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Transplantation is currently the only effective treatment for patients with end-stage liver failure. Many advanced studies have been conducted to improve the efficiency of organ preservation techniques. Modifying the composition of the preservation fluids currently used may improve graft function and increase the likelihood of transplantation success. The modified fluid is expected to extend the period of safe liver storage in the peri-transplantation period and to increase the pool of organs for transplantation with livers from marginal donors.
Author, Year of Publication |
Antioxidant | Species | Preservation Solution Modification /Cold Ischemia |
Outcome Measures, (Intervention, I/Control, C) | Antioxidant Dose | Effects of Antioxidant |
---|---|---|---|---|---|---|
Enzymatic antioxidant | ||||||
Lauschke et al., 2003 [15] | Taurine SOD |
Isolated perfused rat liver model | UW 24 h; 4 °C; SCS with VSOP |
I1: UW + SOD I2: UW + TAU C: UW |
SOD: 600 U/mL; Taurine: 0.5 mg/mL |
↓ lipid peroxidation; ↓ vascular resistance; ↓ LDH, GLDH; ↑ bile production |
Minor et al., 1995 [16] | Taurine | Wistar rats | UW 24 h; 4 °C; SCS |
I: UW + TAU C1: UW |
1 mM/L | improve hepatic circulation; enhance viability of the liver upon reperfusion |
Non-enzymatic antioxidants | ||||||
Low-molecular-weight antioxidant | ||||||
Bardallo et al., 2022 [17] | PEG35, Glutathione |
Zücker rats | IGL 24 h; 4 °C; SCS |
I1: IGL + GSH I2: IGL + PEG35 + GSH C: IGL |
PEG35: 1 g/L, 5 g/L GSH: 3 mM/L, 9 mM/L |
IGL + PEG35 (5 g/L) + GSH (9 mM/L): maintained ATP production; ↓ succinate accumulation; ↑ expression of the OXPHOS complexes, UCP2, PINK-1, Nrf2, and HO-1; protected against lipid and protein oxidation; increased the GSH/GSSG ratio; ↓ inflammasome NLRP3 expression; protecting mitochondrial integrity |
Quintana et al., 2001 [18] | S-Nitrosoglutathione | Isolated perfused rat liver model | UW 48 h; 4 °C; SCS |
I: UW + GSNO C: UW |
100 µM | the hepatic morphology was conserved showing little vacuolation; avoiding hepatic injury post cold preservation/reperfusion |
Quintana et al., 2002 [19] | S-Nitrosoglutathione | Isolated perfused rat liver model | UW 48 h; 0 °C; SCS |
I: UW + GSNO C: UW |
50 µM, 100 µM, 250 µM, 500 µM | 100 µM: prevented the ischemia/reperfusion injuries; ↓ LDH; improved bile production; partially reduced endothelial cell damage |
Quintana et al., 2004 [20] | S-Nitrosoglutathione | Isolated perfused rat liver model | UW 48 h; 0 °C; SCS |
I: UW + GSNO C: UW |
500 μM 100 μM |
500 μM: interstitial edema after normothermic reperfusion; 100 μM: damages on mast cells were avoided |
Minor et al., 2000 [21] | N-Acetylcysteine, SOD |
Isolated perfused rat liver model | UW 24 h; 4 °C; SCS VSOP |
I1: UW + SOD I2: UW + NAC C: UW |
SOD: 600 U/mL; NAC: 20 mM |
prevented an increase in free radical-mediated lipid peroxidation; NAC counteracted the phosphorylation of Iκb |
Srinivasan et al., 2014 [22] | N-Acetylcysteine | Lewis rat | HTK 1 h, 3 h, 24 h, 168 h; 5 °C; SCS |
I: HTK + NAC C: HTK |
20 mM | ↓ PVP; ↓ ALT; improved microcirculation; diminished histologic graft damage; ↓ lipid peroxidation; ↑ total antioxidant capacity |
Scherer de Fraga et al., 2010 [23] | S-Nitroso-N-Acetylcysteine | Wistar rats | UW 2 h, 4 h, 6 h; 4 °C; SCS |
I: UW + SNAC C: UW |
200 nM | ↓ AST ↓ Liver injury |
Kerkweg et al., 2002 [24] | Deferoxamine | Hepatocytes from male Wistar rats, rat liver endothelial cells |
UW 24 h; 4 °C; SCS |
I: UW + DFX C: UW |
10 mM | ↓ lipid peroxidation; ↓ apoptosis |
Jain et al., 2008 [25] |
N-Acetylcysteine, Trolox C, Deferoxamine |
Isolated perfused rat liver model | UW 4 °C; HMP |
I: UW + Gly + NAC + TRX-C + DFX C: UW |
NAC: 5 mM TRX-C: 0.2 mM DFX: 0.25 mM |
↓ LDH, ALT; ↑ bile production; improved mitochondrial function; improved liver microcirculation; intact hepatocytes |
Vreugdenhil et al., 1997 [26] | Deferoxamine, Trolox C, Dithiothreitol |
Hepatocytes from Sprague-Dawley rats; isolated perfused rat liver model |
UW 24 h, 48 h; 4 °C; SCS |
I1: UW + DFX I2: UW + TRX I3: UW + DTT C: UW |
DFX: 2.5 mM, 5 mM, 10 mM TRX: 3 mM, 5 mM, 10 mM DTT: 5 mM, 10 mM, 20 mM |
poor distribution of antioxidants in isolated rat liver; only DFX was effective when added to the UW: suppressed oxidative stress only in isolated hepatocytes stored in cold storage; ↓ LDH |
Wu et al., 2009 [27] |
LK 614 | Isolated perfused rat liver model | HTK 24 h; 4 °C; SCS |
I: HTK + LK 614 C: HTK |
20 μM | ↓ LDH during reperfusion; increased bile secretion; better preserved hepatic microcirculation |
Stegemann et al., 2010 [28] | Deferoxamine, LK 614 |
Wistar rats | HTK 18 h; 4 °C; HMP |
I: HTK-N + LK 614 + DFX C1: HTK C2:HTK-N |
DFX: 25 μM LK 614: 2.5 μM, 7.5 μM |
↓ ALT, LDH; DFX: 25μM and LK 614: 2.5μM improved metabolic activity, reduced cleavage of caspase 9 and apoptotic index |
Mitochondria-targeted antioxidants | ||||||
Cherkashina et al., 2011 [29] | SkQ1 | Rat | Sucrose–saline 24 h; 4 °C; SCS |
I: Sucrose–saline + SkQ1 C: Sucrose–saline |
1 μM | ↓ hepatic injury and oxidative stress; ↑ liver and mitochondrial function |
Wieland et al., 1995 [30] | Idebenone (QSA-10) |
Rat liver microsomal model | UW, HTK 4 °C; SCS |
I1: UW + QSA-10 I2: UW + Q-10 I3: HTK + QSA-10 I4: HTK + Q-10 C1: UW C2: HTK |
QSA-10: 0.1 µM/L, 20 µM/L Q-10: 20 µM/L, 100 µM/L |
protection against lipid peroxidation (HTK + QSA-10: 0.1 µM/L); prevented protein damage (HTK + QSA-10: 20 µM/L and UW + QSA-10: 20 µM/L); Q-10: 20 µM/ partial protection in UW; QSA-10 have the potential to increase the efficacy of organ preservation |
Kondo et al., 2013 [31] | Phosphoenolpyruvate | Mouse liver (ex vivo) | UW, PBS 24 h, 48 h, 72 h, 4 °C; SCS |
I1: UW + PEP I2: PBS + PEP C1: UW C2: PBS |
PEP: 1 mM, 10 mM, 100 mM (PBS) PEP: 100 mM (UW) |
↓ oxidative stress; attenuate ATP depletion; prevents increases in biochemical parameters |
Polyphenols | ||||||
Johnston et al., 1999 [32] | Curcumin | Sprague-Dawley rat livers (ex vivo) |
UW, EC 24 h; 4 °C; oxygenated perfusion |
I1: EC+ CUR C1: EC C2: UW |
100 μM | curcumin-enhanced EC solution was equivalent to the UW solution |
Chen et al., 2006 [33] |
Curcumin | Sprague-Dawley rat livers | UW, EC, PBS 24 h, 36 h, 48 h; 4 °C; SCS |
I1: UW + CUR I2: EC+ CUR I3: PBS+ CUR C1: UW C2: EC C3: PBS |
25–200 μM | curcumin at 100 μM concentration had the optimal preservation characteristics; ↑ portal flow rates and bile production; ↓ ALT, AST, LDH; improves the quality of organs |
McNally et al., 2006 [34] | Curcumin | Human hepatocytes | UW 16 h, 24 h, 48 h, 72 h; 4 °C; SCS |
I: UW + CUR C: UW |
10 μM | induces HO-1; maximum protection cells between 16 and 24 h of CS |
Kato et al., 2020 [35] |
Quercetin | Rat (isolated hepatocytes and whole liver) |
UW 24 h; 4 °C; SCS |
I: UW + QE C: UW |
QE: 0.33; 33.1 µM/L Suc: 0.1 M/L |
optimal dose of QE: 33,1 µM/L ↓ ALT mild vascular degradation; improvement of histological changes |
Ligeret et al., 2008 [36] | Silibinin | Isolated perfused rat liver model | UW 24 h; 4 °C; SCS |
I: UW + SB C: UW |
100 μM | ↑ ATP, RCR ↓ oxidative stress |
Chiu et al., 1999 [37] |
Magnolol | Rat | UW, Ringer’s lactate 24 h, 48 h; 96 h, 4 °C; SCS |
I1: UW + MAG I2: Ringer’s lactate + MAG C1: UW C2: Ringer’s lactate |
10–6 M/L | ↓ lipid peroxidation |
Bioactive metabolites from marine algae | ||||||
Gdara et al., 2018 [38] | Phycocyanin | Rat | KH 12 h, 24 h; 4 °C; SCS |
I: KH + Pc C:KH |
0.1; 0.2 mg ml−1 g−1 of liver | optimal dose of Pc: 0.1 mg ml−1 g−1; ↓ ALT, AST, ALP; ↓ MDA; ↓ GST, GPx |
Slim et al., 2020 [39] |
Fucoidan | Isolated perfused rat liver model | IGL-1 24 h, 4 °C; SCS |
I1: IGL-1 + FUC C1: IGL-1 C2: Ringer’s lactate |
10 mg/L, 50 mg/L, 100 mg/L, 250 mg/L |
optimal dose of FUC: 100 mg/L; ↓ ALT, AST; ↑ phosphorylation of AMPK, AKT protein kinase, and GSK-3β; reduction in apoptosis (caspase 3); reduction of mitochondrial damage; reduction oxidative stress; reduction of ER stress markers; ↓ ERK1/2 and p38 MAPKs phosphorylation |
Vitamins and vitamin-like substances | ||||||
Bae et al., 2014 [40] |
α-Tocopherol | Wistar rats after cardiac death | Vasosol 4 °C; HMP |
I: Vasosol + α-TCP C1: Vasosol C2: KPS-1 |
5.4 × 10−2 mM | ↓ ALT; ↓ inflammatory cytokines (IL-6, TNF-α, MCP-1); ↓ caspase 3/7 expression in the circulation |
Tolba et al., 2003 [41] | L-carnitine | Isolated perfused rat liver model | HTK 24 h, 4 °C; SCS |
I: HTK + L-CAR C: HTK |
5 mM | ↓ ALT, GLDH; improved the hepatic energy metabolism; preserved integrity of the mitochondria and the endoplasmic reticulum |
Coskun et al., 2007 [42] | L-carnitine | Wistar Albino rat | UW 2 h, 24 h, 36 h, 48 h; 4 °C; SCS |
I: UW + L-CAR C: UW |
5 mM/L | ↓ ALT, ACP; ↓ MDA |
Drugs | ||||||
Ben et al., 2010 [43] |
Carvedilol | Isolated Zücker rat liver (steatotic and non-steatotic) |
UW 24 h; 4 °C; SCS |
I: UW + CVD C: UW |
10−5 M/L | reduced hepatic injury, and improved hepatic functionality in both liver types |
Ben et al., 2006 [44] |
Trimetazidine | Zücker rats (steatotic and non-steatotic) |
UW 24 h; 4 °C; SCS |
I: UW + TMZ C: UW |
10−6 M/L | protects against mitochondrial damage; preserves more ATP; decreases oxidative stress higher bile production |
Ben et al., 2007 [45] |
Trimetazidine, aminoimidazole-4-carboxamide ribonucleoside |
Zücker rats (steatotic and non-steatotic) |
UW 24 h; 4 °C; SCS |
I1: UW + TMZ I2: UW + AICAR C: UW |
TMZ: 10−8 M/L 10−6 M/L, 10−4 M/L AICAR: 10 μM/L, 20 μM/L, 40 μM/L, 80 μM/L TMZ + AICAR: 10−6 M/L + 20 μM/L; 10−6 M/L + 40 μM/L; |
↓ AST (TMZ) TMZ improved bile production; increase in cNOS via increasing AMPK; TMZ and AICAR protected, with a similar degree of effectiveness, against cold I/R injury in steatotic and non-steatotic livers; not necessary to combine AICAR and TMZ |
Zaouali et al., 2010 [46] | Trimetazidine | Zücker rats | IGL-1 24 h; 4 °C; SCS |
I: IGL-1 + TMZ C: IGL-1 |
10−6 M/L | ↓ AST, ALT; higher bile production; increased NO production; HIF-1α accumulation; increased HO-1 expression |
Zaouali et al., 2013 [47] | Trimetazidine melatonin |
Zücker rats (steatotic) |
UW, IGL-1 24 h, 4 °C; SCS |
I2: IGL-1 + TMZ +MEL C1: IGL-1 C2: UW |
TMZ: 10−3 µM MEL: 100 µM | ↑ liver autophagy; ↓ GRP78, pPERK, and CHOP after reperfusion; improved steatotic liver preservation through AMPK activation; synergism of action MEL and TMZ |
Zaouali et al., 2017 [48] | Trimetazidine | Sprague-Dawley rats | UW, IGL-1 8 h, 4 °C; SCS |
I1: IGL-1 + TMZ C: IGL-1 C: UW |
10−6 M/L | ↓ ALT, GLDH, MDA; protects the mitochondria; inhibited of GSK3β and VDAC phosphorylation; reduced apoptosis; decreased ER stress |
Zaouali et al., 2017 [49] | Trimetazidine | Homozygous obese and lean Zücker rats | IGL-1 24 h, 4 °C; SCS |
I: IGL-1 + TMZ C: IGL-1 |
10−5 M/L | ↓ ALT, AST (especially in steatotic livers); ↑ SIRT1 protein levels; ↓ HMGB1 protein level; ↓ TNF-α release; increasing the tolerance of steatotic liver graft against cold IRI |
Pantazi et al., 2015 [50] | Trimetazidine | Rat orthotopic liver transplantation | IGL-1 8 h, 4 °C; SCS |
I: IGL-1 + TMZ C: IGL-1 |
10−6 M/L | ↓ ALT, GLDH; Reduction of oxidative stress; reduction of mitochondrial damage; enhanced SIRT1 protein expression |
Kozaki et al., 1995 [51] | Pentoxifylline | Isolated perfused rat liver model | UW 4 h, 24 h; 0–4 °C; SCS |
I: UW + PTX C: UW |
25 mg PTX/kg body weight | the Kupffer cells produced significantly less O2− and TNF-α |
Arnault et al., 2003 [52] | Pentoxifylline | Isolated perfused Wistar rat liver model | UW 18 h, 24 h; 4 °C; SCS |
I: UW + PTX C: UW |
30 mM (during cold storage) 3 mM (at reperfusion); |
improve microcirculation in the liver; decrease in vascular resistance at reperfusion of 18 h and 24 h; decreased number of foci of peliosis after an 18 h preservation; ↓ LDH, AST, ALT after 24 h cold ischemia time |
Asong-Fontem et al., 2021 [53] | M101 | Zücker rats | IGL-1 24 h, 4 °C, SCS 2 h, 37 °C, NR |
I: IGL-1 + M101 C: IGL-1 |
1 g/L | ↓ AST, ALT, Lactate, GLDH; ↓ MDA; higher production of NO2-NO3; less inflammation (HMGB1) |
Author, Year of Publication |
Antioxidant | Species | Preservation Solution Modification /Cold Ischemia |
Outcome Measures, (Intervention, I/Control, C) | Antioxidant Dose | Effects of Antioxidant |
---|---|---|---|---|---|---|
Enzymatic antioxidant | ||||||
Hide et al., 2014 [54] |
rMnSOD | human liver samples, LSEC, liver grafts from healthy and steatotic rats |
Celsior 16 h, 4 °C; SCS |
I: Celsior + rMnSOD C: no SCS |
rMnSOD: 0,15 µM | ↓ oxidative stress; ↑ NO; |
Non-enzymatic antioxidants | ||||||
Low-molecular-weight antioxidant | ||||||
Aliakbarian et al., 2017 [55] | N-Acetylcysteine | Human | UW 4 °C; SCS |
I: UW + NAC C: UW |
2 g | addition of NAC does not decrease the rate of ischemia–reperfusion injury |
Mitochondria-targeted antioxidants | ||||||
Aghdaie et al., 2019 [56] | α-Lipoic acid (ALA) ursodeoxycholic acid (UDCA) |
Isolated human hepatocytes derived from livers of deceased donors | UW 24 h; 4 °C; SCS |
I1: UW + α-Lipoic acid I2: UW + ursodeoxycholic acid C: UW |
ALA: 5 mM/L UDCA: 5 mM/L |
does not increase the number of viable hepatocytes |
Polyphenols | ||||||
Otani et al., 2023 [57] |
Quercetin | Isolated pig livers | UW 6 h, 4 °C; SCS |
I: UW+ QE C:UW |
QE: 33.1 µM/L Suc: 0.1 M/L |
↓ ALT, AST, LDH; improvement of histological changes; prevent tissue edema |
Drugs | ||||||
Qing et al., 2006 [58] |
Pentoxifylline | Simple porcine orthotopic liver transplantation | UW 12 h, 16 h, 20 h; 4 °C; SCS |
I: UW + PTX C: UW |
1 g/L | ↓ TNF-α, MDA; ↓ ALT, AST; ↑ ATP; 100% 1-week survival; improved microcirculation |
Alix et al., 2020 [59] |
M101 | Pig allogeneic liver orthotopic transplantation |
UW 9 h, 4 °C; SCS |
I: UW + M101 C: UW |
1 g/L | improved liver graft oxygenation during SCS; livers cold stored with UWSCS + M101 did not reach the oxygenation level achieved with machine perfusion |