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Human antigen R (HuR), which is a mRNA‐binding protein that stabilizes and regulates mRNA translation, is found to have increased expression in inflammation, cancer and other diseases, making HuR to be a promising drug target. This study reports a peptide‐based nanoparticle (NP) system exhibits potent anti‐inflammatory activity to ameliorate acute liver injury via the ability of peptides to inhibit the mRNA binding site of HuR and block downstream signaling. Molecular modeling provided structural evidence indicating that the peptides interact with the RNA‐binding site of HuR, mainly via hydrogen‐bonding and hydrophobic interactions. These peptide‐based NPs can act as nanocarriers to deliver peptides into cells to compete with the mRNA binding site of HuR, evidenced by the reduction of antibody recognition to the native protein and the exhibition of anti‐inflammatory activity against activated macrophage cells, with no adverse effect in vitro and in vivo. In LPS/D‐GalN‐induced hepatic sepsis with high dosage of LPS/GalN, administration of the NPs significantly attenuated necrosis and HuR expression, resulting in the significant improvement of animal survival rate, suggesting their therapeutic potential for hepatic inflammation and a broad range of HuR‐overexpressed diseases.
Human antigen R (HuR), which is a mRNA‐binding protein that stabilizes and regulates mRNA translation, is found to have increased expression in inflammation, cancer and other diseases, making HuR to be a promising drug target. This study reports a peptide‐based nanoparticle (NP) system exhibits potent anti‐inflammatory activity to ameliorate acute liver injury via the ability of peptides to inhibit the mRNA binding site of HuR and block downstream signaling. Molecular modeling provided structural evidence indicating that the peptides interact with the RNA‐binding site of HuR, mainly via hydrogen‐bonding and hydrophobic interactions. These peptide‐based NPs can act as nanocarriers to deliver peptides into cells to compete with the mRNA binding site of HuR, evidenced by the reduction of antibody recognition to the native protein and the exhibition of anti‐inflammatory activity against activated macrophage cells, with no adverse effect in vitro and in vivo. In LPS/D‐GalN‐induced hepatic sepsis with high dosage of LPS/GalN, administration of the NPs significantly attenuated necrosis and HuR expression, resulting in the significant improvement of animal survival rate, suggesting their therapeutic potential for hepatic inflammation and a broad range of HuR‐overexpressed diseases.
Background Renal dysfunction is a common complication following liver transplantation (LT). This study aimed to determine whether a comprehensive assessment of kidney function using nineteen serum and urinary biomarkers (BMs) within the first 48 h post-LT could enhance the prediction of severe acute kidney injury (AKI) and the need of kidney replacement therapy (KRT) during the first postoperative week. Methods Blood and urine (U) samples were collected during the pre- and postoperative periods. Nineteen BMs were evaluated to assess kidney health in the first 48 h after LT. Classification and regression tree (CART) cross-validation identified key predictors to determine the best BM combination for predicting outcomes. Results Among 100 LT patients, 36 developed severe AKI, and 34 required KRT within the first postoperative week. Preoperative assessment of U neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) predicted the need for KRT with 75% accuracy. The combined assessment of U osmolality (OSM), U kidney injury molecule 1 (KIM-1), and tissue inhibitor of metalloproteinase (TIMP-1) within 48 h post-LT predicted severe AKI with 80% accuracy. U-OSM alone, measured within 48 h post-LT, had an accuracy of 83% for predicting KRT need, outperforming any BM combination. Conclusions Combined BM analysis can accurately predict severe AKI and KRT needs in the perioperative period of LT. U-OSM alone proved to be an effective tool for monitoring the risk of severe AKI, available in most centers. Further studies are needed to assess its impact on AKI progression postoperatively. Registered at Clinical Trials (clinicaltrials.gov) in March 24th, 2014 by title ‘Acute Kidney Injury Biomarkers: Diagnosis and Application in Pre-operative Period of Liver Transplantation (AKIB)’ and identifier NCT02095431.
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