PMID- 38103659
OWN - NLM
STAT- MEDLINE
DCOM- 20240124
LR  - 20240217
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 212
DP  - 2024 Feb 20
TI  - Impact of amino acid substitutions in hepatitis C virus core region on the severe 
      oxidative stress.
PG  - 199-206
LID - S0891-5849(23)01159-0 [pii]
LID - 10.1016/j.freeradbiomed.2023.12.014 [doi]
AB  - Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, 
      leading to liver steatosis, fibrosis, and hepatocellular carcinoma (HCC). Despite 
      the accumulation of clinical data showing the impact of amino acid substitutions 
      at positions 70 (R70Q/H) and/or 91 (L91M) in the HCV core protein in progressive 
      liver diseases, including HCC, the underlying mechanisms have not been 
      elucidated. We analyzed 72 liver biopsy specimens from patients with chronic HCV 
      genotype 1b (HCV-1b) infection prior to antiviral treatment. Levels of 
      8-hydroxy-2'-deoxyguanosine (8-OHdG) and nuclear factor erythroid 2-related 
      factor 2 (NRF2) in the nucleus were quantified using liver tissue 
      immunohistochemistry. The effects of amino acid substitutions in the HCV core 
      region on hepatocellular oxidative stress were investigated using wild-type or 
      double-mutant (R70Q/H+L91M) HCV-1b core transfection and stable expression in 
      human hepatoma HuH-7 cells. Overall, 24, 19, 11, and 18 patients had the 
      wild-type, R70Q/H, L91M, and R70Q/H+L91M genotypes, respectively, in the HCV 
      core. A significantly higher accumulation of hepatocellular 8-OHdG and a lower 
      NRF2/8-OHdG ratio were observed in patients with R70Q/H+L91M than in those with 
      the wild-type disease. Increased levels of intracellular superoxide and hydrogen 
      peroxide in the cytoplasm and mitochondria, mRNA expression of enzymes generating 
      oxidative stress, and nuclear expression of nicotinamide adenine dinucleotide 
      phosphate oxidase 4 were augmented in cells treated with R70Q+L91M. HCV core 
      proteins harboring either or both substitutions of R70Q/H or L91M enhanced 
      hepatocellular oxidative stress in vivo and in vitro. These amino acid 
      substitutions may affect HCC development by enhancing hepatic oxidative stress in 
      patients with chronic HCV-1b infection.
CI  - Copyright (c) 2023 Elsevier Inc. All rights reserved.
FAU - Chida, Takeshi
AU  - Chida T
AD  - Hepatology Division, Department of Internal Medicine II, Hamamatsu University 
      School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan; 
      Department of Regional Medical Care Support, Hamamatsu University School of 
      Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
FAU - Watanabe, Shinya
AU  - Watanabe S
AD  - Department of Gastroenterology, Shimada General Medical Center, 1200-5 Noda, 
      Shimada, Shizuoka, 427-8502, Japan.
FAU - Ohta, Kazuyoshi
AU  - Ohta K
AD  - Hepatology Division, Department of Internal Medicine II, Hamamatsu University 
      School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
FAU - Noritake, Hidenao
AU  - Noritake H
AD  - Hepatology Division, Department of Internal Medicine II, Hamamatsu University 
      School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
FAU - Ito, Masahiko
AU  - Ito M
AD  - Department of Microbiology & Immunology, Hamamatsu University School of Medicine, 
      1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
FAU - Suzuki, Tetsuro
AU  - Suzuki T
AD  - Department of Microbiology & Immunology, Hamamatsu University School of Medicine, 
      1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
FAU - Suda, Takafumi
AU  - Suda T
AD  - Hepatology Division, Department of Internal Medicine II, Hamamatsu University 
      School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan.
FAU - Kawata, Kazuhito
AU  - Kawata K
AD  - Hepatology Division, Department of Internal Medicine II, Hamamatsu University 
      School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka, 431-3192, Japan. 
      Electronic address: kawata@hama-med.ac.jp.
LA  - eng
PT  - Journal Article
DEP - 20231214
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (NF-E2-Related Factor 2)
RN  - 88847-89-6 (8-Hydroxy-2'-Deoxyguanosine)
RN  - 0 (Viral Core Proteins)
SB  - IM
MH  - Humans
MH  - *Carcinoma, Hepatocellular/pathology
MH  - Hepacivirus/genetics
MH  - *Liver Neoplasms/pathology
MH  - Amino Acid Substitution
MH  - NF-E2-Related Factor 2/genetics
MH  - *Hepatitis C/genetics
MH  - *Hepatitis C, Chronic/genetics
MH  - Oxidative Stress/genetics
MH  - 8-Hydroxy-2'-Deoxyguanosine
MH  - Viral Core Proteins/genetics/pharmacology/therapeutic use
MH  - Genotype
OTO - NOTNLM
OT  - Amino acid substitutions
OT  - Core
OT  - Hepatitis C virus (HCV)
OT  - Nicotinamide adenine dinucleotide phosphate oxidase 4 (NOX4)
OT  - Nuclear factor erythroid 2-related factor 2 (NRF2)
OT  - Oxidative stress
COIS- Declaration of competing interest The authors report no conflicts of interest.
EDAT- 2023/12/17 09:45
MHDA- 2024/01/24 06:43
CRDT- 2023/12/16 19:26
PHST- 2023/06/18 00:00 [received]
PHST- 2023/12/08 00:00 [revised]
PHST- 2023/12/11 00:00 [accepted]
PHST- 2024/01/24 06:43 [medline]
PHST- 2023/12/17 09:45 [pubmed]
PHST- 2023/12/16 19:26 [entrez]
AID - S0891-5849(23)01159-0 [pii]
AID - 10.1016/j.freeradbiomed.2023.12.014 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2024 Feb 20;212:199-206. doi: 
      10.1016/j.freeradbiomed.2023.12.014. Epub 2023 Dec 14.