Table 2.
Summary of the main preclinical findings of the respective micronutrients with reference to the individual organs. Main categories of outcomes are presented in bold.
| Micronutrient | Organ | Species | Route of administration |
Outcome |
|---|---|---|---|---|
| ALA | Kidney | rat [23,24,25,26] |
i.p. [23,24,25,26] |
organ function [24] decreased expression of aquaporins and sodium transporters [23,26] preserved kidney function (decreased creatin and urea levels) [23,26] anti-inflammatory effects [23] antioxidative effects [25] endothelium protective activity (eNOS increased, ET-1 decreased) [24] synergistic effects with XO inhibitor febuxostat [25] |
| Liver | rat [29,30,31,33,34] |
i.v. [29,31] i.p. [30,33,34] |
preservation of tissue integrity reduced levels of LDH [29], ALT [30,31], AST [30] increased ATP content [30] increased survival of animals [33,34] anti-apoptotic effects downregulation of proapoptotic proteins [33,34] anti-inflammatory effects inhibition of NFκB [29,31] reduced secretion of proinflammatory cytokines [30] anti-oxidative effects increased endogenous antioxidants [29,31] reduced activity of prooxidant enzymes [30] effects were mainly mediated via PI3K/Akt axis [29] |
|
| Heart | rat [36,37,38,39,40,41] pig [42] |
p.o [36,40,42] i.v. [37] i.p. [38] ex vivo [39,41] |
enhanced graft survival [36] reduced LDH and CK release [37,38] decreased infarct size [37] anti-oxidative and anti-toxicity effect induction of ALDH2 expression (detoxification of aldehydes) [39] preserved cardiac function [40] decreased number of arrythmias [41] improved coronary flow [40] increased peak arterial pressure [40] anti-inflammatory inhibition of NFκB and ERK [42] anti-arrhythmic effects activation of K-dependent ATPase by release of H2S [41] activation of PI3K/Akt/Nrf2/HO-1 pathway [37] |
|
| Astaxanthin | Kidney | in vitro [52] mouse [52] rats [53] |
p.o. [52,53] |
anti-oxidative effects [52] protection against H2O2-induced cell death [52] increased SOD [52,53] decreased MDA [52,53] decreased total thiols and 8-hydroxydeoxyguanoside [53] graft function improved serum levels of urea nitrogen and creatinine [52] improved histopathologic scores [52] anti-apoptotic effects decrease of caspase (3, 8, 9) [53] anti-inflammatory effects decreased levels of TNF-a and IL-6 [53] |
| Liver | rats [54] mouse [55,56] |
intragastric intubation [54] p.o. [55,56] |
antioxidative effects reduced levels of xanthine oxidase [54] reduced tissue protein carbonyl levels [54] reduced level of oxidative stress [55] tissue preservation reduction of histopathologic scoring [54] anti-apoptotic [55,56] induction of autophagy [56] decreased level of necrosis [55] anti-inflammatory effects decreased level of macrophage infiltration [55] |
|
| Heart | rabbit [58] mouse [59] in vitro [60] |
i.v. [58] p.o. [59] |
graft function reduced infarct size [58,59] reduced inflammation and myocardial injury [58] anti-inflammatory effects inhibition of complement activation [58] antioxidative effects improved mitochondrial parameters [59] cell protection [60] |
|
| CoQ10 | Kidney | rat [62,63,64,65] |
i.m. [62] p.o. [65] i.p. [64] |
improved organ function increased survival rate [62] improved kidney function [63] improved histopathological scores [64] improved renal morphology [65] decreased blood urea nitrogen [65] enhanced rate of ATP resynthesis [62] anti-oxidative effects [64] decreased NO-levels [65] decreased MDA levels [65] improved SOD activity [65] anti-inflammatory effects decreased levels of TNF-α [65] |
| Liver | rat [66,67,69,70,71,72] mouse [68] |
i.v. [66,68,71] i.p. [70] p.o. [67,69] |
improved organ function decreased activities of serum glutamic oxaloacetic transaminase [66] decreased activity of serum glutamic pyruvic transaminase [66] increased survival rate [66,72] increased level of total protein [66] improved histopathology [67] reduced serum ALT levels [68] anti-oxidative effects [67] increased levels of glutathione [69,71] decreased MDA levels [69] protection of endogenous CoQ10 levels [70,71] improved mitochondrial function [70] anti-apoptotic effects reduced biomarkers of apoptosis [67] |
|
| Heart | rat [85,86,87,90] pig [88] rabbit [89] |
i.m. [85] i.p. [85] i.v. [86,87,90] p.o. [88] intracardial injection [89] |
improved energy metabolism increase of aerobic energy production [85] preservation/delay of aerobic efficiency [85] preservation of mitochondrial function [90] improved organ function [87] improved myocardial function [86] decreased oxidative injury [86] reduced cardiac stunning time [88] reduced area of infarction risk [89] |
|
| Curcumin | Kidney | rats [96] mouse [96] |
i.p. [96] i.v. [96] p.o. [96] |
anti-inflammatory effects [96] inhibition of NFκB [96] inhibition of NMDA [96] induction of Nrf2 pathway [96] anti-apoptotic effects [96] inhibition of caspase 3 [96] induction of NO/cGMP/PKG pathway [96] antifibrotic effects [96] activation of APPL [96] inhibition of Akt [96] |
| Liver | mouse [108] rat [109,110,111,112,113,114,116] in vitro [114,115] |
i.p. [108] p.o. [109,110] i.v. [111,113] preservation solution [116] |
prevention of liver injury [108,109,110,111] attenuated liver enzymes AST, ALT [112,113] restoration of ATP content [110] protection against injury during warm und cold storage [116] increased survival [116] anti-inflammatory effects reduced expression of proinflammatory cytokines [114] reduced expression of adhesion molecules [113,115] anti-inflammatory priming of Kupffer cells [108] inhibition of NFκB [114] lower pulmonary levels of TNFα and MMP-9 activity [112] antioxidative effects activation of antioxidant enzymes [112] upregulation of HO-1 [111] Hsp70 expression [111] |
|
| Heart | rat [128,129,130,131,135,280] in vitro [129,134,137,138] mouse [132,133] |
intracardial injection [128] perfusion solution [129,280] p.o. [130,132,133,135] i.p. [131] |
improved organ function restoration of organ function [128,129,130] attenuation of cardiac lesions [131,132,133] amelioration of cold-storage induced damage [134] anti-apoptotic effects [128,132,135] anti-inflammatory effects [132] anti-oxidative effects [132,137,138] mechanisms activation of JAK2/STAT3 pathway [128,133,280] downregulation of Notch1 pathway [138] |
|
| Glycine | Kidney | ex vivo [141,142] rat [140,144,145] in vitro [143] |
preservation solution [140,141,142] i.p. [145] p.o. [144] |
improved organ function reduced cellular damage (LDH release and alkaline phosphatase) [140,142,143] protection against IR injury [141] no effect on regeneration of ATP content or mitochondrial function [142] cell protection (reduced LDH release) improved glomerular filtration rate [144] reduced urinary LDH [144] |
| Liver | rat [148,281] |
p.o. [281] perfusion solution [148] |
improved organ function reduced liver injury [281] anti-inflammatory effects inhibition of Kupffer cell activation [148] |
|
| Heart | rat [155] pig [156] |
p.o. [155] i.v. [156] |
improved organ function decreased intimal and medial thickening [155] inhibition of proliferation and migration of VSMC [155] increased volume load [156] increased postischemic right ventricular end-diastolic compliance [156] no effect on maximal right ventricular developed pressure [156] anti-inflammatory effects reduced infiltration of macrophages [155] |
|
| n3-PUFA | Kidney | mouse [162] rat [163,164,165] |
p.o. [162,163,164,165] |
improved organ function preserved tubular integrity [162] less histologic damage [163] improved renal function [165] anti-oxidative effects [163,164] anti-apoptotic effects [164] |
| Liver | rat [177,180] mouse [179] in vitro [181] |
p.o. [177,180] i.v. [179] |
improved organ function hepatic tissue protection [177,179,180] anti-inflammatory effects [180,181] inhibition of NFκB by activation of PPARα [180] inhibition of NFκB by activation of PI3K/Akt [181] inhibition of TLR4 recruitment [177] |
|
| Heart | mouse [183,184] rat [185] |
i.p. [183,184] p.o. [185] |
improved organ function increased graft survival [183,184] anti-inflammatory effects shift towards Treg via activation of PPARγ [183,184] inhibition of macrophage recruitment [185] inhibition of MCP-1/IP-10 [185] |
|
| NAC | Kidney | - | - | - |
| Liver | - | - | - | |
| Heart | rat [202] | i.v. [202] |
improved organ function improved shortening of isograft [202] decreased serum LDH [202] improved liver biomarkers (AST, ALT) [202] anti-inflammatory effects decreased serum TNFα [202] decreased serum IL-1 [202] anti-oxidative stress increased SOD activity [202] increased SOD/LPO [202] |
|
| Quercetin | Kidney | rat [91,98,99,100,101] pig [97] in vitro [102] mouse [103] |
i.p. [91,98,99,100,101,103] preservation solution [97] |
anti-oxidative effects [91,97,98,99] decrease of TBARS [100] decreased MDA [101] increased level of antioxidant enzymes [101] anti-inflammatory effects [91,99] anti-apoptotic effects [99,102] induction of autophagy [103] |
| Liver | rat [98,104,105,107] mouse [106] |
i.p. [98,104] p.o. [106] i.m. [107] |
improved organ function improved level of liver enzymes AST, ALT [98,104] attenuation of liver injury [98] anti-oxidative effects [104,105] anti-apoptotic and anti-autophagy effects [106] downregulation of ERK/NFκB [98] synergistic effects with remote ischemic reperfusion preconditioning [98] synergistic effects with Fe2+ chelator desferrioxamine [107] |
|
| Heart | rat [117,120,121,122,123,124,282] in vitro [118,119,121,283] ex vivo [118] mouse [119] |
preservation solution [117,118] i.p. [119] p.o. [119,120,123,124,282] |
improved organ function improved cardiac flow [117] alleviated cardiac dysfunction [118] decreased infarct size [119,121,122] anti-oxidative effects improved mitochondrial function [124] mechanisms activation of JAK2/STAT3 pathway [282] activation of PI3K/Akt pathway [118] inhibition of HMGB1 pathway [121] upregulation of PKCε [283] anti-apoptotic effects inhibition of SIRT1/PGCα signaling [123] anti-inflammatory effects inhibition of NFκB [119] activation of PPARγ [119] |
|
| Resveratrol | Kidney | pig [210] rat [211,212,213,214,215,216,284,285] in vitro [216] |
preservation solution [210] i.p. [213,216,285] i.v. [211,215] p.o. [212,214,284] |
improved organ function [212,214] improved glomerular filtration [210] improved proximal tubular function [210] slowed chronic loss of function [210] slowed chronic onset of histological lesions [210] reduced mortality [211] attenuation of increased serum urea [213] reduced creatinine levels [211] improved organ morphology [210,211,214] attenuated interstitial fibrosis [210] attenuated tubular atrophy [210] preservation of glomerular number reduction [213] preservation of glomerular collapse [215] anti-oxidative effects [210,212,216] restoration of antioxidant enzyme pool [214] decreased levels of MDA [284] decreased levels of TBARS [214] decreased levels of lipid peroxidation products [211] increased levels of GSH [284,285] increased levels of NO [211,214,285] anti-apoptotic effects [210] Nrf2/TLR4/caspase 3 axis [212] induction of autophagy via SIRT-1 [216] anti-inflammatory effects [212] |
| Liver | rat [219,220,221,222,223,224,225] mouse [218] |
preservation solution [223] reperfusion solution [223] i.p. [218,222] i.v. [219,220,221,224,225] |
improved organ function decreased plasma aminotransferase activity [219] reduced levels of histological liver injury [219] improved bile production [220] improved portal vein flow volume [220] preserved sinusoidal endothelial cells [220] ameliorated ATP levels [220] decreased VEGF [224] anti-oxidative effects inhibition of lipid peroxidation [223] protection of mitochondria [223] reduced levels of MDA [219] increased levels of GPx [219] increased levels of CAT [219] expression of Txnip [221] reduced expression of thioredoxin [221] attenuation of GSH depletion [225] increased GSH reductase [225] increased SOD [219,225] attenuation of HIF-1α [224] anti-inflammatory effects decreased levels of TNFα [218,220] suppressed leucocyte infiltration [218] decreased levels of IFNγ [218] increases apoptosis of anti-graft lymphocytes [222] anti-apoptotic effects reduction of apoptotic and necrotic markers [223] reduced release of cytochrome C [223] |
|
| Heart | rat [227,228,229,230,231,232,233] | perfusion solution [228,233] i.v. [229,230,232] i.p. [231] p.o. [227] |
improved organ function [228,232] reduced rhythm disturbances [231] anti-apoptotic effects [227,229] reduced infarct size [227,228,229,230,231] reduced levels of LDH [230,231,232] reduced levels of CK [231,232] alleviated myocardial injury [233] anti-oxidative effects increased expression of Nrf2 [232] increased expression of HO-1 [232,233] enhanced activity of SOD and GPx [232] reduced levels of superoxide [227,232] reduced levels of MDA [232] suppression of myeloperoxidase [229] anti-inflammatory effects attenuation of TLR4 and NFκB expression [229] reduced activation of iNOS [231] reduced generation of TNFα [230] improved endothelial function increased VEGF-B [227] increased p-eNOS [226,227,230] increased NO-production [226] |
|
| Sulforaphane | Kidney | in vitro [234] rat [234,235,236] |
i.v. [234,235,236] |
improved organ function reduced cellular toxicity [234] induction of phase II enzymes [234] reduced renal injury [234,236] improved histopathologic scoring [234] lower blood urea nitrogen levels [236] decreased serum creatinine levels [236] improved kidney function [235] anti-oxidative effects inhibition of lipid peroxidation products [234] preservation of mitochondrial microstructure [236] increase of SOD-2 expression [236] anti-inflammatory effects [235] anti-apoptotic effects [235] |
| Liver | mouse [239] rat [240,241,242] |
i.p. [240,241,242] p.o. [241] |
improved organ function decreased levels of liver enzymes (AST and ALT) [239,240,242] decreased tissue injury [239,240,241] anti-inflammatory effects decreased levels of TNFα [239] decreased levels of IL-6 [239] anti-oxidative effects trend towards increased Nrf2-related transcription products [239] improved total antioxidant capacity [241] improved total antioxidant status [241] decreased levels of MDA [240] decreased levels of MPO [240] improved activity of SOD [240,242] improved levels of GSH [240,242] improved activity of GPx [240,242] increased expression of Nqo1 [240] increased expression of Nrf2 [240] increased expression of HO-1 [240] induction of Nrf2 pathway [242] anti-apoptotic effects [240] |
|
| Heart | rat [243,246,247,249] mouse [244] |
p.o. [246] i.p. [244,245,247] i.v. [243] intracardial injection [248,249] |
improved organ function less post-ischemic myocardial infarction [246] decreased cardiomyocyte apoptosis [246] expression of phase II enzymes [246] increased graft survival [245] decreased levels of TnT, CK, CK-MB and LDH [243] improved liver function (decreased levels of AST and ALT) [243] improved graft function [243,244] improved survival [243] anti-apoptotic effects decreased markers of apoptosis (caspase 3) [243,244] increased expression of SIRT1 [248,249] antioxidative effects decreased oxidative stress [247] no effect on CAT [247] no effect on GPx [247] |
|
| Vitamin C | Kidney | rat [254,256] mouse [255] |
i.v. [254] p.o. [255] i.p. [256] |
anti-oxidative effects [254] anti-inflammatory effects [254] restoration of endogenous antioxidant capacity [255] improved graft function [256] |
| Liver | rat [261,263] |
i.v. [261] i.p. [263] |
improved organ function improved liver function biomarkers (ALT, AST) [261] mitochondrial health improved glutamate dehydrogenase activity [261] anti-oxidative effects [263] |
|
| Heart | mouse [279] | preservation solution [279] | graft protection [279] |