Custodiol® Supplemented with Synthetic Human Relaxin Decreases Ischemia-Reperfusion Injury after Porcine Kidney Transplantation

Abstract

Objective. Ischemia-reperfusion injury (IRI) is inevitable after kidney transplantation (KT), impairing outcomes. Relaxin-2 (RLX) is a promising insulin-related peptide hormone that protects against renal IRI in rodents, although large animal models are needed before RLX can be tested in a human setting. Methods. In this blinded, randomized, and placebo-controlled experimental study kidneys from 19 donor pigs were retrieved after perfusion with Custodiol® ± RLX (5 or 20 nmol/L) and underwent static cold storage (SCS) for 24 and 48 h, respectively. Subsequently, KT was performed after unilateral right nephrectomy. Study outcomes included markers for kidney function, oxidative stress, lipid peroxidation, and endothelial cell damage. PCR analysis for oxidative stress and apoptosis-related gene panels as well as immunohistochemistry were performed. Results. RLX upregulated SOD2 and NFKB expression to 135% (p = 0.042) and 125% (p = 0.019), respectively, while RIPK1 expression was downregulated to 82% (p = 0.016) of corresponding controls. Further RLX significantly downregulated RIPK1 and MLKL expression and decreased the number of Caspase 3- and MPO-positive cells in grafts after SCS. Conclusions. RLX supplemented Custodiol® significantly decreased IRI via both antioxidant and anti-apoptotic mechanisms. Clinical trials are warranted to implement synthetic human RLX as a novel additive to preservation solutions against IRI.

Sulforaphane has an additive anticancer effect to FOLFOX in highly metastatic human colon carcinoma cells

“…SF and FOLFOX impact on cell viability. SF significantly decreased the viability of the CX-1 cells in a dose-dependent manner to 89 (85-96), 80 (77-85), 58 (65-66), 33 (30)(31)(32)(33)(34) and 27% (25-29%) of the control at concentrations of 2.5, 5, 10, 15 and 20 µM, respectively (all P<0.05) (Fig. 2A).…”

“…The results of the present study show effectively that both therapies cooperatively potentiate apoptosis, as apoptotic cell number in the FOLFOX + SF group in the TUNEL assay was significantly higher than that in groups treated with monotherapy. Furthermore, FOLFOX + SF impacted the expression of the pro-apoptotic BAX and anti-apoptotic BCL-2 genes (33). The balance between these two genes impacts the sensitivity of cells to apoptotic stimuli (34,35).…”

Experimental Static Cold Storage of the Rat Uterus: Protective Effects of Relaxin- or Erythropoietin-Supplemented HTK-N Solutions

“…RLN is one of the protective agents that is already being widely studied in preclinical kidney, lung, heart and liver transplantation research [ 23 , 29 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]; however, to our knowledge, this has not yet been applied in a uterine transplant. RLN acts through different target molecules and pathways of which some are organ related [ 54 ].…”

“…Uterus SCS was performed by using Custodiol-N (HTK-N) solution in different compositions: Group HTKN (HTK-N + no additives), Group EPO (HTK-N + 10 IU/mL recombinant human erythropoietin (Erypo; Janssen-Cilag GmbH, Germany)) and Group RLN (HTK-N + 20 nM synthetic human relaxin-2 (Relaxera, Bensheim, Germany)). The concentrations for experimental substances were chosen according to previously published studies [ 28 , 29 ]. Uterine horns were gently flushed with the respective experimental preservation solution, immediately packaged into the same solution and placed on ice at 4 °C.…”