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Folic acid alleviates jaundice of phenylhydrazine (PHA)-induced neonatal rats by reducing Lys-homocysteinylation of albumin

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Abstract

Neonatal jaundice is a common symptom that occurs in neonates during the first month of their life and is generally divided into physiological and pathological subtypes. In serious cases, pathological neonatal jaundice frequently shows complications including seizures, cerebral palsy, and kernicterus. However, due to the unclear pathogenesis of pathological neonatal jaundice, effective drugs for this disease remain unsatisfied. In the present study, we first estimated the protective effects of folic acid (FA) on phenylhydrazine (PHA) or homocysteine (Hcy)-injected neonatal rats (2–3 days aged). Intriguingly, we found that FA significantly decreased the elevated total bilirubin (TBIL) and direct bilirubin (DBIL) concentration, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) activity in PHA- or Hcy-injected rats, indicating that FA improves liver functions. Meanwhile, our results also showed that the plasma Hcy level and N-homocysteinylation (N-Hcy) modification of albumin were significantly elevated in the jaundice rats, which were obviously reversed after FA administration. Furthermore, we identified a novel N-Hcy modification site K545 of human serum albumin (HSA) using LC-MS/MS, and the mutagenesis assay in HEK293 further validated these observations. Besides, we demonstrated that the N-Hcy modification of albumin functionally inhibits the bilirubin-binding ability of albumin without altering its protein level both in vitro and in vivo. Altogether, we highlight a mechanism that FA reduces the plasma Hcy level and thereby enhance the bilirubin-binding ability of albumin, which may provide a novel therapeutic strategy for the treatment of pathological neonatal jaundice.

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Funding

This study is supported by the National Natural Science Foundation of China (No. 81671082), National Natural Science Foundation of Shanghai (No. 19ZR1400400), and Shanghai Pudong New Area Municipal Commission of Health and Family Planning Funding (Nos. PW2015D-3).

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Authors and Affiliations

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Contributions

F.X. and W.F. conceived and designed the study. H.Q., E.L., X.Z., X.Y., and J.M. collected the samples and performed experiments. H.Q. wrote the manuscript. H.Q., E.L., and X.Z. prepared all figures and tables. All authors read and discussed and revised the manuscript.

Corresponding authors

Correspondence to Wei-Feng Yu or Fei-Xiang Wu.

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This declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigor of preclinical research as stated in the BJP guidelines for design and analysis and animal experimentation, as recommended by funding agencies, publishers, and other organizations engaged with supporting research.

Ethics approval

All experimental procedures and protocols involved in the present study were approved by the Institutional Animal Care and Use Committee (IACUC) of Second Military Medical University.

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The authors declare no competing interests.

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Highlights

Plasma homocysteine level was elevated in phenylhydrazine-injected rats.

Folic acid intervention alleviates phenylhydrazine- or homocysteine-induced injury of liver function.

Human albumin can be N-homocysteinylated at sites of K4/545 by homocysteine active form.

K4/545 N-homocysteinylation of albumin weakens its bilirubin-binding ability.

Supplementary information

Fig. S1.

(A-B) Plasma Hcy/HTL level (A) and N-Hcy level (B) of total plasma proteins of neonates with pathological jaundice. Western blot results are the representatives of the quantification data. 87 patients with neonatal jaundice and 94 normal donors were involved in the study.*p < 0.05, ***p < 0.001. (C) The plasma albumin level in patients with pathological neonatal jaundice. Western blot results are the representatives of the quantification data. ns, no significance in the statistic. (PDF 3322 kb)

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Wang, HQ., Kong, EL., Zhang, X. et al. Folic acid alleviates jaundice of phenylhydrazine (PHA)-induced neonatal rats by reducing Lys-homocysteinylation of albumin. Cell Biol Toxicol 37, 679–693 (2021). https://doi.org/10.1007/s10565-021-09602-3

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  • DOI: https://doi.org/10.1007/s10565-021-09602-3

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