018. RESULTS Spouses represented 18.8% (n = 123) of living liver donors. Female donors comprised 78.9% (n = 97) of spousal donors, and the proportion of male donors in the children group was 72.6% (n = 387). The mean donor operation time of the spousal group was shorter than that of the children group (330 min vs. 358 min; P = 0.011), and the complication rate in the spousal group was lower than that in the children group (12.2% vs. 22.9%; P = 0.006). However, there were no differences in severe complication rates, hospitalization, or liver function tests between the 2 groups at 3 months after donor surgery. The overall survival of recipients in the spousal group was not reduced compared to that of recipients in the children group. CONCLUSION The present study suggests that, with careful selection, spousal donation is feasible and safe in LDLT.
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Affiliation(s)
- Okjoo Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea.
| | - Sang Jin Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea
| | - Jinsoo Rhu
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea
| | - Gyu-Seong Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Korea
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Weighted Gene Coexpression Network Analysis in Mouse Livers following Ischemia-Reperfusion and Extensive Hepatectomy. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2022; 2021:3897715. [PMID: 35003298 PMCID: PMC8736699 DOI: 10.1155/2021/3897715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 11/23/2021] [Indexed: 11/17/2022]
Abstract
In mouse models, the recovery of liver volume is mainly mediated by the proliferation of hepatocytes after partial hepatectomy that is commonly accompanied with ischemia-reperfusion. The identification of differently expressed genes in liver following partial hepatectomy benefits the better understanding of the molecular mechanisms during liver regeneration (LR) with appliable clinical significance. Briefly, studying different gene expression patterns in liver tissues collected from the mice group that survived through extensive hepatectomy will be of huge critical importance in LR than those collected from the mice group that survived through appropriate hepatectomy. In this study, we performed the weighted gene coexpression network analysis (WGCNA) to address the central candidate genes and to construct the free-scale gene coexpression networks using the identified dynamic different expressive genes in liver specimens from the mice with 85% hepatectomy (20% for seven-day survial rate) and 50% hepatectomy (100% for seven-day survial rate under ischemia-reperfusion condition compared with the sham group control mice). The WGCNA combined with Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses pinpointed out the apparent distinguished importance of three gene expression modules: the blue module for apoptotic process, the turquoise module for lipid metabolism, and the green module for fatty acid metabolic process in LR following extensive hepatectomy. WGCNA analysis and protein-protein interaction (PPI) network construction highlighted FAM175B, OGT, and PDE3B were the potential three hub genes in the previously mentioned three modules. This work may help to provide new clues to the future fundamental study and treatment strategy for LR following liver injury and hepatectomy.
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11
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Lyu N, Yi JZ, Zhao M. Immunotherapy in older patients with hepatocellular carcinoma. Eur J Cancer 2021; 162:76-98. [PMID: 34954439 DOI: 10.1016/j.ejca.2021.11.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 10/31/2021] [Accepted: 11/21/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of cancer globally and is currently the third leading cause of cancer-related deaths. Recently, immunotherapy using immune checkpoint inhibitors (ICIs) has been shown with encouraging anticancer activity and safety in clinical trials. To reverse the phenomenon of tumours evading immune response, ICIs can be used to stimulate the natural antitumour potential of cancer cells by blocking the relevant checkpoints to activate T cells. However, the components and functions of the immune system may undergo a series of changes with ageing, known as 'immunosenescence,' potentially affecting the antitumour effect and safety of immunotherapy. In the current phase III clinical trials of ICIs including nivolumab, pembrolizumab and atezolizumab, the proportion of patients with HCC older than 65 years in CheckMate 459, KEYNOTE-240 and IMbrave150 is 51%, 58% and 50%, respectively, which is less than 70%-73% of epidemiological investigation. Therefore, the elderly population recruited in clinical trials may not accurately represent the real-world elderly patients with HCC, which affects the extrapolation of the efficacy and safety profile obtained in clinical trials to the elderly population in the real world. This review provides the latest advances in ICIs immuno-treatment available for HCC and relevant information about their therapeutic effects and safety on elderly patients. We discuss the benefits of ICIs for older HCC patients, and relevant recommendations about conducting further clinical trials are proposed for more complete answers to this clinical issue.
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Affiliation(s)
- Ning Lyu
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jun-Zhe Yi
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Ming Zhao
- Department of Minimally Invasive Interventional Therapy, Liver Cancer Study and Service Group, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, China; Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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12
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Jalil S, Black SM, Washburn K, Rangwani N, Hinton A, Kelly SG, Conteh L, Hanje J, Michaels A, Mumtaz K. Trends and Health Care Outcomes Among Living Liver Donors: Are We Ready to Expand the Donor Pool With Living Liver Donations? Liver Transpl 2021; 27:1603-1612. [PMID: 34213813 DOI: 10.1002/lt.26223] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 06/15/2021] [Indexed: 12/13/2022]
Abstract
We studied the trends and various outcomes, including the readmission rates, health care utilization, and complications among living liver donors (LLDs) in the United States. We queried the National Database for data from 2010 to 2017 for all LLDs. The primary outcomes were 30-day and 90-day readmission rates. The secondary outcomes included health care use (length of stay [LOS], cost of care), index admission, and calendar-year mortality. Logistic regression models were fit for various outcomes. A total of 1316 LLDs underwent hepatectomy during the study period. The median donor age was 35.0 years (interquartile range, 27.4-43.6), and donors were predominantly women (54.2%). The trend of LLD surgeries remained stable at large medical centers (85.3%). The 30-day and 90-day readmission rates were low at 5% and 5.9%, respectively. Older age (50 years and older; 8%; confidence interval [CI], 0.6%-15.9%; P = 0.03) and hepatectomy at small to medium-sized hospitals were associated with increased index LOS (13.4%; 95% CI, 3.1%-24.7%; P = 0.01). Moreover, older age of donor (-11.3%; 95% CI, -20.3% to -1.4%; P = 0.03), Elixhauser score ≥3 (17%; 95% CI, 1.2%-35.3%; P = 0.03), and Medicaid insurance (24.5%; 95% CI, 1.2%-53.1%; P = 0.04) were also associated with increased cost. The overall rate of any complications during index admission was 42.8%. Male sex (odds ratio [OR], 1.63; 95% CI, 1.19-2.23) was an independent predictor of post-LLD complications. There was no index admission or calendar-year mortality reported during the study period. This is the largest national report of LLDs to date, showing that the trend of LLD surgeries is stable in the United States. With established safety, fewer complications, and less health care utilization, LLDs can be a potential source of continuation of liver transplantation in the context of changing liver allocation policies in the United States.
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Affiliation(s)
- Sajid Jalil
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.,Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Sylvester M Black
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Ken Washburn
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Neil Rangwani
- Division of Hospital Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Alice Hinton
- Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Sean G Kelly
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.,Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Lanla Conteh
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.,Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - James Hanje
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.,Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Anthony Michaels
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.,Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Khalid Mumtaz
- Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.,Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
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Hu C, Zhao L, Zhang F, Li L. Regulation of autophagy protects against liver injury in liver surgery-induced ischaemia/reperfusion. J Cell Mol Med 2021; 25:9905-9917. [PMID: 34626066 PMCID: PMC8572770 DOI: 10.1111/jcmm.16943] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 08/10/2021] [Accepted: 09/08/2021] [Indexed: 12/16/2022] Open
Abstract
Transient ischaemia and reperfusion in liver tissue induce hepatic ischaemia/reperfusion (I/R) tissue injury and a profound inflammatory response in vivo. Hepatic I/R can be classified into warm I/R and cold I/R and is characterized by three main types of cell death, apoptosis, necrosis and autophagy, in rodents or patients following I/R. Warm I/R is observed in patients or animal models undergoing liver resection, haemorrhagic shock, trauma, cardiac arrest or hepatic sinusoidal obstruction syndrome when vascular occlusion inhibits normal blood perfusion in liver tissue. Cold I/R is a condition that affects only patients who have undergone liver transplantation (LT) and is caused by donated liver graft preservation in a hypothermic environment prior to entering a warm reperfusion phase. Under stress conditions, autophagy plays a critical role in promoting cell survival and maintaining liver homeostasis by generating new adenosine triphosphate (ATP) and organelle components after the degradation of macromolecules and organelles in liver tissue. This role of autophagy may contribute to the protection of hepatic I/R‐induced liver injury; however, a considerable amount of evidence has shown that autophagy inhibition also protects against hepatic I/R injury by inhibiting autophagic cell death under specific circumstances. In this review, we comprehensively discuss current strategies and underlying mechanisms of autophagy regulation that alleviates I/R injury after liver resection and LT. Directed autophagy regulation can maintain liver homeostasis and improve liver function in individuals undergoing warm or cold I/R. In this way, autophagy regulation can contribute to improving the prognosis of patients undergoing liver resection or LT.
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Affiliation(s)
- Chenxia Hu
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lingfei Zhao
- Key Laboratory of Kidney Disease Prevention and Control Technology, Kidney Disease Center, Institute of Nephrology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Fen Zhang
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lanjuan Li
- Collaborative Innovation Center for the Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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Abstract
Significance: During aging, excessive production of reactive species in the liver leads to redox imbalance with consequent oxidative damage and impaired organ homeostasis. Nevertheless, slight amounts of reactive species may modulate several transcription factors, acting as second messengers and regulating specific signaling pathways. These redox-dependent alterations may impact the age-associated decline in liver regeneration. Recent Advances: In the last few decades, relevant findings related to redox alterations in the aging liver were investigated. Consistently, recent research broadened understanding of redox modifications and signaling related to liver regeneration. Other than reporting the effect of oxidative stress, epigenetic and post-translational modifications, as well as modulation of specific redox-sensitive cellular signaling, were described. Among them, the present review focuses on Wnt/β-catenin, the nuclear factor (erythroid-derived 2)-like 2 (NRF2), members of the Forkhead box O (FoxO) family, and the p53 tumor suppressor. Critical Issues: Even though alteration in redox homeostasis occurs both in aging and in impaired liver regeneration, the associative mechanisms are not clearly defined. Of note, antioxidants are not effective in slowing hepatic senescence, and do not clearly improve liver repopulation after hepatectomy or transplant in humans. Future Directions: Further investigations are needed to define mutual redox-dependent molecular pathways involved both in aging and in the decline of liver regeneration. Preclinical studies aimed at the characterization of these pathways would define possible therapeutic targets for human trials. Antioxid. Redox Signal. 35, 832-847.
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Affiliation(s)
- Francesco Bellanti
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Gianluigi Vendemiale
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
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15
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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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Pavlović N, Heindryckx F. Exploring the Role of Endoplasmic Reticulum Stress in Hepatocellular Carcinoma through mining of the Human Protein Atlas. BIOLOGY 2021; 10:biology10070640. [PMID: 34356495 PMCID: PMC8301178 DOI: 10.3390/biology10070640] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 06/30/2021] [Accepted: 07/07/2021] [Indexed: 12/22/2022]
Abstract
Simple Summary Hepatocellular carcinoma is a highly deadly primary liver cancer. It is usually diagnosed at a late stage, when therapeutic options are scarce, and the lack of predictive biomarkers poses a challenge for early detection. A known hallmark of hepatocellular carcinoma is the accumulation of misfolded proteins in the endoplasmic reticulum (ER), known as ER-stress. Growing experimental evidence suggests that ER-stress is involved in liver cancer initiation and progression. However, it remains unclear if ER-stress markers can be used as therapeutic targets or biomarkers for patients with liver cancer. In this study, we evaluated the prognostic value of proteins involved in managing ER-stress in liver cancer by mining a publicly available patient-derived database, the Human Protein Atlas. We thereby identified 44 ER-stress-associated proteins as prognostic markers in liver cancer. Furthermore, we discussed the expression of these markers in relation to disease stage, age, sex, ethnicity, and tissue localization. Abstract Endoplasmic reticulum (ER) stress and actors of unfolded protein response (UPR) have emerged as key hallmarks of hepatocarcinogenesis. Numerous reports have shown that the main actors in the UPR pathways are upregulated in HCC and contribute to the different facets of tumor initiation and disease progression. Furthermore, ER-stress inducers and inhibitors have shown success in preclinical HCC models. Despite the mounting evidence of the UPR’s involvement in HCC pathogenesis, it remains unclear how ER-stress components can be used safely and effectively as therapeutic targets or predictive biomarkers for HCC patients. In an effort to add a clinical context to these findings and explore the translational potential of ER-stress in HCC, we performed a systematic overview of UPR-associated proteins as predictive biomarkers in HCC by mining the Human Protein Atlas database. Aside from evaluating the prognostic value of these markers in HCC, we discussed their expression in relation to patient age, sex, ethnicity, disease stage, and tissue localization. We thereby identified 44 UPR-associated proteins as unfavorable prognostic markers in HCC. The expression of these markers was found to be higher in tumors compared to the stroma of the hepatic HCC patient tissues.
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Yoshiya S, Harada N, Tomiyama T, Takeishi K, Toshima T, Iguchi T, Itoh S, Ninomiya M, Yoshizumi T, Mori M. The Significant Prognostic Factors in Prolonged Intensive/High Care Unit Stay After Living Donor Liver Transplantation. Transplant Proc 2021; 53:1630-1638. [PMID: 33934913 DOI: 10.1016/j.transproceed.2021.02.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 01/09/2021] [Accepted: 02/25/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Prolonged stay in an intensive/high care unit (ICU/HCU) after living donor liver transplantation (LDLT) is a significant event with possible mortality. METHODS Adult-to-adult LDLTs (n = 283) were included in this study. Univariate and multivariate analyses were performed for the factors attributed to the prolonged ICU/HCU stay after LDLT. RESULTS Recipients who stayed in the ICU/HCU 9 days or longer were defined as the prolonged group. The prolonged group was older (P = .0010), had a higher model for end-stage liver disease scores (P < .0001), and had higher proportions of patients with preoperative hospitalization (P < .0001). Delirium (P < .0001), pulmonary complications (P < .0001), sepsis (P < .0001), reintubation or tracheostomy (P < .0001), relaparotomy due to bleeding (P = .0015) or other causes (P < .0001), and graft dysfunction (P < .0001) were associated with prolonged ICU/HCU stay. Only sepsis (P = .015) and graft dysfunction (P = .019) were associated with in-hospital mortality among patients with prolonged ICU/HCU stay or graft loss within 9 days of surgery. Among these patients, grafts from donors aged <42 years and with a graft-to-recipient weight ratio of >0.76% had significantly higher graft survival than grafts from others (P = .0013 and P < .0001, respectively). CONCLUSION Prolonged ICU/HCU stay after LDLT was associated with worse short-term outcomes. The use of grafts of sufficient volume from younger donors might improve graft survival.
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Affiliation(s)
- Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Noboru Harada
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takahiro Tomiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuki Takeishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Toshima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomohiro Iguchi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Mizuki Ninomiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Ivanics T, Abreu P, De Martin E, Sapisochin G. Changing Trends in Liver Transplantation: Challenges and Solutions. Transplantation 2021; 105:743-756. [PMID: 32910093 DOI: 10.1097/tp.0000000000003454] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Despite improvements in postliver transplant outcomes through refinements in perioperative management and surgical techniques, several changing trends in liver transplantation have presented challenges. Mortality on the waitlist remains high. In the United States, Europe, and the United Kingdom, there is an increasing need for liver transplantation, primarily as a result of increased incidence of nonalcoholic steatohepatitis-related cirrhosis and cancer indications. Meanwhile, donor suitability has decreased, as donors are often older and have more comorbidities. Despite a mismatch between organ need and availability, many organs are discarded. Notwithstanding this, many solutions have been developed to overcome these challenges. Innovative techniques in allograft preservation, viability assessment, and reconditioning have allowed the use of suboptimal organs with adequate results. Refinements in surgical procedures, including live donor liver transplantations, have increased the organ pool and are decreasing the time and mortality on the waitlist. Despite many challenges, a similar number of solutions and prospects are on the horizon. This review seeks to explore the changing trends and challenges in liver transplantation and highlight possible solutions and future directions.
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Affiliation(s)
- Tommy Ivanics
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Phillipe Abreu
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
| | - Eleonora De Martin
- APHP, Hôpital Paul Brousse, Centre Hépato-Biliaire, INSERM 1193, Université Paris-Sud, DHU Hepatinov, Villejuif, France
| | - Gonzalo Sapisochin
- Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada
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19
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A prognostic score for patients with acute-on-chronic liver failure treated with plasma exchange-centered artificial liver support system. Sci Rep 2021; 11:1469. [PMID: 33446902 PMCID: PMC7809456 DOI: 10.1038/s41598-021-81019-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 12/30/2020] [Indexed: 02/05/2023] Open
Abstract
Artificial liver support system (ALSS) therapy is widely used in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). We aimed to develop a predictive score to identify the subgroups who may benefit from plasma exchange (PE)-centered ALSS therapy. A total of 601 patients were retrospectively enrolled and randomly divided into a derivation cohort of 303 patients and a validation cohort of 298 patients for logistic regression analysis, respectively. Five baseline variables, including liver cirrhosis, total bilirubin, international normalized ratio of prothrombin time, infection and hepatic encephalopathy, were found independently associated with 3-month mortality. A predictive PALS model and the simplified PALS score were developed. The predicative value of PALS score (AUROC = 0.818) to 3-month prognosis was as capable as PALS model (AUROC = 0.839), R score (AUROC = 0.824) and Yue-Meng’ score (AUROC = 0.810) (all p > 0.05), and superior to CART model (AUROC = 0.760) and MELD score (AUROC = 0.765) (all p < 0.05). The PALS score had significant linear correlation with 3-month mortality (R2 = 0.970, p = 0.000). PALS score of 0–2 had both sensitivity and negative predictive value of > 90% for 3-month mortality, while PALS score of 6–9 had both specificity and positive predictive value of > 90%. Patients with PALS score of 3–5 who received 3–5 sessions of ALSS therapy had much lower 3-month mortality than those who received 1–2 sessions (32.8% vs. 59.2%, p < 0.05). The more severe patients with PALS score of 6–9 could still benefit from ≥ 6 sessions of ALSS therapy compared to ≤ 2 sessions (63.6% vs. 97.0%, p < 0.05). The PALS score could predict prognosis reliably and conveniently. It could identify the subgroups who could benefit from PE-centered ALSS therapy, and suggest the reasonable sessions. Trial registration: Chinese Clinical Trial Registry, ChiCTR2000032055. Registered 19th April 2020, http://www.chictr.org.cn/showproj.aspx?proj=52471.
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Barros PP, Eisinger ABDC, GonÇalves GMS, Silva GHD. ORAL RUTIN SUSPENSION INTERVENE IN HEPATIC HYPERPLASIA IN RATS. ARQUIVOS DE GASTROENTEROLOGIA 2020; 57:296-299. [PMID: 33027481 DOI: 10.1590/s0004-2803.202000000-54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 06/11/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Rutin is a flavonol glycoside that can be found in a wide variety of vegetables and has activity, anti-cancer, anti-inflammatory and anti-diabetic properties. OBJECTIVE This study investigated the effect of rutin oral administration on Wistar rats submitted to hepatic hyperplasia after partial hepatectomy (PH). METHODS To achieve this, we considered the analysis of hepatic hyperplastic and plasma biochemical activity of Wistar rats, subjected to treatment with rutin 40 mg/kg/day for 10 days in group 1 (G1) or saline in group 2 (G2), followed by partial hepatectomy. RESULTS The results indicated an increase in the number of mitoses after 24 hours and 48 hours (P=0.0022 and P=0.0152, respectively) of PH in the group that received rutin, as well as an increase in AST serum levels after 24 hours (P=0.0159) and 48 hours (P=0.0158) and alkaline phosphatase after 24 hours (P=0.015) in the same group, in relation to the respective controls. The group that received rutin showed a more evident variation than the control group when comparing the 24 hour and 48 hour results regarding AST, number of mitoses and number of apoptosis (P<0.005). CONCLUSION It was concluded that rutin intervened in hepatic hyperplasia after 24 hours and 48 hours of PH, favoring hepatic hyperplasia.
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Affiliation(s)
- Pedro Paulo Barros
- Pontifícia Universidade Católica de Campinas, Faculdade de Ciências Farmacêuticas, Campinas, SP, Brasil
| | | | - Gisele Mara Silva GonÇalves
- Pontifícia Universidade Católica de Campinas, Programa de Pós Graduação em Ciências da Saúde, Campinas, SP, Brasil
| | - Gustavo Henrique da Silva
- Pontifícia Universidade Católica de Campinas, Faculdade de Ciências Farmacêuticas, Campinas, SP, Brasil
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21
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Xu F, Hua C, Tautenhahn HM, Dirsch O, Dahmen U. The Role of Autophagy for the Regeneration of the Aging Liver. Int J Mol Sci 2020; 21:ijms21103606. [PMID: 32443776 PMCID: PMC7279469 DOI: 10.3390/ijms21103606] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/15/2020] [Accepted: 05/18/2020] [Indexed: 02/07/2023] Open
Abstract
Age is one of the key risk factors to develop malignant diseases leading to a high incidence of hepatic tumors in the elderly population. The only curative treatment for hepatic tumors is surgical removal, which initiates liver regeneration. However, liver regeneration is impaired with aging, leading to an increased surgical risk for the elderly patient. Due to the increased risk, those patients are potentially excluded from curative surgery. Aging impairs autophagy via lipofuscin accumulation and inhibition of autophagosome formation. Autophagy is a recycling mechanism for eukaryotic cells to maintain homeostasis. Its principal function is to degrade endogenous bio-macromolecules for recycling cellular substances. A number of recent studies have shown that the reduced regenerative capacity of the aged remnant liver can be restored by promoting autophagy. Autophagy can be activated via multiple mTOR-dependent and mTOR-independent pathways. However, inducing autophagy through the mTOR-dependent pathway alone severely impairs liver regeneration. In contrast, recent observations suggest that inducing autophagy via mTOR-independent pathways might be promising in promoting liver regeneration. Conclusion: Activation of autophagy via an mTOR-independent autophagy inducer is a potential therapy for promoting liver regeneration, especially in the elderly patients at risk.
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Affiliation(s)
- Fengming Xu
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Chuanfeng Hua
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Hans-Michael Tautenhahn
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
| | - Olaf Dirsch
- Institute of Pathology, Klinikum Chemnitz gGmbH, 09111 Chemnitz, Germany;
| | - Uta Dahmen
- Department of General, Visceral and Vascular Surgery, Jena University Hospital, 07747 Jena, Germany; (F.X.); (C.H.); (H.-M.T.)
- Correspondence: ; Tel.: +49-03641-9325350
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22
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Pravisani R, Soyama A, Ono S, Baccarani U, Isola M, Takatsuki M, Hidaka M, Adachi T, Hara T, Hamada T, Pecquenard F, Risaliti A, Eguchi S. Is there any correlation between liver graft regeneration and recipient's pretransplant skeletal muscle mass?-a study in extended left lobe graft living-donor liver transplantation. Hepatobiliary Surg Nutr 2020; 9:183-194. [PMID: 32355676 PMCID: PMC7188548 DOI: 10.21037/hbsn.2019.11.08] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 05/16/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND The end-stage liver disease causes a metabolic dysfunction whose most prominent clinical feature is the loss of skeletal muscle mass (SMM). In living-donor liver transplantation (LDLT), liver graft regeneration (GR) represents a crucial process to normalize the portal hypertension and to meet the metabolic demand of the recipient. Limited data are available on the correlation between pre-LDLT low SMM and GR. METHODS Retrospective study on a cohort of 106 LDLT patients receiving an extended left liver lobe graft. The skeletal muscle index (SMI) at L3 level was used for muscle mass measurement, and the recommended cut-off values of the Japanese Society of Hepatology guidelines were used as criteria for defining low muscularity. GR was evaluated as rate of volume increase at 1 month post-LT [graft regeneration rate (GRR)]. RESULTS The median GRR at 1 month post-LT was 91% (IQR, 65-128%) and a significant correlation with graft volume-to-recipient standard liver volume ratio (GV/SLV) (rho -0.467, P<0.001), graft-to-recipient weight ratio (GRWR) (rho -0.414, P<0.001), donor age (rho -0.306, P=0.001), 1 month post-LT cholinesterase serum levels (rho 0.397, P=0.002) and pre-LT low muscularity [absent vs. present GRR 97.5% (73.1-130%) vs. 83.5% (45.2-110.9%), P=0.041] was noted. Moreover in male recipients, but not in women, it was shown a direct correlation with pre-LT SMI (rho 0.352, P=0.020) and inverse correlation with 1 month post-LT SMI variation (rho -0.301, P=0.049). A low GRR was identified as an independent prognostic factor for recipient overall survival (HR 6.045, P<0.001). CONCLUSIONS Additionally to the hemodynamic factors of portal circulation and the quality of the graft, the metabolic status of the recipients has a significant role in the GR process. A pre-LT low SMM is associated with impaired GRR and this negative impact is more evident in male recipients.
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Affiliation(s)
- Riccardo Pravisani
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Liver-Kidney Transplant Unit, Department of Medicine, University of Udine, Udine, Italy
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Shinichiro Ono
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Umberto Baccarani
- Liver-Kidney Transplant Unit, Department of Medicine, University of Udine, Udine, Italy
| | - Miriam Isola
- Division of Medical Statistic, Department of Medicine, University of Udine, Udine, Italy
| | - Mitsuhisa Takatsuki
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takanobu Hara
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Takashi Hamada
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Florian Pecquenard
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Andrea Risaliti
- Liver-Kidney Transplant Unit, Department of Medicine, University of Udine, Udine, Italy
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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23
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Rohn F, Kordes C, Buschmann T, Reichert D, Wammers M, Poschmann G, Stühler K, Benk AS, Geiger F, Spatz JP, Häussinger D. Impaired integrin α 5 /β 1 -mediated hepatocyte growth factor release by stellate cells of the aged liver. Aging Cell 2020; 19:e13131. [PMID: 32157808 PMCID: PMC7189994 DOI: 10.1111/acel.13131] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 01/20/2020] [Accepted: 02/16/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatic blood flow and sinusoidal endothelial fenestration decrease during aging. Consequently, fluid mechanical forces are reduced in the space of Disse where hepatic stellate cells (HSC) have their niche. We provide evidence that integrin α5 /β1 is an important mechanosensor in HSC involved in shear stress-induced release of hepatocyte growth factor (HGF), an essential inductor of liver regeneration which is impaired during aging. The expression of the integrin subunits α5 and β1 decreases in liver and HSC from aged rats. CRISPR/Cas9-mediated integrin α5 and β1 knockouts in isolated HSC lead to lowered HGF release and impaired cellular adhesion. Fluid mechanical forces increase integrin α5 and laminin gene expression whereas integrin β1 remains unaffected. In the aged liver, laminin β2 and γ1 protein chains as components of laminin-521 are lowered. The integrin α5 knockout in HSC reduces laminin expression via mechanosensory mechanisms. Culture of HSC on nanostructured surfaces functionalized with laminin-521 enhances Hgf expression in HSC, demonstrating that these ECM proteins are critically involved in HSC function. During aging, HSC acquire a senescence-associated secretory phenotype and lower their growth factor expression essential for tissue repair. Our findings suggest that impaired mechanosensing via integrin α5 /β1 in HSC contributes to age-related reduction of ECM and HGF release that could affect liver regeneration.
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Affiliation(s)
- Friederike Rohn
- Clinic of Gastroenterology, Hepatology and Infectious Diseases Heinrich Heine University Düsseldorf Germany
| | - Claus Kordes
- Clinic of Gastroenterology, Hepatology and Infectious Diseases Heinrich Heine University Düsseldorf Germany
| | - Tobias Buschmann
- Clinic of Gastroenterology, Hepatology and Infectious Diseases Heinrich Heine University Düsseldorf Germany
| | - Doreen Reichert
- Clinic of Gastroenterology, Hepatology and Infectious Diseases Heinrich Heine University Düsseldorf Germany
| | - Marianne Wammers
- Clinic of Gastroenterology, Hepatology and Infectious Diseases Heinrich Heine University Düsseldorf Germany
| | - Gereon Poschmann
- Institute for Molecular Medicine Heinrich Heine University Düsseldorf Germany
| | - Kai Stühler
- Institute for Molecular Medicine Heinrich Heine University Düsseldorf Germany
- Molecular Proteomics Laboratory BMFZ Heinrich Heine University Düsseldorf Düsseldorf Germany
| | - Amelie S. Benk
- Department of Cellular Biophysics Max‐Planck‐Institute for Medical Research Heidelberg Germany
- Department of Biophysical Chemistry University of Heidelberg Heidelberg Germany
| | - Fania Geiger
- Department of Cellular Biophysics Max‐Planck‐Institute for Medical Research Heidelberg Germany
- Department of Biophysical Chemistry University of Heidelberg Heidelberg Germany
| | - Joachim P. Spatz
- Department of Cellular Biophysics Max‐Planck‐Institute for Medical Research Heidelberg Germany
- Department of Biophysical Chemistry University of Heidelberg Heidelberg Germany
| | - Dieter Häussinger
- Clinic of Gastroenterology, Hepatology and Infectious Diseases Heinrich Heine University Düsseldorf Germany
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24
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Ritschka B, Knauer-Meyer T, Gonçalves DS, Mas A, Plassat JL, Durik M, Jacobs H, Pedone E, Di Vicino U, Cosma MP, Keyes WM. The senotherapeutic drug ABT-737 disrupts aberrant p21 expression to restore liver regeneration in adult mice. Genes Dev 2020; 34:489-494. [PMID: 32139422 PMCID: PMC7111259 DOI: 10.1101/gad.332643.119] [Citation(s) in RCA: 72] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 02/04/2020] [Indexed: 12/15/2022]
Abstract
In this study, Ritschka et al. investigated whether cellular senescence might play a role in loss of regenerative capacity during liver regeneration. They show that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response, and that treatment with a senescence-inhibiting drug improves regeneration through targeting aberrantly prolonged p21 expression. Young mammals possess a limited regenerative capacity in some tissues, which is lost upon maturation. We investigated whether cellular senescence might play a role in such loss during liver regeneration. We found that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arf become dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response. However, we show that treatment with a senescence-inhibiting drug improves regeneration, by disrupting aberrantly prolonged p21 expression. This work suggests that senescence may initially develop from heterogeneous cellular responses, and that senotherapeutic drugs might be useful in promoting organ regeneration.
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Affiliation(s)
- Birgit Ritschka
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.,UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France.,U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France.,Université de Strasbourg, Illkirch 67404, France.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain
| | - Tania Knauer-Meyer
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.,UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France.,U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France.,Université de Strasbourg, Illkirch 67404, France
| | - Daniel Sampaio Gonçalves
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.,UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France.,U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France.,Université de Strasbourg, Illkirch 67404, France
| | - Alba Mas
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.,UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France.,U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France.,Université de Strasbourg, Illkirch 67404, France.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain
| | - Jean-Luc Plassat
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.,UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France.,U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France.,Université de Strasbourg, Illkirch 67404, France
| | - Matej Durik
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.,UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France.,U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France.,Université de Strasbourg, Illkirch 67404, France
| | - Hugues Jacobs
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.,UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France.,U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France.,Université de Strasbourg, Illkirch 67404, France
| | - Elisa Pedone
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain
| | - Umberto Di Vicino
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain
| | - Maria Pia Cosma
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.,Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain.,Institución Catalana de Investigación y Estudios Avanzados (ICREA), Barcelona 08010, Spain
| | - William M Keyes
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch 67404, France.,UMR7104, Centre National de la Recherche Scientifique (CNRS), Illkirch 67404, France.,U1258, Institut National de la Santé et de la Recherche Médicale (INSERM), Illkirch 67404, France.,Université de Strasbourg, Illkirch 67404, France.,Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain.,Universitat Pompeu Fabra (UPF), Barcelona 08003, Spain
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25
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Kojima H, Nakamura K, Kupiec-Weglinski JW. Therapeutic targets for liver regeneration after acute severe injury: a preclinical overview. Expert Opin Ther Targets 2020; 24:13-24. [PMID: 31906729 DOI: 10.1080/14728222.2020.1712361] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: Liver transplantation is the only viable treatment with a proven survival benefit for acute liver failure (ALF). Donor organ shortage is, however, a major hurdle; hence, alternative approaches that enable liver regeneration and target acute severe hepatocellular damage are necessary.Areas covered: This article sheds light on therapeutic targets for liver regeneration and considers their therapeutic potential. ALF following extensive hepatocyte damage and small-for-size syndrome (SFSS) are illuminated for the reader while the molecular mechanisms of liver regeneration are assessed in accordance with relevant therapeutic strategies. Furthermore, liver background parameters and predictive biomarkers that might associate with liver regeneration are reviewed.Expert opinion: There are established and novel experimental strategies for liver regeneration to prevent ALF resulting from SFSS. Granulocyte-colony stimulating factor (G-CSF) is a promising agent targeting liver regeneration after acute severe injury. Autophagy and hepatocyte senescence represent attractive new targets for liver regeneration in acute severe hepatic injury. Liver support strategies, including tissue engineering, constitute novel regenerative means; the success of this is dependent on stem cell research advances. However, there is no firm clinical evidence that these supportive strategies may alleviate hepatocellular damage until liver transplantation becomes available or successful self-liver regeneration occurs.
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Affiliation(s)
- Hidenobu Kojima
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Kojiro Nakamura
- Department of Surgery, Kyoto University, Kyoto, Japan.,Department of Surgery, Nishi-Kobe Medical Center, Kobe, Japan
| | - Jerzy W Kupiec-Weglinski
- The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
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26
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Zhao E, Shen Y, Amir M, Farris AB, Czaja MJ. Stathmin 1 Induces Murine Hepatocyte Proliferation and Increased Liver Mass. Hepatol Commun 2020; 4:38-49. [PMID: 31909354 PMCID: PMC6939544 DOI: 10.1002/hep4.1447] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 10/20/2019] [Indexed: 12/15/2022] Open
Abstract
The endogenous cellular signals that initiate the transition of hepatocytes from quiescence to proliferation remain unclear. The protein stathmin 1 (STMN1) is highly expressed in dividing cells, including hepatocytes, and functions to promote cell mitosis through physical interactions with tubulin and microtubules that regulate mitotic spindle formation. The recent finding that STMN1 mediates the resistance of cultured hepatocytes to oxidant stress led to an examination of the expression and function of this protein in the liver in vivo. STMN1 messenger RNA (mRNA) and protein were essentially undetectable in normal mouse liver but increased markedly in response to oxidant injury from carbon tetrachloride. Similarly, levels of STMN1 mRNA and protein were increased in human livers from patients with acute fulminant hepatic failure. To determine STMN1 function in the liver in vivo, mice were infected with a control or Stmn1-expressing adenovirus. Stmn1 expression induced spontaneous liver enlargement with a doubling of the liver to body weight ratio. The increase in liver mass resulted, in part, from hepatocellular hypertrophy but mainly from an induction of hepatocyte proliferation. STMN1 expression led to marked increases in the numbers of 5-bromo-2'-deoxyuridine-positive and mitotic hepatocytes and hepatic nuclear levels of cyclins and cyclin-dependent kinases. STMN1-induced hepatocyte proliferation was followed by an apoptotic response and a return of the liver to its normal mass. Conclusion: STMN1 promotes entry of quiescent hepatocytes into the cell cycle. STMN1 expression by itself in the absence of any reduction in liver mass is sufficient to stimulate a hepatic proliferative response that significantly increases liver mass.
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Affiliation(s)
- Enpeng Zhao
- Department of Genetics and Genomic SciencesIcahn School of Medicine at Mount SinaiNew YorkNY
| | - Yang Shen
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGA
| | - Muhammad Amir
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGA
| | - Alton B. Farris
- Department of Pathology and Laboratory MedicineEmory University School of MedicineAtlantaGA
| | - Mark J. Czaja
- Division of Digestive DiseasesDepartment of MedicineEmory University School of MedicineAtlantaGA
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27
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Ethical Implications in Donor and Recipient Utilization for Liver Transplant. CURRENT TRANSPLANTATION REPORTS 2019. [DOI: 10.1007/s40472-019-00252-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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28
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Ozaki M. Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol 2019; 100:62-73. [PMID: 31669133 DOI: 10.1016/j.semcdb.2019.10.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 01/08/2023]
Abstract
Liver regeneration is an important and necessary process that the liver depends on for recovery from injury. The regeneration process consists of a complex network of cells and organs, including liver cells (parenchymal and non-parenchymal cells) and extrahepatic organs (thyroid, adrenal glands, pancreas, duodenum, spleen, and autonomic nervous system). The regeneration process of a normal, healthy liver depends mainly on hepatocyte proliferation, growth, and programmed cell death. Cell proliferation and growth are regulated in a cooperative manner by interleukin (IL)-6/janus kinase (Jak)/signal transducers and activators of transcription-3 (STAT3), and phosphoinositide 3-kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathways. The IL-6/Jak/STAT3 pathway regulates hepatocyte proliferation and protects against cell death and oxidative stress. The PI3-K/PDK1/Akt pathway is primarily responsible for the regulation of cell size, sending mitotic signals in addition to pro-survival, antiapoptotic and antioxidative signals. Though programmed cell death may interfere with liver regeneration in a pathological situation, it seems to play an important role during the termination phase, even in a normal, healthy liver regeneration. However, further study is needed to fully elucidate the mechanisms regulating the processes of liver regeneration with regard to cell-to-cell and organ-to-organ networks at the molecular and cellular levels.
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Affiliation(s)
- Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
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29
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Pibiri M. Liver regeneration in aged mice: new insights. Aging (Albany NY) 2019; 10:1801-1824. [PMID: 30157472 PMCID: PMC6128415 DOI: 10.18632/aging.101524] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 08/10/2018] [Indexed: 02/06/2023]
Abstract
The regenerative capacity of the liver after resection is reduced with aging. Recent studies on rodents revealed that both intracellular and extracellular factors are involved in the impairment of liver mass recovery during aging. Among the intracellular factors, age-dependent decrease of BubR1 (budding uninhibited by benzimidazole-related 1), YAP (Yes-associated protein) and SIRT1 (Sirtuin-1) have been associated to dampening of tissue reconstitution and inhibition of cell cycle genes following partial hepatectomy. Extra-cellular factors, such as age-dependent changes in hepatic stellate cells affect liver regeneration through inhibition of progenitor cells and reduction of liver perfusion. Furthermore, chronic release of pro-inflammatory proteins by senescent cells (SASP) affects cell proliferation suggesting that senescent cell clearance might improve tissue regeneration. Accordingly, young plasma restores liver regeneration in aged animals through autophagy re-establishment. This review will discuss how intracellular and extracellular factors cooperate to guarantee a proper liver regeneration and the possible causes of its impairment during aging. The possibility that an improvement of the liver regenerative capacity in elderly might be achieved through elimination of senescent cells via autophagy or by administration of direct mitogenic agents devoid of cytotoxicity will also be entertained.
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Affiliation(s)
- Monica Pibiri
- Department of Biomedical Sciences, Oncology and Molecular Pathology Unit, University of Cagliari, Cagliari 09124, Italy
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Impact of Donor Age on Recipient Survival in Adult-to-Adult Living-donor Liver Transplantation. Ann Surg 2019; 267:1126-1133. [PMID: 28288061 DOI: 10.1097/sla.0000000000002194] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To investigate the influence of donor age on recipient outcome after living-donor partial liver transplantation (LDLT). BACKGROUND Donor age is a well-known prognostic factor in deceased donor liver transplantation; however, its role in LDLT remains unclear. METHODS We retrospectively analyzed 315 consecutive cases of primary adult-to-adult LDLT in our center between April 2006 and March 2014. Recipients were divided into 5 groups according to the donor age: D-20s (n = 60); D-30s (n = 72); D-40s (n = 57); D-50s (n = 94); and D-60s (n = 32). The recipient survival and the association with various clinical factors were investigated. RESULTS Recipient survival proportions were significantly higher in D-20s compared with all the other groups (P = 0.008, < 0.001, < 0.001, and = 0.006, vs D-30s, -40s, -50s, and -60s, respectively), whereas there was no association between recipient survival and their own age. There are 3 typical relationships between donors and recipients in adult-to-adult LDLT: from child-to-parent, between spouses/siblings, and from parent-to-child. The overall survival in child-to-parent was significantly higher than in spouses/siblings (P = 0.002) and in parent-to-child (P = 0.005), despite significantly higher recipient age in child-to-parent [59 (42-69) years, P < 0.001]. Contrastingly, parent-to-child exhibited the lowest survival, despite the youngest recipient age [26 (20-43) years, P < 0.001]. In addition, younger donor age exhibited significantly better recipient survival both in hepatitis C virus-related and in non-hepatitis C virus diseases. Univariate and multivariate analyses both demonstrated that donor age and graft-type (right-sided livers) are independent prognostic factors for recipient survival. CONCLUSIONS Donor age is an independent, strong prognostic factor in adult-to-adult LDLT.
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Mesenchymal Stem Cells for Liver Regeneration in Liver Failure: From Experimental Models to Clinical Trials. Stem Cells Int 2019; 2019:3945672. [PMID: 31191671 PMCID: PMC6525815 DOI: 10.1155/2019/3945672] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 03/05/2019] [Accepted: 03/20/2019] [Indexed: 02/07/2023] Open
Abstract
The liver centralizes the systemic metabolism and thus controls and modulates the functions of the central and peripheral nervous systems, the immune system, and the endocrine system. In addition, the liver intervenes between the splanchnic and systemic venous circulation, determining an abdominal portal circulatory system. The liver displays a powerful regenerative potential that rebuilds the parenchyma after an injury. This regenerative mission is mainly carried out by resident liver cells. However, in many cases this regenerative capacity is insufficient and organ failure occurs. In normal livers, if the size of the liver is at least 30% of the original volume, hepatectomy can be performed safely. In cirrhotic livers, the threshold is 50% based on current practice and available data. Typically, portal vein embolization of the part of the liver that is going to be resected is employed to allow liver regeneration in two-stage liver resection after portal vein occlusion (PVO). However, hepatic resection often cannot be performed due to advanced disease progression or because it is not indicated in patients with cirrhosis. In such cases, liver transplantation is the only treatment possibility, and the need for transplantation is the common outcome of progressive liver disease. It is the only effective treatment and has high survival rates of 83% after the first year. However, donated organs are becoming less available, and mortality and the waiting lists have increased, leading to the initiation of living donor liver transplantations. This type of transplant has overall complications of 38%. In order to improve the treatment of hepatic injury, much research has been devoted to stem cells, in particular mesenchymal stem cells (MSCs), to promote liver regeneration. In this review, we will focus on the advances made using MSCs in animal models, human patients, ongoing clinical trials, and new strategies using 3D organoids.
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Abstract
The average age of liver transplant donors and recipients has increased over the years. Independent of the cause of liver disease, older candidates have more comorbidities, higher waitlist mortality and higher post-transplant mortality than younger patients. However, transplant benefit may be similar in older and younger recipients, provided older recipients are carefully selected. The cohort of elderly patients transplanted decades ago is also increasingly raising issues concerning long-term exposure to immunosuppression and aging of the transplanted liver. Excellent results can be achieved with elderly donors and there is virtually no upper age limit for donors after brain death liver transplantation. The issue is how to optimise selection, procurement and matching to ensure good results with elderly donors. The impact of old donor age is more pronounced in younger recipients and patients with a high model for end-stage liver disease score. Age matching between the donor and the recipient should be incorporated into allocation policies with a multistep approach. However, age matching may vary depending on the objectives of different allocation policies. In addition, age matching must be revisited in the era of direct-acting antivirals. More restrictive limits have been adopted in donation after circulatory death. Perfusion machines which are currently under investigation may help expand these limits. In living donor liver transplantation, donor age limit is essentially guided by morbidity related to procurement. In this review we summarise changing trends in recipient and donor age. We discuss the implications of older age donors and recipients. We also consider different options for age matching in liver transplantation that could improve outcomes.
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Wabitsch S, Benzing C, Krenzien F, Splith K, Haber PK, Arnold A, Nösser M, Kamali C, Hermann F, Günther C, Hirsch D, Sauer IM, Pratschke J, Schmelzle M. Human Stem Cells Promote Liver Regeneration After Partial Hepatectomy in BALB/C Nude Mice. J Surg Res 2019; 239:191-200. [PMID: 30844633 DOI: 10.1016/j.jss.2019.02.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 01/16/2019] [Accepted: 02/05/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have been suggested to augment liver regeneration after surgically and pharmacologically induced liver failure. To further investigate this we processed human bone marrow-derived MSC according to good manufacturing practice (GMP) and tested those cells for their modulatory capacities of metabolic alterations and liver regeneration after partial hepatectomy in BALB/c nude mice. METHODS Human MSCs were obtained by bone marrow aspiration of healthy donors as in a previously described GMP process. Transgenic GFP-MSCs were administered i.p. 24 h after 70% hepatectomy in BALB/c nude mice, whereas control mice received phosphate-buffered saline. Mice were sacrificed 2, 3, and 5 d after partial hepatectomy. Blood and organs were harvested and metabolic alterations as well as liver regeneration subsequently assessed by liver function tests, multianalyte profiling immunoassays, histology, and immunostaining. RESULTS Hepatocyte and sinusoidal endothelial cell proliferation were significantly increased after partial hepatectomy in mice receiving MSC compared to control mice (Hepatocyte postoperative day 3, P < 0.01; endothelial cell postoperative day 5, P < 0.05). Hepatocyte fat accumulation correlated inversely with hepatocyte proliferation (r2 = 0.4064, P < 0.01) 2 d after partial hepatectomy, with mice receiving MSC being protected from severe fat accumulation. No GFP-positive cells could be detected in the samples. Serum levels of IL-6, HGF, and IL-10 were significantly decreased at day 3 in mice receiving MSC when compared to control mice (P < 0.05). Relative body weight loss was significantly attenuated after partial hepatectomy in mice receiving MSC (2 d and 3 d, both P < 0.001) with a trend toward a faster relative restoration of liver weight, when compared to control mice. CONCLUSIONS Human bone marrow-derived MSC attenuate metabolic alterations and improve liver regeneration after partial hepatectomy in BALB/c nude mice. Obtained results using GMP-processed human MSC suggest functional links between fat accumulation and hepatocyte proliferation, without any evidence for cellular homing. This study using GMP-proceeded MSC has important regulatory implications for an urgently needed translation into a clinical trial.
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Affiliation(s)
- Simon Wabitsch
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany.
| | - Christian Benzing
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Felix Krenzien
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Katrin Splith
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Philipp Konstantin Haber
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Alexander Arnold
- Departement of Pathology, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Maximilian Nösser
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Can Kamali
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | | | | | | | - Igor M Sauer
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Johann Pratschke
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
| | - Moritz Schmelzle
- Department of Surgery, Campus Charité Mitte and Campus Virchow-Klinikum, Charité - Universitaetsmedizin, Berlin, Germany
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Verma BK, Subramaniam P, Vadigepalli R. Model-based virtual patient analysis of human liver regeneration predicts critical perioperative factors controlling the dynamic mode of response to resection. BMC SYSTEMS BIOLOGY 2019; 13:9. [PMID: 30651095 PMCID: PMC6335689 DOI: 10.1186/s12918-019-0678-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 01/02/2019] [Indexed: 11/10/2022]
Abstract
BACKGROUND Liver has the unique ability to regenerate following injury, with a wide range of variability of the regenerative response across individuals. Existing computational models of the liver regeneration are largely tuned based on rodent data and hence it is not clear how well these models capture the dynamics of human liver regeneration. Recent availability of human liver volumetry time series data has enabled new opportunities to tune the computational models for human-relevant time scales, and to predict factors that can significantly alter the dynamics of liver regeneration following a resection. METHODS We utilized a mathematical model that integrates signaling mechanisms and cellular functional state transitions. We tuned the model parameters to match the time scale of human liver regeneration using an elastic net based regularization approach for identifying optimal parameter values. We initially examined the effect of each parameter individually on the response mode (normal, suppressed, failure) and extent of recovery to identify critical parameters. We employed phase plane analysis to compute the threshold of resection. We mapped the distribution of the response modes and threshold of resection in a virtual patient cohort generated in silico via simultaneous variations in two most critical parameters. RESULTS Analysis of the responses to resection with individual parameter variations showed that the response mode and extent of recovery following resection were most sensitive to variations in two perioperative factors, metabolic load and cell death post partial hepatectomy. Phase plane analysis identified two steady states corresponding to recovery and failure, with a threshold of resection separating the two basins of attraction. The size of the basin of attraction for the recovery mode varied as a function of metabolic load and cell death sensitivity, leading to a change in the multiplicity of the system in response to changes in these two parameters. CONCLUSIONS Our results suggest that the response mode and threshold of failure are critically dependent on the metabolic load and cell death sensitivity parameters that are likely to be patient-specific. Interventions that modulate these critical perioperative factors may be helpful to drive the liver regenerative response process towards a complete recovery mode.
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Affiliation(s)
- Babita K Verma
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
- Department of Chemical Engineering, Indian Institute of Technology-Madras, Chennai, India
| | | | - Rajanikanth Vadigepalli
- Daniel Baugh Institute for Functional Genomics/Computational Biology, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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Vagus-macrophage-hepatocyte link promotes post-injury liver regeneration and whole-body survival through hepatic FoxM1 activation. Nat Commun 2018; 9:5300. [PMID: 30546054 PMCID: PMC6294142 DOI: 10.1038/s41467-018-07747-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 11/23/2018] [Indexed: 12/18/2022] Open
Abstract
The liver possesses a high regenerative capacity. Liver regeneration is a compensatory response overcoming disturbances of whole-body homeostasis provoked by organ defects. Here we show that a vagus-macrophage-hepatocyte link regulates acute liver regeneration after liver injury and that this system is critical for promoting survival. Hepatic Foxm1 is rapidly upregulated after partial hepatectomy (PHx). Hepatic branch vagotomy (HV) suppresses this upregulation and hepatocyte proliferation, thereby increasing mortality. In addition, hepatic FoxM1 supplementation in vagotomized mice reverses the suppression of liver regeneration and blocks the increase in post-PHx mortality. Hepatic macrophage depletion suppresses both post-PHx Foxm1 upregulation and remnant liver regeneration, and increases mortality. Hepatic Il-6 rises rapidly after PHx and this is suppressed by HV, muscarinic blockade or resident macrophage depletion. Furthermore, IL-6 neutralization suppresses post-PHx Foxm1 upregulation and remnant liver regeneration. Collectively, vagal signal-mediated IL-6 production in hepatic macrophages upregulates hepatocyte FoxM1, leading to liver regeneration and assures survival. The mechanisms underlying the regenerative capacity of the liver are not fully understood. Here, the authors show that the acute regenerative response to liver injury in mice is regulated by the communication involving the vagus nerve, macrophages, and hepatocytes, leading to hepatic FoxM1 activation and promotion of overall survival.
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Yamaguchi T, Kokudo T, Akamatsu N, Kaneko J, Arita J, Sakamoto Y, Kokudo N, Hasegawa K. Liver Regeneration is Preserved After At Least Four Repeated Liver Resections for Hepatocellular Carcinoma. World J Surg 2018; 42:4070-4080. [PMID: 29947985 DOI: 10.1007/s00268-018-4714-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Repeated resection is known to prolong survival, with an acceptable morbidity rate, in patients with hepatocellular carcinoma. However, little is known about the effect of repeated liver resection on postoperative liver regeneration and liver function. The aim of this study is to determine the impact of repeated liver resections on the postoperative liver regeneration rate and liver function. METHODS A total of 71 patients, who had undergone more than three liver resections for hepatocellular carcinoma between May 2001 and December 2013 at a tertiary care hospital in Japan, were included in the analysis. Among them, CT-volumetric data for the first, second, third, and fourth or more resections were available for 36, 49, 53, and 24 patients. We analyzed the regeneration index (RI) defined as the postoperative TLV/preoperative TLV × 100 was calculated after each operation to measure the degree of regeneration. Liver function was evaluated using the indocyanine green retention rate at 15 min (ICG-R15). RESULTS No significant differences in RI were observed among the first, second, and third or more liver resection groups. No significant difference in the ICG R15 value was seen between the first liver resection group and the second or more liver resection group (P = 0.75). However, a significant difference in the RI was observed when the 1 segmentectomy or less liver resection group (median [range] RI 98.1 [72.9-119.9]) was compared with the 2 or more segmentectomy group (median [range] RI 90.5 [62.6-113.6]) (P = 0.005). CONCLUSION The regeneration process is maintained after as many as four repeated resections. Patients with sustained liver function can safely undergo repeated liver resections for recurrences of HCC.
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Affiliation(s)
- Takamune Yamaguchi
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Takashi Kokudo
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Nobuhisa Akamatsu
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Junichi Kaneko
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Yoshihiro Sakamoto
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Norihiro Kokudo
- National Center for Global Health and Medicine, Tokyo, Japan.
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.
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Chul Yoon K, Song S, Jwa EK, Lee S, Man Kim J, Kim OK, Kyun Hong S, Yi NJ, Lee KW, Soo Kim M, Hwang S, Suh KS, Lee SK. Survival Outcomes in Split Compared With Whole Liver Transplantation. Liver Transpl 2018; 24:1411-1424. [PMID: 29747216 DOI: 10.1002/lt.25196] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 04/20/2018] [Accepted: 05/03/2018] [Indexed: 12/11/2022]
Abstract
Split-liver transplantation (SLT) should be cautiously considered because the right trisection (RTS) graft can be a marginal graft in adult recipients. Herein, we analyzed the outcomes of RTS-SLT in Korea, where >75% of adult liver transplantations are performed with living donor liver transplantation. Among 2462 patients who underwent deceased donor liver transplantations (DDLTs) from 2005 to 2014, we retrospectively reviewed 86 (3.5%) adult patients who received a RTS graft (RTS-SLT group). The outcomes of the RTS-SLT group were compared with those of 303 recipients of whole liver (WL; WL-DDLT group). Recipient age, laboratory Model for End-Stage-Liver Disease (L-MELD) score, ischemia time, and donor-to-recipient weight ratio (DRWR) were not different between the 2 groups (P > 0.05). However, malignancy was uncommon (4.7% versus 36.3%), and the donor was younger (25.2 versus 42.7 years) in the RST-SLT group than in the WL-DDLT group (P < 0.05). The technical complication rates and the 5-year graft survival rates (89.0% versus 92.8%) were not different between the 2 groups (P > 0.05). The 5-year overall survival (OS) rate (63.1%) and graft-failure-free survival rate (63.1%) of the RTS-SLT group were worse than that of the WL-DDLT group (79.3% and 79.3%; P < 0.05). The factors affecting graft survival rates were not definite. However, the factors affecting OS in the RTS-SLT group were L-MELD score >30 and DRWR ≤1.0. In the subgroup analysis, OS was not different between the 2 groups if the DRWR was >1.0, regardless of the L-MELD score (P > 0.05). In conclusion, a sufficient volume of the graft estimated from DRWR-matching could lead to better outcomes of adult SLTs with a RTS graft, even in patients with high L-MELD scores.
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Affiliation(s)
- Kyung Chul Yoon
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Sanghee Song
- Transplantation Center, Seoul National University Hospital, Seoul, South Korea
| | - Eun-Kyoung Jwa
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Ulsan College of Medicine, Seoul, South Korea
| | - Sanghoon Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jong Man Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Ok-Kyoung Kim
- Transplantation Center, Seoul National University Hospital, Seoul, South Korea
| | - Suk Kyun Hong
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Nam-Joon Yi
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Kwang-Woong Lee
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Myoung Soo Kim
- Department of Surgery and The Research Institute for Transplantation, Yonsei University College of Medicine, Seoul, South Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, University of Ulsan College of Medicine, Seoul, South Korea
| | - Kyung-Suk Suh
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Suk-Koo Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
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Czarkowska-Paczek B, Wyczalkowska-Tomasik A, Paczek L. Laboratory blood test results beyond normal ranges could not be attributed to healthy aging. Medicine (Baltimore) 2018; 97:e11414. [PMID: 29995788 PMCID: PMC6076198 DOI: 10.1097/md.0000000000011414] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Aging is related to a decline in the function of many organs. The results of blood tests are essential for clinical management and could change over a lifespan reflecting aging. The aim of this study was to examine serum levels of liver, kidney, and bone marrow function and to study their dynamics as a function of age and sex.The cross-sectional study conducted in Poland included 180 healthy individuals (20-90 years) divided into subgroups by sex and decade. These included subgroups of ≥65 or <65 years (men and women). We investigated serum levels of creatinine, estimated glomerular filtration rate, estimated effective renal blood/plasma flow, urine pH, urine neutrophil gelatinase-associated lipocalin (NGAL) as well as serum levels of transaminases, bilirubin, total cholesterol (TC), international normalized ratio (INR), and blood morphology.All parameters were within normal range in all groups. Urine NGAL was higher in men aged ≥65 years than women (25.67 ± 53.65 vs 16.49 ± 34.66, P = .001); serum levels of TC and platelet (PLT) count were higher in women than men aged ≥65 years (221.0 ± 41.7 vs 188.4 ± 48.2 and 250.3 ± 47.8 vs 202.5 ± 57.9, P = .003 and P = .038, respectively). The INR was lower in women (0.97 ± .06 vs 1.19 ± 0.48, P = .03).These blood tests were normal in healthy people aged ≥65 years. Higher PLT and TC and lower INR in women might indicate a higher risk of cardiovascular diseases. These changes in blood tests were not attributed to aging itself.
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Affiliation(s)
| | | | - Leszek Paczek
- Department of Immunology, Transplantology, and Internal Diseases, Medical University of Warsaw, Warsaw, Poland
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Abstract
The liver has a unique ability of regenerating after injuries or partial loss of its mass. The mechanisms responsible for liver regeneration - mostly occurring when the hepatic tissue is damaged or functionally compromised by metabolic stress - have been studied in considerable detail over the last few decades, because this phenomenon has both basic-biology and clinical relevance. More specifically, recent interest has been focusing on the widespread occurrence of abnormal nutritional habits in the Western world that result in an increased prevalence of non-alcoholic fatty liver disease (NAFLD). NAFLD is closely associated with insulin resistance and dyslipidemia, and it represents a major clinical challenge. The disease may progress to steatohepatitis with persistent inflammation and progressive liver damage, both of which will compromise regeneration under conditions of partial hepatectomy in surgical oncology or in liver transplantation procedures. Here, we analyze the impact of ER stress and SIRT1 in lipid metabolism and in fatty liver pathology, and their consequences on liver regeneration. Moreover, we discuss the fine interplay between ER stress and SIRT1 functioning when contextualized to liver regeneration. An improved understanding of the cellular and molecular intricacies contributing to liver regeneration could be of great clinical relevance in areas as diverse as obesity, metabolic syndrome and type 2 diabetes, as well as oncology and transplantation.
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Affiliation(s)
| | - Giuseppe Servillo
- Department of Experimental Medicine, University of Perugia, Perugia, Italy
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Okada H, Takabatake R, Honda M, Takegoshi K, Yamashita T, Nakamura M, Shirasaki T, Sakai Y, Shimakami T, Nagata N, Takamura T, Tanaka T, Kaneko S. Peretinoin, an acyclic retinoid, suppresses steatohepatitis and tumorigenesis by activating autophagy in mice fed an atherogenic high-fat diet. Oncotarget 2018; 8:39978-39993. [PMID: 28591717 PMCID: PMC5522259 DOI: 10.18632/oncotarget.18116] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 05/12/2017] [Indexed: 01/21/2023] Open
Abstract
The pathogenesis of non-alcoholic steatohepatitis (NASH) is still unclear and the prevention of the development of hepatocellular carcinoma (HCC) has not been established. We established an atherogenic and high-fat diet mouse model that develops hepatic steatosis, inflammation, fibrosis, and liver tumors at a high frequency. Using two NASH-HCC mouse models, we showed that peretinoin, an acyclic retinoid, significantly improved liver histology and reduced the incidence of liver tumors. Interestingly, we found that peretinoin induced autophagy in the liver of mice, which was characterized by the increased co-localized expression of microtubule-associated protein light chain 3B-II and lysosome-associated membrane protein 2, and increased autophagosome formation and autophagy flux in the liver. These findings were confirmed using primary mouse hepatocytes. Among representative autophagy pathways, the autophagy related (Atg) 5-Atg12-Atg16L1 pathway was impaired; especially, Atg16L1 was repressed at both the mRNA and protein level. Decreased Atg16L1 mRNA expression was also found in the liver of patients with NASH according to disease progression. Promoter analysis revealed that peretinoin activated the promoter of Atg16L1 by increasing the expression of CCAAT/enhancer-binding-protein-alpha. Interestingly, Atg16L1 overexpression in HepG2 cells inhibited palmitate-induced NF-kB activation and interleukin-6-induced STAT3 activation. We showed that Atg16L1 induced the de-phosphorylation of Gp130, a receptor subunit of interleukin-6 family cytokines, which subsequently repressed phosphorylated-STAT3 (Tyr705) levels, and this process might be independent of autophagy function. Thus, peretinoin prevents the progression of NASH and the development of HCC through activating the autophagy pathway by increased Atg16L1 expression, which is an essential regulator of autophagy and anti-inflammatory proteins.
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Affiliation(s)
- Hikari Okada
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Riuta Takabatake
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Masao Honda
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.,Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Kai Takegoshi
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Taro Yamashita
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Mikiko Nakamura
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Takayoshi Shirasaki
- Department of Advanced Medical Technology, Kanazawa University Graduate School of Health Medicine, Kanazawa, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Tetsuro Shimakami
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan
| | - Naoto Nagata
- Department of Cell Metabolism and Nutrition, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Japan
| | - Toshinari Takamura
- Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
| | - Takuji Tanaka
- The Tohkai Cytopathology Institute, Cancer Research and Prevention, Gifu, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.,Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan
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Jung KW, Kim WJ, Jeong HW, Kwon HM, Moon YJ, Jun IG, Song JG, Hwang GS. Impact of Inhalational Anesthetics on Liver Regeneration After Living Donor Hepatectomy. Anesth Analg 2018; 126:796-804. [DOI: 10.1213/ane.0000000000002756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Moris D, Dimitroulis D, Papalampros A, Petrou A, Felekouras E. ALPPS Procedure for Hepatocellular Carcinoma in Patients With Chronic Liver Disease: Revealing a Terra Incognita. Ann Surg 2017; 266:e106-e107. [PMID: 27433912 DOI: 10.1097/sla.0000000000001890] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Demetrios Moris
- Lerner Research Institute, Cleveland Clinic, Foundation, Cleveland, Ohio Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Alvarez-Sola G, Uriarte I, Latasa MU, Jimenez M, Barcena-Varela M, Santamaría E, Urtasun R, Rodriguez-Ortigosa C, Prieto J, Corrales FJ, Baulies A, García-Ruiz C, Fernandez-Checa JC, Berraondo P, Fernandez-Barrena MG, Berasain C, Avila MA. Engineered fibroblast growth factor 19 protects from acetaminophen-induced liver injury and stimulates aged liver regeneration in mice. Cell Death Dis 2017; 8:e3083. [PMID: 28981086 PMCID: PMC5682649 DOI: 10.1038/cddis.2017.480] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 07/31/2017] [Accepted: 08/09/2017] [Indexed: 02/07/2023]
Abstract
The liver displays a remarkable regenerative capacity triggered upon tissue injury or resection. However, liver regeneration can be overwhelmed by excessive parenchymal destruction or diminished by pre-existing conditions hampering repair. Fibroblast growth factor 19 (FGF19, rodent FGF15) is an enterokine that regulates liver bile acid and lipid metabolism, and stimulates hepatocellular protein synthesis and proliferation. FGF19/15 is also important for liver regeneration after partial hepatectomy (PH). Therefore recombinant FGF19 would be an ideal molecule to stimulate liver regeneration, but its applicability may be curtailed by its short half-life. We developed a chimaeric molecule termed Fibapo in which FGF19 is covalently coupled to apolipoprotein A-I. Fibapo retains FGF19 biological activities but has significantly increased half-life and hepatotropism. Here we evaluated the pro-regenerative activity of Fibapo in two clinically relevant models where liver regeneration may be impaired: acetaminophen (APAP) poisoning, and PH in aged mice. The only approved therapy for APAP intoxication is N-acetylcysteine (NAC) and no drugs are available to stimulate liver regeneration. We demonstrate that Fibapo reduced liver injury and boosted regeneration in APAP-intoxicated mice. Fibapo improved survival of APAP-poisoned mice when given at later time points, when NAC is ineffective. Mechanistically, Fibapo accelerated recovery of hepatic glutathione levels, potentiated cell growth-related pathways and increased functional liver mass. When Fibapo was administered to old mice prior to PH, liver regeneration was markedly increased. The exacerbated injury developing in these mice upon PH was attenuated, and the hepatic biosynthetic capacity was enhanced. Fibapo reversed metabolic and molecular alterations that impede regeneration in aged livers. It reduced liver steatosis and downregulated p21 and hepatocyte nuclear factor 4 α (Hnf4α) levels, whereas it stimulated Foxm1b gene expression. Together our findings indicate that FGF19 variants retaining the metabolic and growth-promoting effects of this enterokine may be valuable for the stimulation of liver regeneration.
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Affiliation(s)
- Gloria Alvarez-Sola
- CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain
| | - Iker Uriarte
- CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain
| | - Maria U Latasa
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Maddalen Jimenez
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Marina Barcena-Varela
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Eva Santamaría
- CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain
| | - Raquel Urtasun
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Carlos Rodriguez-Ortigosa
- CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Jesús Prieto
- CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Fernando J Corrales
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
- CIBERehd, Instituto de Salud Carlos III, Barcelona, Spain
| | - Anna Baulies
- CIBERehd, Instituto de Salud Carlos III, Barcelona, Spain
- Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC and Liver Unit-Hospital Clinic-IDIBAPS, Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles 90033, CA, USA
| | - Carmen García-Ruiz
- CIBERehd, Instituto de Salud Carlos III, Barcelona, Spain
- Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC and Liver Unit-Hospital Clinic-IDIBAPS, Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles 90033, CA, USA
| | - Jose C Fernandez-Checa
- CIBERehd, Instituto de Salud Carlos III, Barcelona, Spain
- Department of Cell Death and Proliferation, Instituto de Investigaciones Biomédicas de Barcelona, CSIC and Liver Unit-Hospital Clinic-IDIBAPS, Barcelona, Spain
- Research Center for ALPD, Keck School of Medicine, University of Southern California, Los Angeles 90033, CA, USA
| | - Pedro Berraondo
- Immunology and Immunotherapy Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Maite G Fernandez-Barrena
- CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Carmen Berasain
- CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
| | - Matías A Avila
- CIBERehd, Instituto de Salud Carlos III, Clinica Universidad de Navarra, Avda, Pio XII, n 36, Pamplona 31008, Spain
- Hepatology Programme, CIMA, Idisna, Universidad de Navarra, Avda, Pio XII, n 55, Pamplona 31008, Spain
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Zhong HH, Hu SJ, Yu B, Jiang SS, Zhang J, Luo D, Yang MW, Su WY, Shao YL, Deng HL, Hong FF, Yang SL. Apoptosis in the aging liver. Oncotarget 2017; 8:102640-102652. [PMID: 29254277 PMCID: PMC5731987 DOI: 10.18632/oncotarget.21123] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Accepted: 08/15/2017] [Indexed: 12/11/2022] Open
Abstract
Various changes in the liver during aging can reduce hepatic function and promote liver injury. Aging is associated with high morbidity and a poor prognosis in patients with various liver diseases, including nonalcoholic fatty liver disease, hepatitis C and liver cancer, as well as with surgeries such as partial hepatectomy and liver transplantation. In addition, apoptosis increases with liver aging. Because apoptosis is involved in regeneration, fibrosis and cancer prevention during liver aging, and restoration of the appropriate level of apoptosis can alleviate the adverse effects of liver aging, it is important to understand the mechanisms underlying this process. Herein, we elaborate on the causes of apoptosis during liver aging, with a focus on oxidative stress, genomic instability, lipotoxicity, endoplasmic reticulum stress, dysregulation of nutrient sensing, and liver stem/progenitor cell activity.
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Affiliation(s)
- Hua-Hua Zhong
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Shao-Jie Hu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Bo Yu
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Sha-Sha Jiang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Jin Zhang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Dan Luo
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Mei-Wen Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Wan-Ying Su
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Ya-Lan Shao
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Hao-Lin Deng
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
| | - Fen-Fang Hong
- Department of Experimental Teaching Center, Nanchang University, Nanchang 330031, China
| | - Shu-Long Yang
- Department of Physiology, College of Medicine, Nanchang University, Nanchang 330006, China
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Krüppel-like factor 6 is a transcriptional activator of autophagy in acute liver injury. Sci Rep 2017; 7:8119. [PMID: 28808340 PMCID: PMC5556119 DOI: 10.1038/s41598-017-08680-w] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 07/13/2017] [Indexed: 02/07/2023] Open
Abstract
Krüppel-like factor 6 (KLF6) is a transcription factor and tumor suppressor. We previously identified KLF6 as mediator of hepatocyte glucose and lipid homeostasis. The loss or reduction of KLF6 is linked to the progression of hepatocellular carcinoma, but its contribution to liver regeneration and repair in acute liver injury are lacking so far. Here we explore the role of KLF6 in acute liver injury models in mice, and in patients with acute liver failure (ALF). KLF6 was induced in hepatocytes in ALF, and in both acetaminophen (APAP)- and carbon tetrachloride (CCl4)-treated mice. In mice with hepatocyte-specific Klf6 knockout (DeltaKlf6), cell proliferation following partial hepatectomy (PHx) was increased compared to controls. Interestingly, key autophagic markers and mediators LC3-II, Atg7 and Beclin1 were reduced in DeltaKlf6 mice livers. Using luciferase assay and ChIP, KLF6 was established as a direct transcriptional activator of ATG7 and BECLIN1, but was dependent on the presence of p53. Here we show, that KLF6 expression is induced in ALF and in the regenerating liver, where it activates autophagy by transcriptional induction of ATG7 and BECLIN1 in a p53-dependent manner. These findings couple the activity of an important growth inhibitor in liver to the induction of autophagy in hepatocytes.
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Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance. Hepatobiliary Pancreat Dis Int 2017; 16:245-256. [PMID: 28603092 PMCID: PMC7172563 DOI: 10.1016/s1499-3872(17)60014-6] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions. DATA SOURCES The data of mouse hepatic models and relevant human liver diseases presented in this review are systematically collected from PubMed, ScienceDirect and the Web of Science databases published in English. RESULTS The hepatotoxic liver injury in mice induced by the metabolites of CCl4, acetaminophen or alcohol represent necrotic cell death with activation of cytochrome pathway, formation of reactive oxygen species (ROS) and mitochondrial damage. The Fas or TNF-alpha induced apoptotic liver injury was dependent on activation of caspases, release of cytochrome c and apoptosome formation. The ConA-hepatitis demonstrated the involvement of TRAIL-dependent necrotic/necroptotic cell death with activation of RIPK1/3. The alpha-GalCer-induced liver injury was mediated by TNF-alpha. The LPS-induced hepatitis involved TNF-alpha, Fas/FasL, and perforin/granzyme cell death pathways. The MHV3 or Poly(I:C) induced liver injury was mediated by natural killer cells and TNF-alpha signaling. The necrotic ischemia-reperfusion liver injury was mediated by hypoxia, ROS, and pro-inflammatory cytokines; however, necroptotic cell death was found in partial hepatectomy. The crucial role of immune cells and cell death mediators in viral hepatitis (HBV, HCV), drug-induced liver injury, non-alcoholic fatty liver disease and alcoholic liver disease in human were discussed. CONCLUSIONS The mouse animal models of hepatitis provide a parallel approach for the study of human liver pathology. Blocking or stimulating the pathways associated with liver cell death could unveil the novel therapeutic strategies in the management of liver diseases.
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Huang TH, Chen CC, Liu HM, Lee TY, Shieh SH. Resveratrol Pretreatment Attenuates Concanavalin A-induced Hepatitis through Reverse of Aberration in the Immune Response and Regenerative Capacity in Aged Mice. Sci Rep 2017; 7:2705. [PMID: 28578410 PMCID: PMC5457448 DOI: 10.1038/s41598-017-02881-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2017] [Accepted: 04/19/2017] [Indexed: 12/22/2022] Open
Abstract
Loss of regenerative capacity plays a critical role in age-related autoimmune hepatitis. Evidence implicates SIRT1 and p66shc in cell senescence, apoptosis, oxidative stress, and proliferation. This study investigated the effect of resveratrol on concanavalin A (Con A)-induced hepatitis in aged mice and the roles of SIRT1 and p66shc. Aged mice were administrated resveratrol (30 mg/kg orally) seven times at an interval of 12 h before a single intravenous injection of Con A (20 mg/kg). Results showed that the cytokines, TNF-α, IL-6, IFN-γ, and MCP-1, as well as infiltration of macrophages, neutrophils, and T lymphocytes in liver were dramatically enhanced in the mice given only Con A. The aged mouse livers showed markedly raised oxidative stress and cell apoptosis. This oxidative stress further aggravated regenerative dysfunction as indicated by the decreased levels of Ki67, PCNA, Cyclin D1, and Cdk2. Conversely, these phenomena were attenuated by pretreatment with resveratrol. Moreover, resveratrol suppressed the elevation of p66shc in the liver by reversing Con-A-mediated downregulation of SIRT1. The findings suggest that resveratrol protected against Con A-induced hepatitis in aged mice by attenuating an aberration of immune response and liver regeneration, partially via the mechanism of SIRT1-mediated repression of p66shc expression.
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Affiliation(s)
- Tse-Hung Huang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC.,School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,School of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan, ROC
| | - Chin-Chang Chen
- School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.,Division of Urology, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan, ROC
| | - Hsuan-Miao Liu
- Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Tzung-Yan Lee
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan, ROC. .,School of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, ROC. .,Graduate Institute of Traditional Chinese Medicine, Chang Gung University, Taoyuan, Taiwan, ROC.
| | - Sue-Heui Shieh
- Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan, ROC.
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Saito Y, Morine Y, Shimada M. Mechanism of impairment on liver regeneration in elderly patients: Role of hepatic stellate cell function. Hepatol Res 2017; 47:505-513. [PMID: 28186674 DOI: 10.1111/hepr.12872] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2016] [Revised: 02/08/2017] [Accepted: 02/08/2017] [Indexed: 12/13/2022]
Abstract
Japan, along with most other countries in the world, is facing an increasingly aging population with a prolonged life expectancy. Concurrently, the need for medical intervention, including hepatectomy, has also increased for the elderly. Although surgical outcomes for older patients are reported to be comparable with those for younger patients, additional care in the selection of older patients for hepatectomy is considered necessary. Although the effect of aging on human liver regeneration is not fully understood, the regeneration of liver tissue after hepatectomy in elderly patients is shown to be generally worse than in younger patients and, to date, the mechanisms involved in the impairment of liver regeneration have not been fully clarified. Hepatic stellate cells (HSCs) are liver-specific mesenchymal cells that play critical roles in liver physiology and fibrogenesis. Recent studies in liver regeneration have increasingly focused on HSCs rather than on hepatocytes, Kupffer cells, endothelial cells, or infiltrating immune cells and suggest that HSCs might play a critical role in liver regeneration. In this review, we summarize the mechanisms involved in the impairment of liver regeneration in elderly patients, especially focusing on HSCs. We also discuss how HSCs contribute to the impairment of liver regeneration.
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Affiliation(s)
- Yu Saito
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Yuji Morine
- Department of Surgery, Tokushima University, Tokushima, Japan
| | - Mitsuo Shimada
- Department of Surgery, Tokushima University, Tokushima, Japan
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Kirkland JL, Stout MB, Sierra F. Resilience in Aging Mice. J Gerontol A Biol Sci Med Sci 2016; 71:1407-1414. [PMID: 27535963 DOI: 10.1093/gerona/glw086] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Accepted: 04/19/2016] [Indexed: 12/17/2022] Open
Abstract
Recently discovered interventions that target fundamental aging mechanisms have been shown to increase life span in mice and other species, and in some cases, these same manipulations have been shown to enhance health span and alleviate multiple age-related diseases and conditions. Aging is generally associated with decreases in resilience, the capacity to respond to or recover from clinically relevant stresses such as surgery, infections, or vascular events. We hypothesize that the age-related increase in susceptibility to those diseases and conditions is driven by or associated with the decrease in resilience. Thus, a test for resilience at middle age or even earlier could represent a surrogate approach to test the hypothesis that an intervention delays the process of aging itself. For this, animal models to test resilience accurately and predictably are needed. In addition, interventions that increase resilience might lead to treatments aimed at enhancing recovery following acute illnesses, or preventing poor outcomes from medical interventions in older, prefrail subjects. At a meeting of basic researchers and clinicians engaged in research on mechanisms of aging and care of the elderly, the merits and drawbacks of investigating effects of interventions on resilience in mice were considered. Available and potential stressors for assessing physiological resilience as well as the notion of developing a limited battery of such stressors and how to rank them were discussed. Relevant ranking parameters included value in assessing general health (as opposed to focusing on a single physiological system), ease of use, cost, reproducibility, clinical relevance, and feasibility of being repeated in the same animal longitudinally. During the discussions it became clear that, while this is an important area, very little is known or established. Much more research is needed in the near future to develop appropriate tests of resilience in animal models within an aging context. The preliminary set of tests ranked by the participants is discussed here, recognizing that this is a first attempt.
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Affiliation(s)
- James L Kirkland
- Mayo Clinic Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota
| | - Michael B Stout
- Mayo Clinic Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota
| | - Felipe Sierra
- Division of Aging Biology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland.
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Cieslak KP, Baur O, Verheij J, Bennink RJ, van Gulik TM. Liver function declines with increased age. HPB (Oxford) 2016; 18:691-6. [PMID: 27485064 PMCID: PMC4972366 DOI: 10.1016/j.hpb.2016.05.011] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2016] [Accepted: 05/25/2016] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Age itself is not considered a contraindication for high impact surgery. However, the aging process of the liver remains largely unknown. This study evaluates age-dependent changes in liver function using a quantitative liver function test. METHODS Between January 2005 and December 2014, 508 patients underwent (99m)Tc-mebrofenin hepatobiliary scintigraphy (HBS) for the assessment of liver function. These included 203 patients with healthy livers (group A) and 57 patients with HCC and Child-Pugh A (group B). (99m)Tc-mebrofenin-uptake-rate of the whole liver corrected for body surface area (cMUR) was calculated for all patients. Linear regression analysis was performed to assess the relationship between age and cMUR. RESULTS The mean cMUR was 8.50 ± 2.05%/min/m(2) and 6.94 ± 2.03%/min/m(2) in group A and B, respectively. A negative linear correlation was found between patient's age and cMUR in group A, r = 0.244, p = 0.000. In group B, there was no correlation between age and cMUR, however, a trend in decline of liver function with age was noted. CONCLUSION This study shows that liver function deteriorates with age. Since the regenerative capacity of the liver correlates with liver function, this finding should be taken into account when assessing surgical risk in patients considered for major liver resection.
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Affiliation(s)
- Kasia P. Cieslak
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands,Correspondence K.P. Cieslak, Candidate Department of Surgery, Academic Medical Center, IWO 1-A1-113.1, 1100 DD Amsterdam, The Netherlands. Tel: +31 205665568. Fax: +31 206976621.Candidate Department of SurgeryAcademic Medical CenterIWO 1-A1-113.1Amsterdam1100 DDThe Netherlands
| | - Onno Baur
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - Joanne Verheij
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - Roelof J. Bennink
- Department of Nuclear Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Thomas M. van Gulik
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands,T.M. van Gulik, Department of Surgery, Academic Medical Center, IWO IA.1-119, 1100 DD Amsterdam, The Netherlands. Tel: +31 205665570. Fax: +31 206976621.Department of SurgeryAcademic Medical CenterIWO IA.1-119Amsterdam1100 DDThe Netherlands
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