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Tomulic Brusich K, Škrtić A, Sobočan N, Acan I, Čipak Gašparović A. Role of NRF2 and reactive aldehydes in acute cellular rejection in liver transplant recipients. Pathol Res Pract 2023; 250:154826. [PMID: 37742477 DOI: 10.1016/j.prp.2023.154826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 09/16/2023] [Indexed: 09/26/2023]
Abstract
OBJECTIVE To evaluate the level of oxidative stress and antioxidative response in the transplanted liver and its role in acute cellular rejection (ACR). Particular attention was paid to ACR diagnosis in patients with hepatitis C (HCV), as histopathological features of ACR and viral disease recurrence overlap. METHODS This retrospective study included 40 liver transplant patients who underwent liver transplantation with two consecutive liver biopsies performed during one hospitalization period: 1.) initial biopsy of the donor liver (before implantation) and 2.) indication biopsy (after suspected ACR). Based on the etiology, patients were divided into two groups: 22 patients with alcoholic liver cirrhosis (EtOH group) and 18 patients with hepatitis C cirrhosis (HCV group). We analyzed the presence of acrolein, HNE (4-hydroxynonenal), and the major antioxidant transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) in both biopsies. RESULTS The presence of acrolein and HNE in both biopsies indicates increased oxidative stress, while the decrease in these aldehydes in the indication biopsies indicates a decrease in oxidative stress over time, reflecting liver graft recovery. The absence of NRF2 in both biopsies reflects significantly reduced antioxidant protection in patients undergoing liver transplantation. CONCLUSION The results support the role of oxidative stress in the pathogenesis of ACR. The presence of acrolein and the absence of HNE in the indication biopsy in patients with ACR could contribute to the diagnosis of ACR in clinical practice when functional antibodies are tested in the clinical setting.
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Affiliation(s)
- Katarina Tomulic Brusich
- Department of Anesthesiology, Intensive Care and Pain Medicine, Clinical Hospital Centre Rijeka, 51000 Rijeka, Croatia.
| | - Anita Škrtić
- Department of Pathology and Cytology, University Hospital Merkur, Zagreb, Croatia; School of Medicine, University of Zagreb, Croatia
| | - Nikola Sobočan
- School of Medicine, University of Zagreb, Croatia; Department of Gastroenterology, University Hospital Merkur, Zagreb, Croatia, University of Zagreb, Croatia
| | - Ivana Acan
- Department of Anaesthesiology and Surgical Intensive Care, University Medical Center Ljubljana, Ljubljana, Slovenia
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Erdoğan MM, Erdemli ME, Özhan O, Erdemli Z, Gözükara Bağ HG, Vardı N. Effect of Melatonin on Increasing the Effectiveness of Liver Preservation Solution. THE TURKISH JOURNAL OF GASTROENTEROLOGY : THE OFFICIAL JOURNAL OF TURKISH SOCIETY OF GASTROENTEROLOGY 2023; 34:943-951. [PMID: 37485562 PMCID: PMC10544131 DOI: 10.5152/tjg.2023.22694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 11/29/2022] [Indexed: 07/25/2023]
Abstract
BACKGROUND/AIMS Various tissue preservation solutions are used during the removal of the organ and during transplantation to protect the normal histological and biochemical characteristics of tissue while performing a successful liver transplant. In our study, it was aimed to investigate the effects of intraperitoneal melatonin administration on liver preservation damage before transplantation. MATERIALS AND METHODS In our study, the histological and biochemical characteristics of University of Wisconsin+melatonin group rats treated with melatonin 45 minutes before hepatectomy were compared between serum physiologic group and University of Wisconsin group. RESULTS When hematoxylin and eosin staining was evaluated in terms of hydropic degeneration, sinusoidal dilatation, and hepatocyte necrosis, there was no statistically significant difference. Caspase 3 immunohistochemical staining showed a significant increase in Caspase 3 immunoreactivity positivity at the 12th-hour University of Wisconsin group compared to University of Wisconsin+melatonin group. As a result of biochemical analysis, the malondialdehyde and total oxidant status levels in the University of Wisconsin+melatonin group decreased significantly compared to the University of Wisconsin group. When the reduced glutathione activity and total antioxidant capacity level were compared, a significant increase was observed in the University of Wisconsin+melatonin group compared to the University of Wisconsin group at the 12th hour. It was also found that aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels decreased significantly in the University of Wisconsin+melatonin 12th-hour group compared to the University of Wisconsin 12th hour and control group. CONCLUSION When the findings were evaluated, intraperitoneal administration of melatonin, a cytoprotective antioxidant, was found to play an effective role in preserving immunohistochemical and biochemical properties of liver tissue integrity and hepatocytes in University of Wisconsin solution.
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Affiliation(s)
- Mehmet Mustafa Erdoğan
- Department of Histology and Embryology, Malatya Education and Research Hospital, Malatya, Turkey
| | - Mehmet Erman Erdemli
- Department of Medical Biochemistry, İnönü University Faculty of Medicine, Malatya, Turkey
| | - Onural Özhan
- Department of Medical Pharmacology, İnönü University Faculty of Medicine, Malatya, Turkey
| | - Zeynep Erdemli
- Department of Medical Biochemistry, İnönü University Faculty of Medicine, Malatya, Turkey
| | - Harika Gözde Gözükara Bağ
- Department of Biostatistics and Medical Informatics, İnönü University Faculty of Medicine, Malatya, Turkey
| | - Nigar Vardı
- Department of Histology and Embryology, İnönü University Faculty of Medicine, Malatya, Turkey
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Schleicher J, Dahmen U. Computational Modeling of Oxidative Stress in Fatty Livers Elucidates the Underlying Mechanism of the Increased Susceptibility to Ischemia/Reperfusion Injury. Comput Struct Biotechnol J 2018; 16:511-522. [PMID: 30505404 PMCID: PMC6247397 DOI: 10.1016/j.csbj.2018.10.013] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 10/25/2018] [Accepted: 10/26/2018] [Indexed: 02/06/2023] Open
Abstract
QUESTION Donor liver organs with moderate to high fat content (i.e. steatosis) suffer from an enhanced susceptibility to ischemia/reperfusion injury (IRI) during liver transplantation. Responsible for the cellular injury is an increased level of oxidative stress, however the underlying mechanistic network is still not fully understood. METHOD We developed a phenomenological mathematical model of key processes of hepatic lipid metabolism linked to pathways of oxidative stress. The model allows the simulation of hypoxia (i.e. ischemia-like conditions) and reoxygenation (i.e. reperfusion-like conditions) for various degrees of steatosis and predicts the level of hepatic lipid peroxidation (LPO) as a marker of cell damage caused by oxidative stress. RESULTS & CONCLUSIONS Our modeling results show that the underlying feedback loop between the formation of reactive oxygen species (ROS) and LPO leads to bistable systems behavior. Here, the first stable state corresponds to a low basal level of ROS production. The system is directed to this state for healthy, non-steatotic livers. The second stable state corresponds to a high level of oxidative stress with an enhanced formation of ROS and LPO. This state is reached, if steatotic livers with a high fat content undergo a hypoxic phase. Theoretically, our proposed mechanistic network would support the prediction of the maximal tolerable ischemia time for steatotic livers: Exceeding this limit during the transplantation process would lead to severe IRI and a considerable increased risk for liver failure.
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Key Words
- 4HNE, 4-Hydroxynonenal
- 8-OHdG, 8-Hydroxydeoxyguanosine
- ALOX12, Arachidonate 12-lipoxygenase
- AOD, Antioxidative defense
- CAT, Catalase
- DNL, de novo lipogenesis
- FA, Fatty acid
- GPx, Glutathione peroxidase
- GSH, Reduced glutathione
- GSSG, Oxidized glutathione
- H2O2, Hydrogen peroxide
- HFD, High-fat diet
- HIF, Hypoxia-inducible factor
- Hepatic fatty acid metabolism
- IL, Interleukin
- IR, Ischemia/reperfusion
- IRI, Ischemia/reperfusion injury
- LPO, Lipid peroxidation
- Lipid peroxidation
- MDA, Malondialdehyde
- NFκB, Nuclear factor kappa B
- O2, Oxygen
- O2–, Superoxide anion
- OH⁎, Hydroxyl radical
- Oxidative stress
- ROS, Reactive oxygen species
- Reactive oxygen species
- Steatosis
- TBARS, Thiobarbituric acid reactive substances
- TG, Triglyceride
- TNF, Tumor necrosis factor
- UCP2, Uncoupling protein-2
- cAMP, Cyclic adenosine monophosphate
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Affiliation(s)
- Jana Schleicher
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany
- Department of Bioinformatics, Friedrich Schiller University Jena, Jena, Germany
| | - Uta Dahmen
- Experimental Transplantation Surgery, Department of General, Visceral and Vascular Surgery, University Hospital Jena, Jena, Germany
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Lorente L. New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2018; 24:4230-4242. [PMID: 30310256 PMCID: PMC6175764 DOI: 10.3748/wjg.v24.i37.4230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife 38320, Spain
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Lorente L, Rodriguez ST, Sanz P, Pérez-Cejas A, Abreu-González P, Padilla J, Díaz D, González A, Martín MM, Jiménez A, Cerro P, Barrera MA. Serum total antioxidant capacity prior to liver transplantation for hepatocellular carcinoma is associated with 1-year liver transplantation survival. J Int Med Res 2018; 46:2641-2649. [PMID: 29911482 PMCID: PMC6124293 DOI: 10.1177/0300060518768150] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Objective To determine whether there was an association between serum total antioxidant capacity (TAC) levels prior to in liver transplantation (LT) for hepatocellular carcinoma (HCC) and 1-year LT mortality. Methods This observational retrospective single-centre study of patients with LT for HCC measured serum levels of TAC and malondialdehyde (as a biomarker of lipid peroxidation) before LT. The study endpoint was 1-year LT mortality. Results This study included 142 patients who underwent LT for HCC. Patients who survived the first year (n = 127) had significantly lower aged liver donors, significantly higher serum TAC levels, and significantly lower serum malondialdehyde levels compared with the non-survivors (n = 15). Logistic regression analysis found that serum TAC levels (odds ratio [OR] 0.275; 95% confidence interval [CI] 0.135, 0.562) and the age of the LT donor (OR 1.050; 95% CI 1.009, 1.094) were associated with 1-year LT mortality. There was an inverse association between serum levels of TAC and malondialdehyde levels (rho = –0.22). Conclusions There was an association between low serum TAC levels prior to LT for HCC and mortality during the first year after LT. There was an inverse association between serum TAC levels and lipid peroxidation as measured by malondialdehyde levels.
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Affiliation(s)
- Leonardo Lorente
- 1 Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Sergio T Rodriguez
- 2 Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife, Spain
| | - Pablo Sanz
- 3 Deparment of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife, Spain
| | - Antonia Pérez-Cejas
- 4 Laboratory Department, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Pedro Abreu-González
- 5 Deparment of Physiology, Faculty of Medicine, University of the La Laguna, Santa Cruz de Tenerife, Spain
| | - Javier Padilla
- 3 Deparment of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife, Spain
| | - Dácil Díaz
- 6 Department of Digestive Medicine, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife, Spain
| | - Antonio González
- 6 Department of Digestive Medicine, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife, Spain
| | - María M Martín
- 2 Intensive Care Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife, Spain
| | - Alejandro Jiménez
- 7 Research Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain
| | - Purificación Cerro
- 8 Transplant Unit, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife, Spain
| | - Manuel A Barrera
- 3 Deparment of Surgery, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz Tenerife, Spain
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Association between Pre-Transplant Serum Malondialdehyde Levels and Survival One Year after Liver Transplantation for Hepatocellular Carcinoma. Int J Mol Sci 2016; 17:500. [PMID: 27058525 PMCID: PMC4848956 DOI: 10.3390/ijms17040500] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Revised: 03/29/2016] [Accepted: 03/30/2016] [Indexed: 12/16/2022] Open
Abstract
Previous studies have found higher levels of serum malondialdehyde (MDA) in hepatocellular carcinoma (HCC) patients compared to healthy controls and higher MDA concentrations in tumoral tissue of HCC patients than in non-tumoral tissue. However, the association between pre-transplant serum levels of MDA and survival in HCC patients after liver transplantation (LT) has not been described, and the aim of the present study was to determine whether such an association exists. In this observational study we measured serum MDA levels in 127 patients before LT. We found higher pre-LT serum MDA levels in 15 non-surviving than in 112 surviving patients one year after LT (p = 0.02). Exact binary logistic regression analysis revealed that pre-LT serum levels of MDA over 3.37 nmol/mL were associated with mortality after one year of LT (Odds ratio = 5.38; 95% confidence interval (CI) = from 1.580 to infinite; p = 0.007) adjusting for age of the deceased donor. The main finding of our study was that there is an association between serum MDA levels before LT for HCC and 1-year survival after LT.
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Srinivasan PK, Yagi S, Nagai K, Afify M, Hata K, Uemoto S, Tolba RH. Impact of oxygen free radicals in rat partial liver transplantation. J Surg Res 2014; 191:469-75. [DOI: 10.1016/j.jss.2014.05.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 04/28/2014] [Accepted: 05/01/2014] [Indexed: 01/15/2023]
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Selvi R, Angayarkanni N, Biswas J, Ramakrishnan S. Total antioxidant capacity in Eales' disease, uveitis & cataract. Indian J Med Res 2011; 134:83-90. [PMID: 21808139 PMCID: PMC3171923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND & OBJECTIVES The human system possesses antioxidants that act harmoniously to neutralize the harmful oxidants. This study was aimed to evaluate the serum total antioxidant capacity (TAC) as a single parameter in Eales' disease (ED) and in an acute inflammatory condition such as uveitis and in cataract which is chronic, compared to healthy controls. METHODS The TAC assay was done spectrophotometrically in the serum of Eales' disease cases (n=20) as well as in other ocular pathologies involving oxidative stress namely, uveitis and cataract (n=20 each). The oxidative stress measured in terms of TBARS, was correlated with the TAC. Individual antioxidants namely vitamin C, E and glutathione were also estimated and correlated with TAC. RESULTS TAC was found to be significantly lower in Eales' disease with active vasculitis (0.28 ± 0.09 mM, P<0.001), Eales' disease with healed vasculitis (0.67 ± 0.09 mM), uveitis (0.46 ± 0.09 mM, P<0.001) and cataract (0.53 ± 0.1 mM, P=0.001) compared to the healthy controls, with a TAC level of 0.77 ± 0.09 mM. The TAC was found to correlate positively with vitamin E levels (P=0.05), GSH (P=0.02) but not with vitamin C, as seen in ED cases. In ED cases supplemented with vitamin E and C, there was a significant increase in the TAC level (P=0.02). INTERPRETATION & CONCLUSIONS The TAC measurement provided a comprehensive assay for establishing a link between the antioxidant capacity and the risk of disease as well as monitoring antioxidant therapy. This method is a good substitute for assay of individual antioxidants as it clearly gives the status of the oxidative stress in the disease process.
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Affiliation(s)
- Radhakrishnan Selvi
- Biochemistry and Cell Biology Department, Vision Research Foundation, Chennai, India
| | - Narayanasamy Angayarkanni
- Biochemistry and Cell Biology Department, Vision Research Foundation, Chennai, India,Reprint requests: Dr Narayanasamy Angayarkanni, Biochemistry & Cell Biology Department, Sankara Nethralaya, Vision Research Foundation, 18, College Road, Chennai 600 006, India
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