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Yan F, Zhang Q, Mutembei BM, Wang C, Alhajeri ZA, Pandit K, Zhang F, Zhang K, Yu Z, Fung KM, Elgenaid SN, Parrack P, Ali W, Hostetler CA, Milam AN, Nave B, Squires R, Martins PN, Battula NR, Potter S, Pan C, Chen Y, Tang Q. Comprehensive Evaluation of Human Donor Liver Viability with Polarization-Sensitive Optical Coherence Tomography. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.31.25321497. [PMID: 40236439 PMCID: PMC11998830 DOI: 10.1101/2025.03.31.25321497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
Human liver transplantation is severely constrained by a critical shortage of donor livers, with approximately one quarter of patients on the waiting list dying due to the scarcity of viable organs. Current liver viability assessments, which rely on invasive pathological methods, are hampered by limited sampling from biopsies, particularly in marginal livers from extended criteria donors (ECD) intended to expand the donor pool. Consequently, there is a pressing need for more comprehensive and non-invasive evaluation techniques to meet the escalating demand for liver transplants. In this study, we propose the use of polarization-sensitive optical coherence tomography (PS-OCT) to perform a thorough viability evaluation across the entire surface of donor livers. PS-OCT imaging was conducted on multiple regions, achieving near-complete coverage of the liver surface, and the findings were cross-validated with histopathological evaluations. The analysis of hepatic parameters derived from pathology highlighted tissue heterogeneity. Leveraging machine learning and texture analysis, we quantified hepatic steatosis, fibrosis, inflammation, and necrosis, and established strong correlations (≥ 80%) between PS-OCT quantifications and pathological assessments. PS-OCT offers a non-invasive assessment of liver viability by quantifying hepatic parenchymal parameters across the entire donor liver, significantly complementing current pathological analysis. These results suggest that PS-OCT provides a robust, non-invasive approach to assessing donor liver viability, which could potentially decrease the discard rate of higher risk livers, thereby expanding the donor pool and reducing the inadvertent use of those livers unsuitable for transplantation.
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Stilkerich A, Schicht G, Seidemann L, Hänsel R, Friebel A, Hoehme S, Seehofer D, Damm G. Cell Homeostasis or Cell Death-The Balancing Act Between Autophagy and Apoptosis Caused by Steatosis-Induced Endoplasmic Reticulum (ER) Stress. Cells 2025; 14:449. [PMID: 40136698 PMCID: PMC11941029 DOI: 10.3390/cells14060449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 03/04/2025] [Accepted: 03/07/2025] [Indexed: 03/27/2025] Open
Abstract
Metabolic-dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition with potential progression to cirrhosis and impaired regeneration post-resection. A key mechanism underlying lipotoxicity is endoplasmic reticulum (ER) stress, particularly the activation of the unfolded protein response (UPR). This study investigates the interplay between lipid accumulation, endoplasmic reticulum (ER) stress, and cellular outcomes, focusing on the balance between autophagy and apoptosis. We cultured primary human hepatocytes (PHH) in a free fatty acid (FFA)-enriched medium for 120 h, assessing lipid accumulation, metabolism, and the expression of selected UPR markers. Additionally, we investigated the effects of lipid load on cell activity and growth in proliferating HepG2 cells. We observed that FFA uptake consistently induced ER stress, shifting cellular responses toward apoptosis under high lipid loads. Donor-specific differences were evident, particularly in lipid storage, excretion, and sensitivity to lipotoxicity. Some donors exhibited limited triglyceride (TAG) storage and excretion, leading to an excess of FFA whose metabolic fate remains unclear. Proliferation was more sensitive to lipid accumulation than overall cell activity, with even low FFA concentrations impairing growth, highlighting the vulnerability of regenerative processes to steatosis. The study elucidates how ER stress pathways, such as PERK-CHOP and IRE1α-JNK, are differentially activated in response to lipid overload, tipping the balance toward apoptosis in severe cases. The limited activation of repair mechanisms, such as autophagy, further emphasizes the critical role of ER stress in determining hepatocyte fate. The donor-dependent variability highlights the need for personalized strategies to mitigate lipotoxic effects and enhance liver regeneration in steatosis-related conditions.
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Affiliation(s)
- Anna Stilkerich
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - Gerda Schicht
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - Lena Seidemann
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - René Hänsel
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - Adrian Friebel
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany
- Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), 04105 Leipzig, Germany
| | - Stefan Hoehme
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
- Interdisciplinary Center for Bioinformatics (IZBI), University of Leipzig, Haertelstraße 16-18, 04107 Leipzig, Germany
- Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), 04105 Leipzig, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University Hospital, Leipzig University, 04103 Leipzig, Germany; (A.S.); (G.S.); (L.S.); (D.S.)
- Saxonian Incubator for Clinical Translation (SIKT), Leipzig University, 04103 Leipzig, Germany; (R.H.); (A.F.); (S.H.)
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Hunyenyiwa T, Kyi P, Scheer M, Joshi M, Gasparri M, Mammoto T, Mammoto A. Inhibition of angiogenesis and regenerative lung growth in Lepob/ob mice through adiponectin-VEGF/VEGFR2 signaling. Front Cardiovasc Med 2024; 11:1491971. [PMID: 39479393 PMCID: PMC11521822 DOI: 10.3389/fcvm.2024.1491971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 10/07/2024] [Indexed: 11/02/2024] Open
Abstract
Introduction Obesity is associated with impairment of wound healing and tissue regeneration. Angiogenesis, the formation of new blood capillaries, plays a key role in regenerative lung growth after unilateral pneumonectomy (PNX). We have reported that obesity inhibits angiogenesis. The effects of obesity on post-PNX lung vascular and alveolar regeneration remain unclear. Methods Unilateral PNX is performed on Lep o b / o b obese mice to examine vascular and alveolar regeneration. Results Regenerative lung growth and expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR2 induced after PNX are inhibited in Lep o b / o b obese mice. The levels of adiponectin that exhibits pro-angiogenic and vascular protective properties increase after unilateral PNX, while the effects are attenuated in Lep o b / o b obese mice. Post-PNX regenerative lung growth and increases in the levels of VEGF and VEGFR2 are inhibited in adiponectin knockout mice. Adiponectin stimulates angiogenic activities in human lung endothelial cells (ECs), which is inhibited by decreasing the levels of transcription factor Twist1. Adiponectin agonist, AdipoRon restores post-PNX lung growth and vascular and alveolar regeneration in Lep o b / o b obese mice. Discussion These findings suggest that obesity impairs lung vascular and alveolar regeneration and adiponectin is one of the key factors to improve lung regeneration in obese people.
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Affiliation(s)
- Tendai Hunyenyiwa
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Priscilla Kyi
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Mikaela Scheer
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Mrudula Joshi
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Mario Gasparri
- Department of Thoracic Surgery, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Tadanori Mammoto
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Akiko Mammoto
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
- Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, United States
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Yanagisawa H, Maeda H, Noguchi I, Tanaka M, Wada N, Nagasaki T, Kobayashi K, Kanazawa G, Taguchi K, Chuang VTG, Sakai H, Nakashima H, Kinoshita M, Kitagishi H, Iwakiri Y, Sasaki Y, Tanaka Y, Otagiri M, Watanabe H, Maruyama T. Carbon monoxide-loaded red blood cells ameliorate metabolic dysfunction-associated steatohepatitis progression via enhancing AMP-activated protein kinase activity and inhibiting Kupffer cell activation. Redox Biol 2024; 76:103314. [PMID: 39163766 PMCID: PMC11381851 DOI: 10.1016/j.redox.2024.103314] [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: 07/09/2024] [Revised: 08/09/2024] [Accepted: 08/14/2024] [Indexed: 08/22/2024] Open
Abstract
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of nonalcoholic fatty liver disease characterised by fat accumulation, inflammation, oxidative stress, fibrosis, and impaired liver regeneration. In this study, we found that heme oxygenase-1 (HO-1) is induced in both MASH patients and in a MASH mouse model. Further, hepatic carbon monoxide (CO) levels in MASH model mice were >2-fold higher than in healthy mice, suggesting that liver HO-1 is activated as MASH progresses. Based on these findings, we used CO-loaded red blood cells (CO-RBCs) as a CO donor in the liver, and evaluated their therapeutic effect in methionine-choline deficient diet (MCDD)-induced and high-fat-diet (HFD)-induced MASH model mice. Intravenously administered CO-RBCs effectively delivered CO to the MASH liver, where they prevented fat accumulation by promoting fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor induction. They also markedly suppressed Kupffer cell activation and their corresponding anti-inflammatory and antioxidative stress activities in MASH mice. CO-RBCs also helped to restore liver regeneration in mice with HFD-induced MASH by activating AMPK. We confirmed the underlying mechanisms by performing in vitro experiments in RAW264.7 cells and palmitate-stimulated HepG2 cells. Taken together, CO-RBCs show potential as a promising cellular treatment for MASH.
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Affiliation(s)
- Hiroki Yanagisawa
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Hitoshi Maeda
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Isamu Noguchi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Motohiko Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan; Department of Gastroenterology and Hepatology, Saiseikai Kumamoto Hospital, Kumamoto, Japan.
| | - Naoki Wada
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Taisei Nagasaki
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Kazuki Kobayashi
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Gai Kanazawa
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Kazuaki Taguchi
- Division of Pharmacodynamics, Faculty of Pharmacy, Keio University, Tokyo, Japan.
| | - Victor Tuan Giam Chuang
- Pharmacy Discipline, Curtin Medical School, Faculty of Health Sciences, Curtin University, GPO Box U1987, Perth, 6845, Western Australia, Australia.
| | - Hiromi Sakai
- Department of Chemistry, Nara Medical University, Nara, Japan.
| | - Hiroyuki Nakashima
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan.
| | - Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Saitama, Japan.
| | - Hiroaki Kitagishi
- Department of Molecular Chemistry and Biochemistry, Doshisha University, Kyotanabe, Kyoto, 610-0321, Japan.
| | - Yasuko Iwakiri
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, 06510, United States.
| | - Yutaka Sasaki
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Masaki Otagiri
- Faculty of Pharmaceutical Sciences and DDS Research Institute, Sojo University, Kumamoto, Japan.
| | - Hiroshi Watanabe
- Department of Clinical Pharmacy and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
| | - Toru Maruyama
- Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan.
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Wu D, van de Graaf SFJ. Maladaptive regeneration and metabolic dysfunction associated steatotic liver disease: Common mechanisms and potential therapeutic targets. Biochem Pharmacol 2024; 227:116437. [PMID: 39025410 DOI: 10.1016/j.bcp.2024.116437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 07/12/2024] [Accepted: 07/15/2024] [Indexed: 07/20/2024]
Abstract
The normal liver has an extraordinary capacity of regeneration. However, this capacity is significantly impaired in steatotic livers. Emerging evidence indicates that metabolic dysfunction associated steatotic liver disease (MASLD) and liver regeneration share several key mechanisms. Some classical liver regeneration pathways, such as HGF/c-Met, EGFR, Wnt/β-catenin and Hippo/YAP-TAZ are affected in MASLD. Some recently established therapeutic targets for MASH such as the Thyroid Hormone (TH) receptors, Glucagon-like protein 1 (GLP1), Farnesoid X receptor (FXR), Peroxisome Proliferator-Activated Receptors (PPARs) as well as Fibroblast Growth Factor 21 (FGF21) are also reported to affect hepatocyte proliferation. With this review we aim to provide insight into common molecular pathways, that may ultimately enable therapeutic strategies that synergistically ameliorate steatohepatitis and improve the regenerating capacity of steatotic livers. With the recent rise of prolonged ex-vivo normothermic liver perfusion prior to organ transplantation such treatment is no longer restricted to patients undergoing major liver resection or transplantation, but may eventually include perfused (steatotic) donor livers or even liver segments, opening hitherto unexplored therapeutic avenues.
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Affiliation(s)
- Dandan Wu
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, the Netherlands
| | - Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Amsterdam Gastroenterology, Endocrinology and Metabolism (AGEM), Amsterdam University Medical Centers, the Netherlands.
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Kulik U, Moesta C, Spanel R, Borlak J. Dysfunctional Cori and Krebs cycle and inhibition of lactate transporters constitute a mechanism of primary nonfunction of fatty liver allografts. Transl Res 2024; 264:33-65. [PMID: 37722450 DOI: 10.1016/j.trsl.2023.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 09/06/2023] [Accepted: 09/06/2023] [Indexed: 09/20/2023]
Abstract
Orthotopic liver transplantation (OLT) is a lifesaving procedure. However, grafts may fail due to primary nonfunction (PNF). In the past, we demonstrated PNFs to be mainly associated with fatty allografts, and given its unpredictable nature, the development of a disease model is urgently needed. In an effort to investigate mechanism of fatty allograft-associated PNFs, we induced fatty liver disease in donor animals by feeding rats a diet deficient in methionine and choline (MCD). We performed OLT with allografts of different grades of hepatic steatosis and compared the results to healthy ones. We assessed liver function by considering serum biochemistries, and investigated genome wide responses following OLT of healthy and fatty allograft-associated PNFs. Furthermore, we performed immunohistochemistry to evaluate markers of oxidative stress and reperfusion injury, inflammation, glycolysis and gluconeogenesis, lactate transport, and its utilization as part of the Cori cycle. Strikingly, PNFs are strictly lipid content dependent. Nonetheless, a fat content of ≤17% and an increase in the size of hepatocytes of ≤11% (ballooning) greatly improved outcome of OLTs and the hepatic microcirculation. Mechanistically, PNFs arise from a dysfunctional Cori cycle with complete ablation of the lactate transporter SLC16A1. Thus, lipid-laden hepatocytes fail to perform gluconeogenesis via lactate reutilization, and the resultant hyperlactatemia and lactic acidosis causes cardiac arrhythmogenicity and death. Furthermore, the genomic and immunohistochemistry investigations underscore a dysfunctional Krebs cycle with impaired energy metabolism in lipid-burdened mitochondria. Together, we show fatty allografts to be highly vulnerable towards ischemia/reperfusion-injury, and stabilizing the Cori cycle is of critical importance to avert PNFs.
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Affiliation(s)
- Ulf Kulik
- Department of General, Visceral- and Transplantation Surgery, Hannover Medical School, Hannover, Germany
| | - Caroline Moesta
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Reinhard Spanel
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany
| | - Jürgen Borlak
- Centre for Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.
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Lopez-Lopez V, Linecker M, Caballero-Llanes A, Reese T, Oldhafer KJ, Hernandez-Alejandro R, Tun-Abraham M, Li J, Fard-Aghaie M, Petrowsky H, Brusadin R, Lopez-Conesa A, Ratti F, Aldrighetti L, Ramouz A, Mehrabi A, Autran Machado M, Ardiles V, De Santibañes E, Marichez A, Adam R, Truant S, Pruvot FR, Olthof PB, Van Gulick TM, Montalti R, Troisi RI, Kron P, Lodge P, Kambakamba P, Hoti E, Martinez-Caceres C, de la Peña-Moral J, Clavien PA, Robles-Campos R. Liver Histology Predicts Liver Regeneration and Outcome in ALPPS: Novel Findings From A Multicenter Study. Ann Surg 2024; 279:306-313. [PMID: 37487004 DOI: 10.1097/sla.0000000000006024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/26/2023]
Abstract
BACKGROUND AND AIMS Alterations in liver histology influence the liver's capacity to regenerate, but the relevance of each of the different changes in rapid liver growth induction is unknown. This study aimed to analyze the influence of the degree of histological alterations during the first and second stages on the ability of the liver to regenerate. METHODS This cohort study included data obtained from the International ALPPS Registry between November 2011 and October 2020. Only patients with colorectal liver metastases were included in the study. We developed a histological risk score based on histological changes (stages 1 and 2) and a tumor pathology score based on the histological factors associated with poor tumor prognosis. RESULTS In total, 395 patients were included. The time to reach stage 2 was shorter in patients with a low histological risk stage 1 (13 vs 17 days, P ˂0.01), low histological risk stage 2 (13 vs 15 days, P <0.01), and low pathological tumor risk (13 vs 15 days, P <0.01). Regarding interval stage, there was a higher inverse correlation in high histological risk stage 1 group compared to low histological risk 1 group in relation with future liver remnant body weight ( r =-0.1 and r =-0.08, respectively), and future liver remnant ( r =-0.15 and r =-0.06, respectively). CONCLUSIONS ALPPS is associated with increased histological alterations in the liver parenchyma. It seems that the more histological alterations present and the higher the number of poor prognostic factors in the tumor histology, the longer the time to reach the second stage.
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Affiliation(s)
- Victor Lopez-Lopez
- Department of Surgery and Liver and Pancreas transplantation, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Michael Linecker
- Department of Surgery and Transplantation, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
| | - Albert Caballero-Llanes
- Department of Pathology, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Tim Reese
- Department of Surgery, Division of Liver, Bileduct and Pancreatic Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | - Karl J Oldhafer
- Department of Surgery, Division of Liver, Bileduct and Pancreatic Surgery, Asklepios Hospital Barmbek, Hamburg, Germany
| | | | - Mauro Tun-Abraham
- Department of Surgery, Western University, London, Ontario, Canada
- Division of Transplantation/Hepatobiliary Surgery, Department of Surgery, University of Rochester, NY
| | - Jun Li
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Mohammad Fard-Aghaie
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Henrik Petrowsky
- Department of Surgery and Transplantation, Swiss HPB and Transplant Center, University Hospital Zurich, Zurich, Switzerland
| | - Roberto Brusadin
- Department of Surgery and Liver and Pancreas transplantation, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Asuncion Lopez-Conesa
- Department of Surgery and Liver and Pancreas transplantation, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Francesca Ratti
- Department of Surgery, Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, School of Medicine, Milan, Italy
| | - Luca Aldrighetti
- Department of Surgery, Hepatobiliary Surgery Division, IRCCS San Raffaele Hospital, School of Medicine, Milan, Italy
| | - Ali Ramouz
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Victoria Ardiles
- Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital Buenos Aires, Argentina
| | - Eduardo De Santibañes
- Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital Buenos Aires, Argentina
| | - Arthur Marichez
- Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France
| | - René Adam
- Centre Hépato-Biliaire, Hôpital Paul Brousse, Villejuif, France
| | - Stéphanie Truant
- Department of Digestive Surgery and Transplantation, University Hospital, Lille, France
| | - Francois-René Pruvot
- Department of Digestive Surgery and Transplantation, University Hospital, Lille, France
| | - Pim B Olthof
- Department of Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Thomas M Van Gulick
- Department of Surgery, Amsterdam University Medical Centers, Amsterdam, The Netherlands
| | - Roberto Montalti
- Department of Clinical Medicine and Surgery, Federico II University Hospital Naples, Napoli, Italy
| | - Roberto I Troisi
- Department of Clinical Medicine and Surgery, Federico II University Hospital Naples, Napoli, Italy
| | - Philipp Kron
- HPB and Transplant Unit, St. James's University Hospital, Leeds, UK
| | - Peter Lodge
- HPB and Transplant Unit, St. James's University Hospital, Leeds, UK
| | - Patryk Kambakamba
- Department of Hepatobiliary Surgery and Liver Transplantation, St. Vincent's University Hospital, Dublin, Ireland
| | - Emir Hoti
- Department of Hepatobiliary Surgery and Liver Transplantation, St. Vincent's University Hospital, Dublin, Ireland
| | | | - Jesus de la Peña-Moral
- Department of Pathology, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
| | - Pierre-Alain Clavien
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ricardo Robles-Campos
- Department of Surgery and Liver and Pancreas transplantation, Virgen de la Arrixaca Clinic and University Hospital, IMIB, Murcia, Spain
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Benedeto-Stojanov D, Ničković VP, Petrović G, Rancić A, Grgov I, Nikolić GR, Marčetić ZP, Popović MR, Lazarević M, Mitić KV, Sokolović D. Melatonin as a Promising Anti-Inflammatory Agent in an In Vivo Animal Model of Sepsis-Induced Rat Liver Damage. Int J Mol Sci 2023; 25:455. [PMID: 38203627 PMCID: PMC10779228 DOI: 10.3390/ijms25010455] [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: 11/06/2023] [Revised: 12/11/2023] [Accepted: 12/16/2023] [Indexed: 01/12/2024] Open
Abstract
Melatonin (MLT), earlier described as an effective anti-inflammatory agent, could be a beneficial adjunctive drug for sepsis treatment. This study aimed to determine the effects of MLT application in lipopolysaccharide (LPS)-induced sepsis in Wistar rats by determining the levels of liver tissue pro-inflammatory cytokines (TNF-α, IL-6) and NF-κB as well as hematological parameters indicating the state of sepsis. Additionally, an immunohistological analysis of CD14 molecule expression was conducted. Our research demonstrated that treatment with MLT prevented an LPS-induced increase in pro-inflammatory cytokines TNF-α and IL-6 and NF-κB levels, and in the neutrophil to lymphocyte ratio (NLR). On the other hand, MLT prevented a decrease in the blood lymphocyte number induced by LPS administration. Also, treatment with MLT decreased the liver tissue expression of the CD14 molecule observed after sepsis induction. In summary, in rats with LPS-induced sepsis, MLT was shown to be a significant anti-inflammatory agent with the potential to change the liver's immunological marker expression, thus ameliorating liver function.
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Affiliation(s)
| | - Vanja P. Ničković
- COVID Hospital Kruševac, University Clinical Centre of Niš, 37000 Kruševac, Serbia;
| | | | - Andrija Rancić
- Clinic of Gastroenterohepatology, University Clinical Centre of Niš, 18000 Niš, Serbia;
| | - Ivan Grgov
- General Hospital Leskovac, Department of General Surgery with Traumatology, 16000 Leskovac, Serbia;
| | - Gordana R. Nikolić
- Faculty of Medicine, University of Priština, 38220 Kosovska Mitrovica, Serbia; (G.R.N.); (Z.P.M.)
| | - Zoran P. Marčetić
- Faculty of Medicine, University of Priština, 38220 Kosovska Mitrovica, Serbia; (G.R.N.); (Z.P.M.)
| | - Milica R. Popović
- Pediatrics Clinic, Clinical Centre Priština, 38205 Gracanica, Serbia;
| | - Milan Lazarević
- Clinic for Cardiovascular and Transplant Surgery, Faculty of Medicine, University Clinical Centre of Niš, 18000 Niš, Serbia;
| | - Katarina V. Mitić
- Institute of Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, 11000 Belgrade, Serbia;
| | - Dušan Sokolović
- Institute for Biochemistry, Faculty of Medicine, University of Niš, 18000 Niš, Serbia;
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Li F, Song G, Wang X, Sun Y, Zhou S, Zhang Y, Hua J, Zhu B, Yang L, Zhang W, Zhou B. Evidence for Adverse Effects on Liver Development and Regeneration in Zebrafish by Decabromodiphenyl Ethane. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023; 57:19419-19429. [PMID: 37946494 DOI: 10.1021/acs.est.3c06747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Decabromodiphenyl ethane (DBDPE), a ubiquitous emerging pollutant, could be enriched in the liver of organisms, but its effects and mechanisms on liver development and regeneration remain largely unknown. In the present study, we first investigated the adverse effects on liver development and found decreased area and intensity of fluorescence in transgenic zebrafish larvae exposed to DBDPE; further results in wild-type zebrafish larvae revealed a possible mechanism involving disturbed MAPK/Fox O signaling pathways and cell cycle arrest as indicated by decreased transcription of growth arrest and DNA-damage-inducible beta a (gadd45ba). Subsequently, an obstructed recovery process of liver tissue after partial hepatectomy was characterized by the changing profiles of ventral lobe-to-intestine ratio in transgenic female adults upon DBDPE exposure; further results confirmed the adverse effects on liver regeneration by the alterations of the hepatic somatic index and proliferating cell nuclear antigen expression in wild-type female adults and also pointed out a potential role of a disturbed signaling pathway involving cell cycles and glycerolipid metabolism. Our results not only provided novel evidence for the hepatotoxicity and underlying mechanism of DBDPE but also were indicative of subsequent ecological and health risk assessment.
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Affiliation(s)
- Fan Li
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Guili Song
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Xiaochen Wang
- Ecology and Environment Monitoring and Scientific Research Center, Ecology and Environment Administration of Yangtze River Basin, Ministry of Ecology and Environment, Wuhan 430010, China
| | - Yumiao Sun
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Shanqi Zhou
- Key Laboratory of Environmental Risk Assessment and Control on Chemical Process, School of Resource and Environmental Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Yindan Zhang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Jianghuan Hua
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Biran Zhu
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Lihua Yang
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Wei Zhang
- Key Laboratory of Environmental Risk Assessment and Control on Chemical Process, School of Resource and Environmental Engineering, East China University of Science and Technology, Shanghai 200237, China
| | - Bingsheng Zhou
- State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
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Tsuge AT, Pereira JDJ, Vollet-Filho JD, Kubrusly MS, Galvão FHF, Ribeiro ON, Moreno CR, Ikegami RN, Chaib E, Castro E Silva OD. Study of laser fluorescence spectroscopy in livers of rats with hypothermic ischemia. Acta Cir Bras 2023; 38:e386023. [PMID: 38055396 DOI: 10.1590/acb386023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/09/2023] [Indexed: 12/08/2023] Open
Abstract
PURPOSE After partial hepatectomy (PH), the remaining liver (RL) undergoes regenerative response proportional to the host. Limited literature exists on hepatic viability after tissue injury during hypothermic preservation. Spectroscopy measures cellular fluorescence and is explored for tissue characterization and parameter investigation. This study aimed to assess fluorescence analysis (spectroscopy) in evaluating liver viability and its relationship with hepatic tissue regeneration 24 hours after PH. Additionally, we analyzed liver regeneration in RL after 70% partial hepatectomy under hypothermic conditions with laser irradiation. METHODS Fifty-six Wistar rats were divided into four groups: total non-perfused liver (control), total perfused liver, partial hepatectomy "in situ", and partial hepatectomy "ex situ". Tissue analysis was performed at 0 and 24 hours using spectroscopy with laser devices emitting at 532 (green) and 405 nm (violet). RESULTS Spectroscopy identified tissue viability based on consistent results with Ki67 staining. The fluorescence spectra and Ki67 analysis displayed similar patterns, linking proliferative activity and absorption intensity. CONCLUSIONS Fluorescence spectroscopy proves to be promising for real-time analysis of cellular activity and viability. Metabolic activity was observed in groups of live animals and hypothermically preserved samples, indicating cellular function even under blood deprivation and hypothermic conditions.
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Affiliation(s)
- Allison Takeo Tsuge
- Universidade de São Paulo - Faculdade de Medicina de Ribeirão Preto - Departamento de Cirurgia e Anatomia -São Paulo(São Paulo), Brazil
| | | | | | - Márcia Saldanha Kubrusly
- Universidade de São Paulo - Hospital das Clínicas - Departamento de Gastroenterologia - São Paulo (SP), Brazil
| | - Flávio Henrique Ferreira Galvão
- Universidade de São Paulo - Hospital das Clínicas - Laboratório de Transplante e Cirurgia de Fígado - São Paulo (SP), Brazil
| | | | - Camila Rodrigues Moreno
- Universidade de São Paulo - Hospital das Clínicas - Instituto do Coração - São Paulo (SP), Brazil
| | - Renata Nishiyama Ikegami
- Universidade de São Paulo - Hospital das Clínicas - Instituto do Coração - São Paulo (SP), Brazil
| | - Eleazar Chaib
- Universidade de São Paulo - Hospital das Clínicas - Laboratório de Transplante e Cirurgia de Fígado - São Paulo (SP), Brazil
| | - Orlando de Castro E Silva
- Universidade de São Paulo - Faculdade de Medicina de Ribeirão Preto - Departamento de Cirurgia e Anatomia -São Paulo(São Paulo), Brazil
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11
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Milana F, Famularo S, Diana M, Mishima K, Reitano E, Cho HD, Kim KH, Marescaux J, Donadon M, Torzilli G. How Much Is Enough? A Surgical Perspective on Imaging Modalities to Estimate Function and Volume of the Future Liver Remnant before Hepatic Resection. Diagnostics (Basel) 2023; 13:2726. [PMID: 37685264 PMCID: PMC10486462 DOI: 10.3390/diagnostics13172726] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 08/19/2023] [Accepted: 08/20/2023] [Indexed: 09/10/2023] Open
Abstract
Liver resection is the first curative option for most hepatic primary and secondary malignancies. However, post-hepatectomy liver failure (PHLF) still represents a non-negligible postoperative complication, embodying the most frequent cause of hepatic-related mortality. In the absence of a specific treatment, the most effective way to deal with PHLF is its prevention through a careful preoperative assessment of future liver remnant (FLR) volume and function. Apart from the clinical score and classical criteria to define the safe limit of resectability, new imaging modalities have shown their ability to assist surgeons in planning the best operative strategy with a precise estimation of the FLR amount. New technologies leading to liver and tumor 3D reconstruction may guide the surgeon along the best resection planes combining the least liver parenchymal sacrifice with oncological appropriateness. Integration with imaging modalities, such as hepatobiliary scintigraphy, capable of estimating total and regional liver function, may bring about a decrease in postoperative complications. Magnetic resonance imaging with hepatobiliary contrast seems to be predominant since it simultaneously integrates hepatic function and volume information along with a precise characterization of the target malignancy.
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Affiliation(s)
- Flavio Milana
- Department of Biomedical Sciences, Humanitas University, Via Montalcini 4, 20090 Pieve Emanuele, MI, Italy
- Division of Hepatobiliary and General Surgery, Department of Hepatobiliary and General Surgery, Humanitas Research Hospital-IRCCS, Humanitas University, Via Manzoni 56, 20089 Rozzano, MI, Italy
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Simone Famularo
- Department of Biomedical Sciences, Humanitas University, Via Montalcini 4, 20090 Pieve Emanuele, MI, Italy
- Division of Hepatobiliary and General Surgery, Department of Hepatobiliary and General Surgery, Humanitas Research Hospital-IRCCS, Humanitas University, Via Manzoni 56, 20089 Rozzano, MI, Italy
- Research Institute Against Digestive Cancer (IRCAD), 67000 Strasbourg, France
| | - Michele Diana
- Research Institute Against Digestive Cancer (IRCAD), 67000 Strasbourg, France
- Photonics Instrumentation for Health, iCube Laboratory, University of Strasbourg, 67000 Strasbourg, France
- Department of General, Digestive and Endocrine Surgery, University Hospital of Strasbourg, 67200 Strasbourg, France
| | - Kohei Mishima
- Research Institute Against Digestive Cancer (IRCAD), 67000 Strasbourg, France
| | - Elisa Reitano
- Research Institute Against Digestive Cancer (IRCAD), 67000 Strasbourg, France
| | - Hwui-Dong Cho
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Ki-Hun Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea
| | - Jacques Marescaux
- Research Institute Against Digestive Cancer (IRCAD), 67000 Strasbourg, France
| | - Matteo Donadon
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, NO, Italy
- Department of General Surgery, University Maggiore Hospital, 28100 Novara, NO, Italy
| | - Guido Torzilli
- Department of Biomedical Sciences, Humanitas University, Via Montalcini 4, 20090 Pieve Emanuele, MI, Italy
- Division of Hepatobiliary and General Surgery, Department of Hepatobiliary and General Surgery, Humanitas Research Hospital-IRCCS, Humanitas University, Via Manzoni 56, 20089 Rozzano, MI, Italy
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12
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Casillas-Ramírez A, Micó-Carnero M, Sánchez-González A, Maroto-Serrat C, Trostchansky A, Peralta C. NO-IL-6/10-IL-1β axis: a new pathway in steatotic and non-steatotic liver grafts from brain-dead donor rats. Front Immunol 2023; 14:1178909. [PMID: 37593740 PMCID: PMC10427871 DOI: 10.3389/fimmu.2023.1178909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 07/11/2023] [Indexed: 08/19/2023] Open
Abstract
INTRODUCTION Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT). MATERIAL AND METHODS Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines. RESULTS BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1β, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1β only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1β inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1β only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1β effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1β action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1β regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1β seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1β, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1β levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage. CONCLUSION Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1β in non-steatotic livers and NO-IL-10-IL-1β in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.
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Affiliation(s)
- Araní Casillas-Ramírez
- Department of Teaching and Research Sub-Direction, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria, Mexico
- Facultad de Medicina e Ingeniería en Sistemas Computacionales de Matamoros, Universidad Autónoma de Tamaulipas, Matamoros, Mexico
| | - Marc Micó-Carnero
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Alfredo Sánchez-González
- Department of Teaching and Research Sub-Direction, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria, Mexico
| | - Cristina Maroto-Serrat
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
| | - Andrés Trostchansky
- Departamento de Bioquímica and Centro de Investigaciones Biomédicas (CEINBIO), Facultad de Medicina, Universidad de la República, Montevideo, Uruguay
| | - Carmen Peralta
- Department of Liver, Digestive System and Metabolism, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
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Toprak V, Akalın SA, Öcal E, Çavuş Y, Özdemir İ. Histopathological examination of the protective effect of intense exercise in apoptotic germ cell damage due to diabetes. Acta Cir Bras 2023; 38:e381423. [PMID: 37098926 PMCID: PMC10129294 DOI: 10.1590/acb381423] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 02/22/2023] [Indexed: 04/27/2023] Open
Abstract
PURPOSE The aim of this study was to determine the protective and antioxidative effects of intensive exercise on streptozotocin (STZ)-induced testicular damage, apoptotic spermatognial cells death, and oxidative stress. METHODS 36 male Sprague Dawley rats were divided into three groups: control, diabetes, and diabetes+intensive exercise (IE) groups. Testicular tissues were examined histopathologically and antioxidant enzymes, including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and malondialdehyde (MDA) activity, as well as serum testosterone level, were measured. RESULTS Seminiferous tubules and germ cells were found to be better in the testis tissue of the intense exercise group than in the diabetes group. Diabetes suppressed antioxidant enzymes CAT, SOD, GPx and testosterone levels were significantly decreased, and increased MDA level in the diabetic group compared to diabetes+IE group (p < 0.001). Following four weeks of treatment, intensive exercise improved the antioxidant defense, significantly decreased MDA activity, and increased testosterone levels in testicular tissue in the diabetic group compared to diabetes+IE group (p < 0.01). CONCLUSIONS STZ-induced diabetes causes damage to the testis tissue. In order to prevent these damages, exercise practice has become very popular nowadays. In present study, our intensive exercise protocol, histological, and biochemical analysis of the effect of diabetes on the testicular tissues is shown.
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Affiliation(s)
- Veysel Toprak
- Eyyübiye Education and Research Hospital - Department of Gynecology and Obstetrics - Şanlıurfa, Turkey
| | - Senem Alkan Akalın
- Private Medical Practice - Department of Gynecology and Obstetrics - Diyarbakir, Turkey
| | - Ece Öcal
- Antalya Research and Education Hospital - Department of Perinatology - Antalya, Turkey
| | - Yunus Çavuş
- Diyarbakir Memorial Hospital - Department of Gynecology and Obstetrics - Diyarbakir, Turkey
| | - İlhan Özdemir
- Atatürk University - Faculty of Medicine - Department of Gynecology and Obstetrics - Erzurum, Turkey
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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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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16
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Neri AA, Dontas IA, Iliopoulos DC, Karatzas T. Pathophysiological Changes During Ischemia-reperfusion Injury in Rodent Hepatic Steatosis. In Vivo 2021; 34:953-964. [PMID: 32354880 DOI: 10.21873/invivo.11863] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 02/03/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND/AIM Ischemia and reperfusion injuries may produce deleterious effects on hepatic tissue after liver surgery and transplantation. The impact of ischemia-reperfusion injury (IRI) on the liver depends on its substrate, the percentage of liver ischemic tissue subjected to IRI and the ischemia time. The consequences of IRI are more evident in pathologic liver substrates, such as steatotic livers. This review is the result of an extended bibliographic PubMed search focused on the last 20 years. It highlights basic differences encountered during IRI in lean and steatotic livers based on studies using rodent experimental models. CONCLUSION The main difference in cell death between lean and steatotic livers is the prevalence of apoptosis in the former and necrosis in the latter. There are also major changes in the effect of intracellular mediators, such as TNFα and IL-1β. Further experimental studies are needed in order to increase current knowledge of IRI effects and relevant mechanisms in both lean and steatotic livers, so that new preventive and therapeutic strategies maybe developed.
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Affiliation(s)
- Anna-Aikaterini Neri
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Ismene A Dontas
- Laboratory for Research of the Musculoskeletal System "Th. Garofalidis", KAT Hospital, School of Medicine, National & Kapodistrian University of Athens, Kifissia, Greece
| | - Dimitrios C Iliopoulos
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
| | - Theodore Karatzas
- Laboratory of Experimental Surgery & Surgical Research "N.S. Christeas", School of Medicine, National & Kapodistrian University of Athens, Athens, Greece.,2 Department of Propedeutic Surgery, School of Medicine, National & Kapodistrian University of Athens, Athens, Greece
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17
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Unraveling the Role of Leptin in Liver Function and Its Relationship with Liver Diseases. Int J Mol Sci 2020; 21:ijms21249368. [PMID: 33316927 PMCID: PMC7764544 DOI: 10.3390/ijms21249368] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/19/2020] [Accepted: 12/04/2020] [Indexed: 02/06/2023] Open
Abstract
Since its discovery twenty-five years ago, the fat-derived hormone leptin has provided a revolutionary framework for studying the physiological role of adipose tissue as an endocrine organ. Leptin exerts pleiotropic effects on many metabolic pathways and is tightly connected with the liver, the major player in systemic metabolism. As a consequence, understanding the metabolic and hormonal interplay between the liver and adipose tissue could provide us with new therapeutic targets for some chronic liver diseases, an increasing problem worldwide. In this review, we assess relevant literature regarding the main metabolic effects of leptin on the liver, by direct regulation or through the central nervous system (CNS). We draw special attention to the contribution of leptin to the non-alcoholic fatty liver disease (NAFLD) pathogenesis and its progression to more advanced stages of the disease as non-alcoholic steatohepatitis (NASH). Likewise, we describe the contribution of leptin to the liver regeneration process after partial hepatectomy, the mainstay of treatment for certain hepatic malignant tumors.
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Yagi S, Hirata M, Miyachi Y, Uemoto S. Liver Regeneration after Hepatectomy and Partial Liver Transplantation. Int J Mol Sci 2020; 21:ijms21218414. [PMID: 33182515 PMCID: PMC7665117 DOI: 10.3390/ijms21218414] [Citation(s) in RCA: 116] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/04/2020] [Accepted: 11/05/2020] [Indexed: 02/07/2023] Open
Abstract
The liver is a unique organ with an abundant regenerative capacity. Therefore, partial hepatectomy (PHx) or partial liver transplantation (PLTx) can be safely performed. Liver regeneration involves a complex network of numerous hepatotropic factors, cytokines, pathways, and transcriptional factors. Compared with liver regeneration after a viral- or drug-induced liver injury, that of post-PHx or -PLTx has several distinct features, such as hemodynamic changes in portal venous flow or pressure, tissue ischemia/hypoxia, and hemostasis/platelet activation. Although some of these changes also occur during liver regeneration after a viral- or drug-induced liver injury, they are more abrupt and drastic following PHx or PLTx, and can thus be the main trigger and driving force of liver regeneration. In this review, we first provide an overview of the molecular biology of liver regeneration post-PHx and -PLTx. Subsequently, we summarize some clinical conditions that negatively, or sometimes positively, interfere with liver regeneration after PHx or PLTx, such as marginal livers including aged or fatty liver and the influence of immunosuppression.
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19
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Žaloudková L, Tichá A, Nekvindová J, Pavlíková L, Zadák Z, Živný P. Different Forms of Ursolic Acid and Their Effect on Liver Regeneration. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:4074068. [PMID: 32774413 PMCID: PMC7399780 DOI: 10.1155/2020/4074068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/25/2020] [Accepted: 07/07/2020] [Indexed: 12/17/2022]
Abstract
The aim of this study was to determine the effect of natural and encapsulated sources of ursolic acid on liver regeneration. Four ursolate sources were tested. Two forms of ursolic acid encapsulates were combined with cyclodextrins, i.e., gamma-CD (gCD) and beta-CD, and two natural sources were adjusted by homogenization (HAP) and micronization of apple peel using Jonagold apples. All ursolate forms were applied intragastrically in daily doses of 20 mg for 7 days. Laboratory rats were fed with standard laboratory diet. Further, gCD and MAP were also tested with a high-fat diet (6 weeks). Partial hepatectomy (PH) was performed 24 hours before the end of the experiment. The concentration of plasma hepatocyte growth factor (HGF) was determined with an immunoassay; simultaneously, the expression of HGF and CYP7A1 in the liver was quantified through qPCR. HGF expression and plasma levels were significantly increased 24 hours after PH in both the HAP (p=0.038) and HFgCD groups (p=0.036), respectively. The correlation between HGF expression and plasma values was significant (p=0.04). The positive effects on liver regeneration were found in both the gCD and HAP forms of ursolic acid, whose effects were confirmed through the upregulation of HGF.
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Affiliation(s)
- Lenka Žaloudková
- Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Sokolska Str. 581, Hradec Kralove 500 05, Czech Republic
| | - Alena Tichá
- Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Sokolska Str. 581, Hradec Kralove 500 05, Czech Republic
| | - Jana Nekvindová
- Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Sokolska Str. 581, Hradec Kralove 500 05, Czech Republic
| | - Ladislava Pavlíková
- Institute of Clinical Biochemistry and Diagnostics, University Hospital Hradec Kralove, Sokolska Str. 581, Hradec Kralove 500 05, Czech Republic
| | - Zdeněk Zadák
- Department of Research and Development, University Hospital Hradec Kralove, Sokolska Str. 581, Hradec Kralove 500 05, Czech Republic
| | - Pavel Živný
- 2nd Department of Internal Medicine–Gastroenterology, Charles University, Faculty of Medicine in Hradec Kralove, Hradec Kralove 500 03, Czech Republic
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Caldez MJ, Bjorklund M, Kaldis P. Cell cycle regulation in NAFLD: when imbalanced metabolism limits cell division. Hepatol Int 2020; 14:463-474. [PMID: 32578019 PMCID: PMC7366567 DOI: 10.1007/s12072-020-10066-6] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Accepted: 06/06/2020] [Indexed: 12/12/2022]
Abstract
Cell division is essential for organismal growth and tissue homeostasis. It is exceptionally significant in tissues chronically exposed to intrinsic and external damage, like the liver. After decades of studying the regulation of cell cycle by extracellular signals, there are still gaps in our knowledge on how these two interact with metabolic pathways in vivo. Studying the cross-talk of these pathways has direct clinical implications as defects in cell division, signaling pathways, and metabolic homeostasis are frequently observed in liver diseases. In this review, we will focus on recent reports which describe various functions of cell cycle regulators in hepatic homeostasis. We will describe the interplay between the cell cycle and metabolism during liver regeneration after acute and chronic damage. We will focus our attention on non-alcoholic fatty liver disease, especially non-alcoholic steatohepatitis. The global incidence of non-alcoholic fatty liver disease is increasing exponentially. Therefore, understanding the interplay between cell cycle regulators and metabolism may lead to the discovery of novel therapeutic targets amenable to intervention.
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Affiliation(s)
- Matias J Caldez
- WPI Immunology Frontiers Research Centre, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Mikael Bjorklund
- Zhejiang University-University of Edinburgh (ZJU-UoE) Institute and 2nd Affiliated Hospital, Zhejiang University School of Medicine, 718 East Haizhou Rd., Haining, 314400, Zhejiang, People's Republic of China
| | - Philipp Kaldis
- Department of Clinical Sciences, Clinical Research Centre (CRC), Lund University, Box 50332, 202 13, Malmö, Sweden.
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Aydın O, Pehlivanlı F, Karaca G, Aydın G, Altunkaya C, Bulut H. May dexpanthenol, platelet-rich plasma, and thymoquinone provide new hope to maintain liver regeneration after partial hepatectomy? TURKISH JOURNAL OF GASTROENTEROLOGY 2020; 30:826-834. [PMID: 31530526 DOI: 10.5152/tjg.2019.18697] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND/AIMS Complete liver regeneration may not always be possible after liver injuries and/or partial liver resection. The present study investigated the effects of dexpanthenol, platelet-rich plasma (PRP), and thymoquinone on liver regeneration in rats after partial hepatectomy (PH). MATERIALS AND METHODS A total of 34 Wistar albino rats, each weighing 250-280 g, were randomly separated into four groups. PH was performed, and except for the control group, intraperitoneal dexpanthenol, PRP, or thymoquinone was administered to the relevant groups for 7 days. All rats were then sacrificed, and the liver tissues were examined histopathologically and biochemically. RESULTS PRP reduced all oxidant-antioxidant parameters in rats that experienced liver regeneration, but did not create histopathological improvement in the liver tissue. Dexpanthenol had a histopathological improving effect on the liver tissue, but had no effect on biochemical parameters. Thymoquinone showed no histopathological or biochemical effects on liver regeneration. CONCLUSION Although dexpanthenol did not affect biochemical oxidative parameters, it was considered to have improving effects on liver regeneration histopathologically. In addition, it was thought that PRP may be used for treatment of ischemia-reperfusion injury and cholestatic damage of the liver. Nevertheless, further studies are required on these subjects.
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Affiliation(s)
- Okan Aydın
- Department of General Surgery, Kırıkkale University School of Medicine, Kırıkkale, Turkey
| | - Faruk Pehlivanlı
- Department of General Surgery, Kırıkkale University School of Medicine, Kırıkkale, Turkey
| | - Gökhan Karaca
- Department of General Surgery, Kırıkkale University School of Medicine, Kırıkkale, Turkey
| | - Gülçin Aydın
- Department of Anesthesiology and Reanimation, Kırıkkale University School of Medicine, Kırıkkale, Turkey
| | - Canan Altunkaya
- Department of Pathology, Kırıkkale University School of Medicine, Kırıkkale, Turkey
| | - Huri Bulut
- Department of Medical Biochemistry, Bezmialem Vakıf University, İstanbul, Turkey
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Safe Use of Right Lobe Live Donor Livers With up to 20% Macrovesicular Steatosis Without Compromising Donor Safety and Recipient Outcome. Transplantation 2020; 104:308-316. [DOI: 10.1097/tp.0000000000002847] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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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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Paraš S, Janković O, Trišić D, Čolović B, Mitrović-Ajtić O, Dekić R, Soldatović I, Živković Sandić M, Živković S, Jokanović V. Influence of nanostructured calcium aluminate and calcium silicate on the liver: histological and unbiased stereological analysis. Int Endod J 2019; 52:1162-1172. [PMID: 30802977 DOI: 10.1111/iej.13105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 02/22/2019] [Indexed: 12/11/2022]
Abstract
AIM To examine the potential systemic toxicity of nanostructured materials based on calcium silicate and calcium aluminate, for potential application in Dentistry. METHODOLOGY Twenty-four Albino Wistar rats aged 2 months were used as an in vivo animal model for subcutaneous implantation of the investigated materials, placed in polyethylene tubes. Thirty days after implantation, the livers of the rats were analysed and following histological and stereological parameters were evaluated for volume density of hepatocytes and blood sinusoids, number and numerical density of hepatocytes, surface of hepatocytes and their nucleuses, nucleocytoplasmic ratio and mitotic index of hepatocytes. Stereological measurements were achieved using Cavalieri's principle, with grid P2 and unbiased analysis. Additionally, immunohistochemistry studies were performed to further analyse changes in liver tissue. Several haematological and biochemical parameters of blood of experimental animals were also analysed, as well as local tissue reactions around the implants. Statistical analysis was performed using parametric (anova and t-test) and nonparametric tests (Kruskal-Wallis and Mann-Whitney U-test) depending on data distribution. RESULTS Implanted dental cements led to an increase in stereological and histological parameters in liver tissue compared to control rats. Although the investigated parameters mostly showed significant differences between control and experimental animals, the liver tissue of the experimental animals did not have visible signs of pathological changes. This was supported by the analysis of blood parameters which were not significantly different between control and experimental animals. Also, the subcutaneous tissues had minimal inflammatory reactions. Immunohistochemistry studies revealed that nanostructured materials induced proliferation of hepatocytes, but that the immunological response to the materials was not strong enough to induce proliferation of immunoreactive cells in liver in the observed time period. CONCLUSIONS This study was performed as a contribution to the attestation of the biocompatibility of dental cements based on calcium silicate and calcium aluminate. Although these materials induced several changes in the liver structure, they were not clinically relevant and represent a normal and reversible response of the liver to the presence of biocompatible materials in the body. Blood and immunohistochemistry analyses and local tissue reactions further confirmed that these materials possess good biocompatible potential.
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Affiliation(s)
- S Paraš
- Department of Zoology, Faculty of Science and Mathematics, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - O Janković
- Department of Stomatology, Faculty of Medicine, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - D Trišić
- Faculty of Stomatology, University of Belgrade, Belgrade, Serbia
| | - B Čolović
- Vinča Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia
| | - O Mitrović-Ajtić
- Department for Molecular Oncology, Institute for Medical Research, University of Belgrade, Belgrade, Serbia
| | - R Dekić
- Department of Zoology, Faculty of Science and Mathematics, University of Banja Luka, Banja Luka, Republic of Srpska, Bosnia and Herzegovina
| | - I Soldatović
- Institute for Biostatistics, University of Belgrade, Belgrade, Serbia
| | | | - S Živković
- Faculty of Stomatology, University of Belgrade, Belgrade, Serbia
| | - V Jokanović
- Vinča Institute of Nuclear Sciences, University of Belgrade, Belgrade, Serbia.,ALBOS LLC, Belgrade, Serbia
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Liver-specific Repin1 deficiency impairs transient hepatic steatosis in liver regeneration. Sci Rep 2018; 8:16858. [PMID: 30442920 PMCID: PMC6237840 DOI: 10.1038/s41598-018-35325-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 11/02/2018] [Indexed: 02/06/2023] Open
Abstract
Transient hepatic steatosis upon liver resection supposes functional relationships between lipid metabolism and liver regeneration. Repin1 has been suggested as candidate gene for obesity and dyslipidemia by regulating key genes of lipid metabolism and lipid storage. Herein, we characterized the regenerative potential of mice with a hepatic deletion of Repin1 (LRep1−/−) after partial hepatectomy (PH) in order to determine the functional significance of Repin1 in liver regeneration. Lipid dynamics and the regenerative response were analyzed at various time points after PH. Hepatic Repin1 deficiency causes a significantly decreased transient hepatic lipid accumulation. Defects in lipid uptake, as analyzed by decreased expression of the fatty acid transporter Cd36 and Fatp5, may contribute to attenuated and shifted lipid accumulation, accompanied by altered extent and chronological sequence of liver cell proliferation in LRep1−/− mice. In vitro steatosis experiments with primary hepatocytes also revealed attenuated lipid accumulation and occurrence of smaller lipid droplets in Repin1-deficient cells, while no direct effect on proliferation in HepG2 cells was observed. Based on these results, we propose that hepatocellular Repin1 might be of functional significance for early accumulation of lipids in hepatocytes after PH, facilitating efficient progression of liver regeneration.
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Goja S, Kumar Yadav S, Singh Soin A. Readdressing the Middle Hepatic Vein in Right Lobe Liver Donation: Triangle of Safety. Liver Transpl 2018; 24:1363-1376. [PMID: 30359489 DOI: 10.1002/lt.25289] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 04/30/2018] [Accepted: 05/16/2018] [Indexed: 02/07/2023]
Abstract
For equipoising donor safety and optimal recipient outcomes, we adopted an algorithmic "triangle of safety" approach to retrieve 3 types of right lobe liver grafts (RLGs), namely, the modified extended right lobe graft (MERLG), the partial right lobe graft (PRLG), and the modified right lobe graft (MRLG). Reconstruction to achieve a single wide anterior sector outflow was ensured in all patients. We present donor and recipient outcomes based on our approach in 665 right lobe (RL) living donor liver transplantations (LDLTs) performed from January 2013 to August 2015. There were 347 patients who received a MERLG, 117 who received a PRLG, and 201 who received a MRLG. A right lobe graft (RLG) with a middle hepatic vein was retrieved only in 3 out of 18 donors with steatosis >10%. Cold ischemia time was significantly more and remnant volume was less in the MRLG group. Of the donors, 29.3% had complications (26% Clavien-Dindo grade I, II) with no statistically significant difference among the groups. The Model for End-Stage Liver Disease score was higher in the MERLG group. There were 34 out of 39 with a graft-to-recipient weight ratio (GRWR) of <0.7% who received a MERLG with inflow modulation. Out of 4 patients who developed small-for-size syndrome in this group, 2 died. The 90-day patient survival rate was similar among different GRWRs and types of RLG. In conclusion, a selective and tailored approach for RL donor hepatectomy based on optimal functional volume and metabolic demands not only addresses the key issue of double equipoise in LDLT but also creates a safe path for extending the limits.
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Affiliation(s)
- Sanjay Goja
- Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurgaon, Delhi, India
| | - Sanjay Kumar Yadav
- Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurgaon, Delhi, India
| | - Arvinder Singh Soin
- Institute of Liver Transplantation and Regenerative Medicine, Medanta-The Medicity, Gurgaon, Delhi, India
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27
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Chae MS, Lee N, Choi HJ, Chung HS, Park CS, Lee J, Choi JH, Hong SH. Comparison of Liver Graft Regeneration Between ABO-Compatible and ABO-Incompatible Living Donor Liver Transplantation: A Propensity Score Matching Analysis. Ann Transplant 2018; 23:507-519. [PMID: 30050031 PMCID: PMC6248061 DOI: 10.12659/aot.908787] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND ABO-incompatible (ABOi) living donor liver transplantation (LDLT) was accepted as a feasible therapy for end-stage liver disease after the introduction of rituximab. The present study investigated the association between ABO incompatibility and graft regeneration in patients who underwent LDLT. MATERIAL AND METHODS A total of 335 adult patients who underwent elective LDLT were divided into ABO-compatible (ABOc) and ABOi LDLT groups using propensity score (PS) matching of graft regeneration-related factors. Postoperative serial changes in graft volumes were compared between the groups. The factors associated with graft volume on postoperative day (POD) 21 were investigated in patients who underwent ABOi LDLT. RESULTS In total, 300 (89.6%) patients underwent ABOc LDLT and 35 (10.4%) patients underwent ABOi LDLT. After PS matching, the ABOc and ABOi groups each included 32 paired patients. The absolute liver graft volumes on POD 21 were significantly lower in the ABOi group than those in the ABOc group in the PS-matched patients (1098.4 [964.0-1,162.0] vs. 1202.0 [1107.8-1455.2] mL; p=0.007). Major complications, including overall patient mortality during the follow-up period, did not differ between the groups. In patients who underwent ABOi LDLT, the preoperative graft volume/standard liver volume ratio and CD4+ cell level on POD 14 were independent factors related to liver graft volume on POD 21. CONCLUSIONS These results suggest that ABO incompatibility could affect postoperative liver graft regeneration. Therefore, graft regeneration must be investigated using a volumetric assessment in patients who have undergone ABOi LDLT.
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Affiliation(s)
- Min Suk Chae
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Nuri Lee
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Ho Joong Choi
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Hyun Sik Chung
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Chul Soo Park
- Anesthesiology and pain medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, , South Korea
| | - Jaemin Lee
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Jong Ho Choi
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Sang Hyun Hong
- Department of Anesthesiology and Pain Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
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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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Undifferentiated Adipose Tissue Stem Cell Transplantation Promotes Hepatic Regeneration, Ameliorates Histopathologic Damage of the Liver, and Upregulates the Expression of Liver Regeneration- and Liver-Specific Genes in a Rat Model of Partial Hepatectomy. Stem Cells Int 2018; 2018:1393607. [PMID: 29731771 PMCID: PMC5872619 DOI: 10.1155/2018/1393607] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 12/06/2017] [Indexed: 02/01/2023] Open
Abstract
Objective Adipose tissue stem cells (ADSCs) present a promising therapeutic method to alleviate liver failure (LF). The purpose of this prospective study was to evaluate the efficacy of undifferentiated ADSC transplantation on liver regeneration and on the expression of liver regeneration- and liver-specific genes, following 60% partial hepatectomy (PHx). Methods Sixty female rats were subjected to PHx and were transplanted with 106 or 2 × 106 ADSCs, either into the portal vein (PV) or into the hepatic parenchyma. Animals of the control group were not transplanted and served as controls. Animals were sacrificed on the 4th, the 7th, or the 15th postoperative day (POD). Results The transplanted ADSCs were successfully engrafted into the liver parenchyma and ameliorated the histopathologic damage on the 7th and 15th POD. All transplanted animals demonstrated a significantly higher liver regeneration rate on the 4th and 7th POD, compared with the control group. The expression of hepatocyte growth factor, α-fetoprotein, tyrosine aminotransferase, hepatocyte nuclear factor 4a, and cytochrome P450 1A2 was significantly upregulated, compared with the control group. Conclusions Although undifferentiated, ADSC transplantation significantly enhanced the liver regeneration process. These findings may be proven clinically valuable, especially in cases of acute LF.
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Haldrup D, Heebøll S, Thomsen KL, Andersen KJ, Meier M, Mortensen FV, Nyengaard JR, Hamilton-Dutoit S, Grønbæk H. Preserved liver regeneration capacity after partial hepatectomy in rats with non-alcoholic steatohepatitis. World J Hepatol 2018; 10:8-21. [PMID: 29399274 PMCID: PMC5787687 DOI: 10.4254/wjh.v10.i1.8] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 11/20/2017] [Accepted: 12/06/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the liver regeneration capacity (LRC) after partial hepatectomy (PH) in experimental non-alcoholic steatohepatitis (NASH).
METHODS Fifty-four female rats were fed a high-fat, high-cholesterol diet (HFCD, 65% fat, 1% cholesterol) or standard diet (STD) for 16 wk. A 70% PH was performed and the animals were euthanised before PH or 2 or 5 d post-PH. LRC was evaluated using: The total number of Ki-67 positive hepatocytes in the caudate lobe, N(Ki-67, lobe) evaluated in a stereology-based design, the regenerated protein ratio (RPR), prothrombin-proconvertin ratio (PP), and mRNA expression of genes related to regeneration.
RESULTS The HFCD NASH model showed significant steatosis with ballooning and inflammation, while no fibrosis was present. Mortality was similar in HFCD and STD animals following PH. HFCD groups were compared to respective STD groups and HFCD animals had a significantly elevated alanine transaminase at baseline (P < 0.001), as well as a significantly elevated bilirubin at day 2 after PH (P < 0.05). HFCD animals had a higher N(Ki-67, lobe) at baseline, (P < 0.0001), day 2 after PH (P = 0.06) and day 5 after PH (P < 0.025). We found no significant difference in RPR or PP neither 2 or 5 d post-PH. Expression of liver regeneration genes (e.g., hepatic growth factor) was higher at both day 2 and 5 post-PH in HFCD groups (P < 0.05).
CONCLUSION NASH rats had a preserved LRC after hepatectomy when compared to STD rats. The methods and models of NASH are essential in understanding and evaluating LRC.
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Affiliation(s)
- David Haldrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
- Department of Internal Medicine, Randers Regional Hospital, Randers NØ DK-8930, Denmark
| | - Sara Heebøll
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | - Karen Louise Thomsen
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | | | - Michelle Meier
- Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | - Frank Viborg Mortensen
- Department of Surgical Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | - Jens Randel Nyengaard
- Stereology and Electron Microscopy Laboratory, Centre for Stochastic Geometry and Advanced Bioimaging, Aarhus University Hospital, Aarhus C DK-8000, Denmark
| | | | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus C DK-8000, Denmark
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Güven D, Altunkaynak BZ, Altun G, Alkan I, Kocak İ. Histomorphometric changes in the placenta and umbilical cord during complications of pregnancy. Biotech Histochem 2018; 93:198-210. [DOI: 10.1080/10520295.2017.1410993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- D Güven
- Department of Obstetrics and Gynecology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - BZ Altunkaynak
- Department of Histology and Embryology, Faculty of Medicine, Okan University, İstanbul, Turkey
| | - G Altun
- Department of Histology and Embryology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - I Alkan
- Department of Histology and Embryology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
| | - İ Kocak
- Department of Obstetrics and Gynecology, Faculty of Medicine, Ondokuz Mayis University, Samsun, Turkey
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Yu Y, Tamai M, Tagawa YI. Nitric oxide is critical for avoiding hepatic lipid overloading via IL-6 induction during liver regeneration after partial hepatectomy in mice. Exp Anim 2017; 66:293-302. [PMID: 28515388 PMCID: PMC5682341 DOI: 10.1538/expanim.17-0017] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Nitric oxide (NO), generated from L-arginine by three different isoforms of nitric oxide synthase (NOS), is a pleiotropic factor to regulate physiological functions in almost every organ and tissue. Each knockout mouse of iNOS or eNOS has been used to suggest that NO has a crucial role in liver regeneration after partial hepatectomy (PH), for NO may inhibit caspase 3 activity and is required for EGFR signaling. In previous reports, defective mitochondrial β-oxidation was observed in eNOS KO mice, and hepatic steatosis was often correlated to deficient liver regeneration, so we focused on metabolic perspective and hypothesized that NO depletion in PH mice would affect hepatocytic lipolysis and impair hepatocytes proliferation. We inhibited all NOS isoforms by administrating L-NG-nitroarginine methyl ester (L-NAME) to PH mice, and hepatocyte DNA synthesis was severely inhibited at 40-44 h post PH in L-NAME (+) group. IL-6 was robustly secreted into circulating blood in L-NAME (-) group, but not in L-NAME (+) group. Down-regulation of carnitine palmytoyltransferase 1A, massive lipid accumulation and elevated endoplasmic reticulum (ER) stress relative genes expression level were observed in L-NAME (+) group mouse liver. The expression level of C/EBP homologous protein, a mediator of ER stress induced apoptosis, significantly increased in L-NAME (+) group. Our findings suggest the lack of NO affected IL-6 induction and hepatocyte lipolysis after PH, consequently leading to excessive hepatic lipid accumulation, elevated ER stress and impaired hepatocyte proliferation.
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Affiliation(s)
- Yue Yu
- Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
| | - Miho Tamai
- Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.,School of Life Science and Technology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.,Course of Oral Medical Science, Graduate School of Dental Medicine, Hokkaido University, Kita 13-jo, Nishi 7-chome, Kita-ku, Sapporo, Hokkaido 060-8586, Japan
| | - Yoh-Ichi Tagawa
- Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan.,School of Life Science and Technology, Tokyo Institute of Technology, 4259 B51, Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
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Ezquer F, Bahamonde J, Huang YL, Ezquer M. Administration of multipotent mesenchymal stromal cells restores liver regeneration and improves liver function in obese mice with hepatic steatosis after partial hepatectomy. Stem Cell Res Ther 2017; 8:20. [PMID: 28129776 PMCID: PMC5273822 DOI: 10.1186/s13287-016-0469-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Revised: 11/11/2016] [Accepted: 12/31/2016] [Indexed: 02/06/2023] Open
Abstract
Background The liver has the remarkable capacity to regenerate in order to compensate for lost or damaged hepatic tissue. However, pre-existing pathological abnormalities, such as hepatic steatosis (HS), inhibits the endogenous regenerative process, becoming an obstacle for liver surgery and living donor transplantation. Recent evidence indicates that multipotent mesenchymal stromal cells (MSCs) administration can improve hepatic function and increase the potential for liver regeneration in patients with liver damage. Since HS is the most common form of chronic hepatic illness, in this study we evaluated the role of MSCs in liver regeneration in an animal model of severe HS with impaired liver regeneration. Methods C57BL/6 mice were fed with a regular diet (normal mice) or with a high-fat diet (obese mice) to induce HS. After 30 weeks of diet exposure, 70% hepatectomy (Hpx) was performed and normal and obese mice were divided into two groups that received 5 × 105 MSCs or vehicle via the tail vein immediately after Hpx. Results We confirmed a significant inhibition of hepatic regeneration when liver steatosis was present, while the hepatic regenerative response was promoted by infusion of MSCs. Specifically, MSC administration improved the hepatocyte proliferative response, PCNA-labeling index, DNA synthesis, liver function, and also reduced the number of apoptotic hepatocytes. These effects may be associated to the paracrine secretion of trophic factors by MSCs and the hepatic upregulation of key cytokines and growth factors relevant for cell proliferation, which ultimately improves the survival rate of the mice. Conclusions MSCs represent a promising therapeutic strategy to improve liver regeneration in patients with HS as well as for increasing the number of donor organs available for transplantation. Electronic supplementary material The online version of this article (doi:10.1186/s13287-016-0469-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fernando Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile
| | - Javiera Bahamonde
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile.,Departamento de Fomento de la Producción Animal, Facultad de Ciencias Veterinarias y Pecuarias, Universidad de Chile, Av. Santa Rosa 11735, La Pintana, Santiago, Chile
| | - Ya-Lin Huang
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile
| | - Marcelo Ezquer
- Centro de Medicina Regenerativa, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Av. Las Condes 12.438, Lo Barnechea, 7710162, Santiago, Chile.
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van Mierlo KMC, Schaap FG, Dejong CHC, Olde Damink SWM. Liver resection for cancer: New developments in prediction, prevention and management of postresectional liver failure. J Hepatol 2016; 65:1217-1231. [PMID: 27312944 DOI: 10.1016/j.jhep.2016.06.006] [Citation(s) in RCA: 86] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2016] [Revised: 06/03/2016] [Accepted: 06/07/2016] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatic failure is a feared complication that accounts for up to 75% of mortality after extensive liver resection. Despite improved perioperative care, the increasing complexity and extensiveness of surgical interventions, in combination with an expanding number of resections in patients with compromised liver function, still results in an incidence of postresectional liver failure (PLF) of 1-9%. Preventive measures aim to enhance future remnant liver size and function. Numerous non-invasive techniques to assess liver function and predict remnant liver volume are being developed, along with introduction of novel surgical strategies that augment growth of the future remnant liver. Detection of PLF is often too late and treatment is primarily symptomatic. Current therapeutic research focuses on ([bio]artificial) liver function support and regenerative medicine. In this review we discuss the current state and new developments in prediction, prevention and management of PLF, in light of novel insights into the aetiology of this complex syndrome. LAY SUMMARY Liver failure is the main cause of death after partial liver resection for cancer, and is presumably caused by an insufficient quantity and function of the liver remnant. Detection of liver failure is often too late, and current treatment focuses on relieve of symptoms. New research initiatives explore artificial support of liver function and stimulation of regrowth of the remnant liver.
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Affiliation(s)
- Kim M C van Mierlo
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Frank G Schaap
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Cornelis H C Dejong
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Steven W M Olde Damink
- Department of Surgery, Maastricht University Medical Centre & NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands; Department of Surgery, Institute of Liver and Digestive Health, Royal Free Hospital, University College London, London, United Kingdom.
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Ohana G, Cohen S, Rath-Wolfson L, Fishman P. A3 adenosine receptor agonist, CF102, protects against hepatic ischemia/reperfusion injury following partial hepatectomy. Mol Med Rep 2016; 14:4335-4341. [PMID: 27666664 DOI: 10.3892/mmr.2016.5746] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2016] [Accepted: 07/25/2016] [Indexed: 11/06/2022] Open
Abstract
Ischemia/reperfusion (IR) injury during clinical hepatic procedures is characterized by inflammatory conditions and the apoptosis of hepatocytes. Nuclear factor‑κB (NF‑κB), nitric oxide and the expression levels of inflammatory cytokines, tumor necrosis factor‑α and interleukin‑1 were observed to increase following IR and mediate the inflammatory response in the liver. CF102 is a highly selective A3 adenosine receptor (A3AR) agonist, and has been identified to induce an anti‑inflammatory and protective effect on the liver via the downregulation of the NF‑κB signaling pathway. The present study aimed to determine the effect of CF102 on protecting the liver against IR injury. The potential protective effect of CF102 (100 µg/kg) was assessed using an IR injury model on 70% of the liver of Wistar rats, which was induced by clamping the hepatic vasculature for 30 min. The regenerative effect of CF102 was assessed by the partial hepatectomy of 70% of the liver during 10 min of IR. CF102 reduced the levels of liver enzymes following IR injury. A higher regeneration rate in the CF102 treatment group was observed compared with the control group, suggesting that CF102 had a positive effect on the proliferation of hepatocytes following hepatectomy. CF102 had a protective effect on the liver of Wistar rats subsequent to IR injury during hepatectomy. This may be due to an anti‑inflammatory and anti‑apoptotic effect mediated by the A3AR.
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Affiliation(s)
- Gil Ohana
- Department of Surgery A/B, Rabin Medical Center, Campus Golda, Sackler Faculty of Medicine Tel‑Aviv University, Petah Tikva 49100, Israel
| | - Shira Cohen
- Can‑Fite BioPharma, Ltd., Kiryat‑Matalon, Petah Tikva 49170, Israel
| | - Lea Rath-Wolfson
- Department of Pathology, Rabin Medical Center, Campus Golda, Sackler Faculty of Medicine Tel‑Aviv University, Petah Tikva 49100, Israel
| | - Pnina Fishman
- Can‑Fite BioPharma, Ltd., Kiryat‑Matalon, Petah Tikva 49170, Israel
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Khan RS, Newsome PN. Non-alcoholic fatty liver disease and liver transplantation. Metabolism 2016; 65:1208-23. [PMID: 26997540 DOI: 10.1016/j.metabol.2016.02.013] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 02/01/2016] [Accepted: 02/23/2016] [Indexed: 02/07/2023]
Abstract
Cirrhosis secondary to non-alcoholic steatohepatitis (NASH) is a common indication for liver transplant. In comparison to other cirrhotic patients, patients with NASH cirrhosis are more likely to be older and have the metabolic syndrome. Pre-transplant, patients require careful evaluation of cardiovascular risk. As the incidence of non-alcoholic fatty liver disease (NAFLD) is rising, a greater proportion of donor grafts have steatosis greater than 30%, which is associated with poor outcomes. Grafts with steatosis greater than 60% are unsuitable for transplant. Overall, post-transplant survival outcomes for patients with NASH cirrhosis are similar to those with cirrhosis without NASH. However, NASH cirrhosis is associated with a higher 30-day mortality, predominantly from an increase in cardiovascular events and infections. Following liver transplant, there is a significant risk of NASH recurrence, although this seldom results in allograft loss. Furthermore, a significant number of patients who had a liver transplant for other reasons develop NASH de novo. When patients with NASH cirrhosis are considered for transplant, one of the major challenges lies in identifying which patients are too high risk for surgery. This review aims to provide information to aid this decision making process, and to provide guidance on the peri-operative care strategies that can modify risk.
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Affiliation(s)
- Reenam S Khan
- Gastroenterology and Hepatology, NIHR Birmingham Liver BRU and Centre for Liver Research, University of Birmingham, Birmingham, UK, B15 2TH.
| | - Philip N Newsome
- Hepatology, NIHR Birmingham Liver BRU and Centre for Liver Research, University of Birmingham, Birmingham, UK, B15 2TH.
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Xue H, Chen D, Zhong Y, Zhou Z, Fang S, Li M, Guo C. Deferoxamine ameliorates hepatosteatosis via several mechanisms in
ob/ob
mice. Ann N Y Acad Sci 2016; 1375:52-65. [DOI: 10.1111/nyas.13174] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/31/2016] [Accepted: 06/14/2016] [Indexed: 01/12/2023]
Affiliation(s)
- Han Xue
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Di Chen
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Yan‐Ke Zhong
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Zhen‐Diao Zhou
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Shi‐Xin Fang
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Ming‐Yao Li
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
| | - Chuang Guo
- College of Life and Health Sciences Northeastern University Shenyang P. R. China
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Brandt HH, Nißler V, Croner RS. The Influence of Liver Resection on Intrahepatic Tumor Growth. J Vis Exp 2016:e53946. [PMID: 27166736 DOI: 10.3791/53946] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The high incidence of tumor recurrence after resection of metastatic liver lesions remains an unsolved problem. Small tumor cell deposits, which are not detectable by routine clinical imaging, may be stimulated by hepatic regeneration factors after liver resection. It is not entirely clear, however, which factors are crucial for tumor recurrence. The presented mouse model may be useful to explore the mechanisms that play a role in the development of recurrent malignant lesions after liver resection. The model combines the easy-to-perform and reproducible techniques of defined amounts of liver tissue removal and tumor induction (by injection) in mice. The animals were treated with either a single laparotomy, a 30% liver resection, or a 70% liver resection. All animals subsequently received a tumor cell injection into the remaining liver tissue. After two weeks of observation, the livers and tumors were evaluated for size and weight and examined by immunohistochemistry. After a 70% liver resection, the tumor volume and weight were significantly increased compared to a laparotomy alone (p <0.05). In addition, immunohistochemistry (Ki67) showed an increased tumor proliferation rate in the resection group (p <0.05). These findings demonstrate the influence of hepatic regeneration mechanisms on intrahepatic tumor growth. Combined with methods like histological workup or RNA analysis, the described mouse model could serve as foundation for a close examination of different factors involved in tumor growth and metastatic disease recurrence within the liver. A considerable number of variables like the length of postoperative observation, the cell line used for injection or the timing of injection and liver resection offer multiple angles when exploring a specific question in the context of post-hepatectomy metastases. The limitations of this procedure are the authorization to perform the procedure on animals, access to an appropriate animal testing facility and acquisition of certain equipment.
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Effect of nebivolol on liver regeneration in an experimental 70% partial hepatectomy model. Asian J Surg 2016; 40:375-379. [PMID: 26920216 DOI: 10.1016/j.asjsur.2015.12.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 12/22/2015] [Accepted: 12/30/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Factors affecting liver regeneration are still relevant. The purpose of this study is to investigate the effect of nebivolol treatment on liver regeneration in rats in which 70% partial hepatectomy was performed. METHODS Three groups were created: the control group, the low dose group, and the high dose group, with 20 rats in each group and 70% hepatectomy was performed in all rats. Immediately after partial liver resection, 2 mL physiological saline solution was administered to the control group via oral gavage, 0.5 mg/kg nebivolol was administered via oral gavage to the low dose group and 2 mg/kg nebivolol was administered via oral gavage to the high dose group. On the 1st and 5th days after liver resection, 10 subjects were sacrificed from each group, and liver weights and the mitotic count and Ki-67 were measured. RESULTS Regenerating liver weight on the 1st and 5th days after partial hepatectomy was statistically different in the low dose and high dose nebivolol groups compared to the control group. Mitotic count on the 1st day after partial hepatectomy was significantly higher in the low dose and high dose nebivolol groups than the control group. There was no statistically significant difference detected between the three groups for the 5th day. On the 1st day, Ki-67 rates were significantly higher in both groups given nebivolol than the control group. However, 5th day results were not statistically significant. CONCLUSION Nebivolol increases regeneration after partial hepatectomy in rats.
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Garnol T, Kučera O, Staňková P, Lotková H, Červinková Z. Does Simple Steatosis Affect Liver Regeneration after Partial Hepatectomy in Rats? ACTA MEDICA (HRADEC KRALOVE) 2016; 59:35-42. [PMID: 27526303 DOI: 10.14712/18059694.2016.87] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
AIM The aim of our study was to assess whether simple steatosis impairs liver regeneration after partial hepatectomy (PHx) in rats. METHODS Male Sprague-Dawley rats were fed a standard diet (ST-1, 10% kcal fat) and high-fat diet (HFD, 71% kcal fat) for 6 weeks. Then the rats were submitted to 2/3 PHx and animals were sacrificed 24, 48 or 72 h after PHx. Serum biochemistry, respiration of mitochondria in liver homogenate, hepatic oxidative stress markers, selected cytokines and DNA content were measured, and histopathological samples were prepared. Liver regeneration was evaluated by incorporation of bromodeoxyuridine (BrdU) to hepatocyte DNA. RESULTS HFD induced simple microvesicular liver steatosis. PHx caused elevation of serum markers of liver injury in both groups; however, an increase in these parameters was delayed in HFD group. Hepatic content of reduced glutathione was significantly increased in both groups after PHx. There were no significant changes in activities of respiratory complexes I and II (state 3). Relative and absolute liver weights, total DNA content, and DNA synthesis exerted very similar changes in both ST-1 and HFD groups after PHx. CONCLUSION PHx-induced regeneration of the rat liver with simple steatosis was not significantly affected when compared to the lean liver.
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Affiliation(s)
- Tomáš Garnol
- Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic
| | - Otto Kučera
- Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic.
| | - Pavla Staňková
- Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic
| | - Halka Lotková
- Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic
| | - Zuzana Červinková
- Department of Physiology, Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic
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Liu YI, Liu Z, Chen Y, Xu K, Dong J. PPARγ activation reduces ischemia/reperfusion-induced metastasis in a murine model of hepatocellular carcinoma. Exp Ther Med 2015; 11:387-396. [PMID: 26893620 PMCID: PMC4734081 DOI: 10.3892/etm.2015.2934] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 08/19/2015] [Indexed: 12/20/2022] Open
Abstract
Ischemia/reperfusion (I/R) injury during liver resection or transplantation for the treatment of hepatocellular carcinoma (HCC) may increase the risk of metastasis. Peroxisome proliferator-activated receptor-γ (PPARγ) activation has been observed to exert a protective effect against hepatic I/R injury. However, whether PPARγ activation exerts a protective effect against I/R-associated liver metastasis remains unknown. Therefore, the present study aimed to investigate the effects of the PPAR agonist rosiglitazone and the specific PPARγ antagonist GW9662 on tumor metastasis following hepatic I/R. An experimental mouse model of hepatic I/R-induced HCC metastasis was designed in order to determine the effects of I/R on tumor metastasis in the liver. Four groups were established: Sham, control (I/R), rosiglitazone (Ro) and rosiglitazone with GW9662 (Ro + GW) groups. In the latter two groups, the treatments were administered intravenously 1 h prior to the induction of ischemia. Tumor load was measured 12 days after the procedure. Furthermore, tissue analyses were conducted to determine the expression levels of alanine aminotransferase, myeloperoxidase (MPO), matrix metalloproteinase (MMP)-9, vascular cell adhesion molecule (VCAM)-1, nuclear factor (NF)-κB and PPARγ. Rosiglitazone pretreatment appeared to significantly mitigate hepatic I/R injury, as indicated by serological and histological analysis. The levels of VCAM-1, MPO and MMP-9 expression in the Ro group were significantly reduced at 8 h following ischemia compared with those in the control and Ro + GW groups. In addition, rosiglitazone inhibited the I/R-induced activation of NF-κB, and GW9662 attenuated the inhibitory effect. To the best of our knowledge, the present study is the first to report on the expression and the functional roles of PPARγ in I/R-associated metastasis. Short-term treatment of mice with rosiglitazone, a potent PPARγ agonist, confers protective effects against hepatic I/R-associated metastasis. Thus, PPARγ may be a potential therapeutic target for the protection of the liver against I/R-associated metastasis.
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Affiliation(s)
- Y I Liu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Zhao Liu
- Department of Hepatobiliary Surgery, Jinan Central Hospital, Shandong University, Jinan, Shandong 250013, P.R. China
| | - Yuxin Chen
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Kesen Xu
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jiahong Dong
- Department of Hepatobiliary Surgery, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China; Department of Hepatobiliary Surgery, Chinese PLA General Hospital, Beijing 100853, P.R. China
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Padrissa-Altés S, Bachofner M, Bogorad RL, Pohlmeier L, Rossolini T, Böhm F, Liebisch G, Hellerbrand C, Koteliansky V, Speicher T, Werner S. Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice. Gut 2015; 64:1444-53. [PMID: 25416068 DOI: 10.1136/gutjnl-2014-307874] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Fibroblast growth factors (Fgfs) are key orchestrators of development, and a role of Fgfs in tissue repair is emerging. Here we studied the consequences of inducible loss of Fgf receptor (Fgfr) 4, the major Fgf receptor (Fgfr) on hepatocytes, alone or in combination with Fgfr1 and Fgfr2, for liver regeneration after PH. DESIGN We used siRNA delivered via nanoparticles combined with liver-specific gene knockout to study Fgfr function in liver regeneration. Liver or blood samples were analysed using histology, immunohistochemistry,real-time RT-PCR, western blotting and ELISA. RESULTS siRNA-mediated knockdown of Fgfr4 severely affected liver regeneration due to impairment of hepatocyte proliferation combined with liver necrosis.Mechanistically, the proliferation defect resulted from inhibition of an Fgf15-Fgfr4-Stat3 signalling pathway,which is required for injury-induced expression of the Foxm1 transcription factor and subsequent cell cycle progression, while elevated levels of intrahepatic toxicbile acids were identified as the likely cause of the necrotic damage. Failure of liver mass restoration in Fgfr4 knockdown mice was prevented at least in part by compensatory hypertrophy of hepatocytes. Most importantly, our data revealed partially redundant functions of Fgf receptors in the liver, since knock down of Fgfr4 in mice lacking Fgfr1 and Fgfr2 in hepatocytes caused liver failure after PH due to severe liver necrosis and a defect in regeneration. CONCLUSIONS These results demonstrate that Fgfr signalling in hepatocytes is essential for liver regeneration and suggest activation of Fgfr signalling asa promising approach for the improvement of the liver's regenerative capacity.
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MESH Headings
- Animals
- Blotting, Western
- Cell Proliferation
- Cell Survival
- Cells, Cultured
- Cytokines/metabolism
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Hepatectomy/methods
- Hepatocytes/metabolism
- Hepatocytes/physiology
- Immunohistochemistry
- Liver/pathology
- Liver Regeneration/physiology
- Male
- Mice
- Mice, Knockout
- RNA, Small Interfering/analysis
- Real-Time Polymerase Chain Reaction/methods
- Receptor, Fibroblast Growth Factor, Type 4/genetics
- Receptor, Fibroblast Growth Factor, Type 4/metabolism
- Signal Transduction
- Statistics, Nonparametric
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Takagi T, Yokoyama Y, Kokuryo T, Yamaguchi J, Nagino M. Liver regeneration following experimental major hepatectomy with choledochojejunostomy. Br J Surg 2015; 102:1410-7. [PMID: 26312457 DOI: 10.1002/bjs.9908] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 06/30/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Surgical treatment for perihilar cholangiocarcinoma frequently involves hepatectomy and extrahepatic bile duct resection with a choledochojejunostomy (CJ). Cholangitis owing to bilioenteric anastomosis is a common complication. The impact of CJ or regurgitating cholangitis on the liver regeneration process after major hepatectomy is unknown. METHODS Rats underwent 70 per cent hepatectomy (Hx group) or hepatectomy with CJ (Hx + CJ group). The intrahepatic inflammatory response, hepatic regeneration rate, and expression of regeneration-associated genes in the liver and blood were compared between these two groups. RESULTS Levels of hepatobiliary markers in the blood were significantly higher 4 and 7 days after operation in the Hx + CJ group than the Hx group. Intrahepatic expression of inflammation-associated genes, such as interleukin 6 and tumour necrosis factor α, was also significantly higher in the Hx + CJ group on days 4 and 7. A progressive periportal inflammatory response was identified in the Hx + CJ group by histological examination. The hepatic regeneration rate was significantly lower in the Hx + CJ group than in the Hx group on day 2 (mean(s.d.) 14·2(6·3) versus 21·4(2·6) per cent; P = 0·013) and day 4 (32·4(5·3) versus 41·3(4·4) per cent; P = 0·004). Gene expression levels of hepatic regeneration-promoting factors such as hepatocyte growth factor were significantly lower in the Hx + CJ group than the Hx group on day 1. CONCLUSION CJ perturbs early liver regeneration after hepatectomy. An excessive inflammatory response in the liver and suppression of liver regeneration-associated factors may play a role. Surgical relevance Patients with perihilar cholangiocarcinoma may need major hepatectomy with extrahepatic bile duct resection and choledochojejunostomy. This carries a substantial risk of postoperative complications including liver failure. A rat model of partial hepatectomy with choledochojejunostomy was established. The molecular mechanisms underlying liver regeneration, and perturbation of this process by duodenobiliary reflux via the choledochojejunostomy, are described. The results give insight into the pathophysiological events following major hepatectomy with extrahepatic bile duct resection and choledochojejunostomy. This may help to develop a treatment strategy to reduce postoperative liver failure.
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Affiliation(s)
- T Takagi
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan 466-8550
| | - Y Yokoyama
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan 466-8550
| | - T Kokuryo
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan 466-8550
| | - J Yamaguchi
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan 466-8550
| | - M Nagino
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan 466-8550
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Zhao YP, Li L, Ma JP, Chen G, Bai JH. LXRalpha gene downregulation by lentiviral-based RNA interference enhances liver function after fatty liver transplantation in rats. Hepatobiliary Pancreat Dis Int 2015; 14:386-93. [PMID: 26256083 DOI: 10.1016/s1499-3872(15)60347-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Steatotic liver grafts, although accepted, increase the risk of poor posttransplantation liver function. However, the growing demand for adequate donor organs has led to the increased use of so-called marginal grafts. Liver X receptor alpha (LXRalpha) is important in fatty acid metabolism and interrelated with the specific ischemia-reperfusion injury in fatty liver transplantation. This study aimed to investigate whether LXRalpha RNA interference (RNAi) could improve the organ function of liver transplant recipients. METHODS Fifty Sprague-Dawley rats were fed with a high-fat diet and 56% alcohol. The livers of these animals had greater than 60% macrovesicular steatosis and were used as liver donors. The experimental donors were treated with 7X107 TU LXRalpha-RNAi-LV of a mixture injection and control donors with negative control-LV vector injection into the portal vein 72 hours before the operation. The effects of LXRalpha-RNAi-LV were assessed by serum aminotransferases, histology, immunostaining, and protein levels. The transcription of LXRalpha mRNA was assessed by reverse transcription-polymerase chain reaction. RESULTS Compared with controls, LXRalpha RNAi inhibited the expression of LXRalpha at the mRNA (0.53+/-0.03 vs 0.94+/-0.02, P<0.05) and protein levels (0.51+/-0.08 vs 1.09+/-0.12, P<0.05). LXRalpha RNAi also decreased the expressions of sterol regulatory element-binding protein 1c (SREBP-1c) and CD36. LXRalpha RNAi consequently reduced fatty acid accumulation in hepatocytes. Compared with control animals, LXRalpha RNAi-treated group had lower serum alanine aminotransferase, aspartate aminotransferase, interleukin-1beta, and tumor necrosis factor-alpha levels and milder pathologic damages. TUNEL analysis revealed a significant reduction of apoptosis in the livers of rats treated with LXRalpha-RNAi-LV, and overall survival as determined by the Kaplan-Meier method was improved among rats treated with LXRalpha-RNAi-LV (P<0.05). CONCLUSION LXRalpha-RNAi-LV treatment significantly downregulated LXRalpha expression and improve steatotic liver graft function and recipient survival after a fatty liver transplantation in rats.
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Affiliation(s)
- Ying-Peng Zhao
- Department of Hepatobiliary and Transplantation Surgery, Ganmei Affiliated Hospital, Kunming Medical University, Kunming 650011, China.
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Tüfek NH, Altunkaynak ME, Altunkaynak BZ, Kaplan S. Effects of thymoquinone on testicular structure and sperm production in male obese rats. Syst Biol Reprod Med 2015; 61:194-204. [DOI: 10.3109/19396368.2015.1044135] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Han S, Ha SY, Park CK, Joh JW, Kwon CHD, Kwon GY, Kim G, Gwak MS, Jeong WK, Ko JS. Microsteatosis may not interact with macrosteatosis in living donor liver transplantation. J Hepatol 2015; 62:556-62. [PMID: 25450710 DOI: 10.1016/j.jhep.2014.10.027] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 10/01/2014] [Accepted: 10/19/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The insignificance of pure microsteatosis (MiS) was reported in living donor liver transplantation (LDLT). However, since steatosis is mostly found in a mixed form of microsteatosis (MiS) and macrosteatosis (MaS), we aimed to determine the importance of MiS mixed with MaS in LDLT. METHODS Donor matching and recipient matching were independently performed with unfixed matching ratios. In donor matching, 51 donors with high (⩾30%) MiS mixed with MaS (H-MiS) were matched with 160 donors with low (⩽10%) MiS mixed with MaS (L-MiS), based on MaS degree, remnant liver volume, and others. In recipient matching, 50 recipients who received H-MiS grafts were matched with 176 recipients who received L-MiS grafts, based on MaS degree, graft volume, MELD score, and others. RESULTS The median MiS degree was 10% (range 0%-10%) vs. 35% (range 30%-80%) in L-MiS livers vs. H-MiS livers after both matching. L-MiS and H-MiS donors were not significantly different regarding postoperative biochemical liver function (e.g. peak AST 232 vs. 246 IU/L, p=0.931). L-MiS and H-MiS recipients were not significantly different regarding 2-week graft regeneration (51% for both) and 5-year survival (HR 0.87, 95% CI 0.43-1.76, p=0.699). Post-transplant donor/recipient complication rates were not significantly different, either. CONCLUSIONS There were no evidences of a significant impact of MiS mixed with MaS on post-LDLT outcomes. The results suggest less importance of MiS, and further indicate that there is no interaction between MiS and MaS. Thus, the risk of steatosis may be determined by the relative composition of MiS and MaS, rather than the total quantitative degree.
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Affiliation(s)
- Sangbin Han
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sang Yun Ha
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Cheol-Keun Park
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jae-Won Joh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Choon Hyuck D Kwon
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Ghee Young Kwon
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Gaabsoo Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Mi Sook Gwak
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Woo Kyoung Jeong
- Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Justin S Ko
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Abstract
OBJECTIVE To investigate the roles and underlying mechanism of an inflammatory mediator-lipocalin-2 (Lcn2) in small-for-size fatty graft liver injury. BACKGROUND Understanding of the distinct mechanism regulating small-for-size fatty liver graft injury will be crucial to prevent marginal graft failure during living donor liver transplantation (LDLT). METHODS The roles of Lcn2 in small fatty graft injury were investigated in orthotopic liver transplantation model rats, human LDLT samples, an in vitro simulated ischemia-reperfusion (IR) model, and a hepatic ischemic reperfusion plus major hepatectomy (IR + H) model in mice. RESULTS Our result showed that Lcn2 was significantly upregulated together with elevation of chemokine (C-X-C motif) ligand 10 (CXCL10) and activation/infiltration of intragraft macrophages after liver transplantation using small-for-size fatty liver graft compared with that of using small-for-size normal liver graft. Intragraft and plasma levels of Lcn2 were intensified in patients who underwent transplantation with small-for-size fatty graft after LDLT. Lcn2 and CXCL10 were expressed higher in fatty hepatocytes after the simulated IR injury compared with normal hepatocytes. Overexpression of Lcn2 significantly deteriorated IR + H-induced hepatic injury in correlation with upregulation of CXCL10 and augmentation of infiltrated macrophages. On the contrary, hepatic injury of small fatty liver remnant after IR + H operation was attenuated in the Lcn-2 mice because of suppression of CXCL10 expression and diminishment of macrophage infiltration. CONCLUSIONS Lcn2 is an important regulator in small-for-size fatty liver graft injury and targeting Lcn2 may be feasible for preventing marginal graft failure in LDLT.
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Schadde E, Ardiles V, Robles-Campos R, Malago M, Machado M, Hernandez-Alejandro R, Soubrane O, Schnitzbauer AA, Raptis D, Tschuor C, Petrowsky H, De Santibanes E, Clavien PA. Early survival and safety of ALPPS: first report of the International ALPPS Registry. Ann Surg 2014; 260:829-838. [PMID: 25379854 DOI: 10.1097/sla.0000000000000947] [Citation(s) in RCA: 346] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES To assess safety and outcomes of the novel 2-stage hepatectomy, Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS), using an international registry. BACKGROUND ALPPS induces accelerated growth of small future liver remnants (FLR) to allow curative resection of liver tumors. There is concern about safety based on reports of higher morbidity and mortality. METHODS A Web-based data entry system was created with password access and data pseudoencryption (NCT01924741). All patients with complete 90-day data were included. Multivariate logistic regression analysis was performed to identify independent risk factors for severe complications and mortality and volume growth of the FLR. RESULTS Complete data were available for 202 patients. A total of 141 (70%) patients had colorectal liver metastases (CRLM). Median starting standardized future liver remnants of 21% increased by 80% within a median of 7 days. Ninety-day mortality was 19/202 (9%). Severe complications including mortalities (Clavien-Dindo≥IIIb) occurred in 27% of patients. Independent factors for severe complications were red blood cell transfusion [odds ratio (OR), 5.2), ALPPS stage I operating time greater than 300 minutes (OR, 4.4), age more than 60 years (OR, 3.8), and non-CRLM (OR, 2.7). Age, use of Pringle maneuver, and histologic changes led to less volume growth. In patients younger than 60 years with CRLM, 90-day mortality was similar to conventional 2-stage hepatectomies for CRLM. CONCLUSIONS This is the first analysis of the ALPPS registry showing that ALPPS has increased perioperative morbidity and mortality in older patients but better outcomes in patients with CRLM.
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Affiliation(s)
- Erik Schadde
- *Swiss HPB and Transplant Center, University Hospital Zurich, Zurich, Switzerland †Department of Surgery, Division of HPB Surgery, Liver Transplant Unit, Italian Hospital Buenos Aires, Buenos Aires, Argentina ‡Department of General Surgery, Liver Transplant Unit, Virgen De La Arrixaca University Hospital, Murcia, Spain §Department of HPB and Liver Transplant Surgery, Royal Free Hospital, University College London, London, United Kingdom ¶Department of Surgery, Sirio Libanes Hospital, University of Sao Paolo, Sao Paolo, Brazil ‖Department of Surgery, Division of HPB Surgery, Western University Medical Center, London, Ontario, Canada **Department of HPB Surgery and Liver Transplantation, St. Antoine Hospital, Paris, France ††Department of Visceral- and Transplantation Surgery, Johann Wolfgang von Goethe University, Frankfurt, Germany. §§Hospital Paul Brousse, Université Paris Sud, Paris, France
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