PMID- 36427546
OWN - NLM
STAT- MEDLINE
DCOM- 20221219
LR  - 20221221
IS  - 1879-0631 (Electronic)
IS  - 0024-3205 (Linking)
VI  - 312
DP  - 2023 Jan 1
TI  - High glucose-induced increasing reactive nitrogen species accumulation triggered 
      mitochondrial dysfunction, inflammation, and apoptosis in keratinocytes.
PG  - 121208
LID - S0024-3205(22)00908-0 [pii]
LID - 10.1016/j.lfs.2022.121208 [doi]
AB  - Growing evidence indicates that skin injuries are a common complication of 
      diabetes. However, the cellular and molecular mechanisms of high glucose (HG) 
      environment trigger nitrosative stress-mediated inflammation and apoptosis in 
      keratinocytes remains unknown. Here we investigated whether reactive nitrogen 
      species (RNS) induced by HG environment restrain antioxidant activity, and 
      mitochondrial dysfunction leading to inflammation, and apoptosis via stress 
      signaling pathways in keratinocytes. Our results established that the HG 
      environment enhanced the production of nitric oxide (NO) and peroxynitrite anion 
      (ONOO-) by inducible NO synthase (iNOS) in keratinocytes. Overproduction of RNS 
      in HG environment suppress the antioxidants activity leading to mitochondrial 
      dysfunction, characterized by loss of mitochondrial membrane potential (DeltaPsim), 
      increase in mitochondrial mass, decrease in mitochondrial transcription factor 
      A(TFAM), increase in mitochondrial DNA (mtDNA) displacement loop (D-loop) and 
      decrease in glycolytic flux concentration, which was attenuated by 
      pharmacological inhibitors of NO/ONOO-, Nomega-Nitro-l-argininemethyl ester 
      hydrochloride (NAME)/hydralazine hydrochloride (Hyd.HCl). Excess production of 
      RNS in HG environment restrained 8-oxoguanine DNA glycosylase-1 (OGG1) expression 
      and increased 8-hydroxydeoxyguanosine (8-OHdG) accumulations in DNA were 
      regulated by NO or ONOO-. Further, HG-induced RNA production caused an increase 
      in the production of inflammatory mediators accompanied by activation of 
      ERK1/2MAPK/Akt/tuberin-mTOR/IRF3 signaling cascade, lipid peroxidation (LPO), and 
      protein carbonylation (PC) reactions followed by breakdown the cell-cell 
      communication and apoptosis. Pre-treatment of cell with NAME/Hyd.HCl, diminished 
      the expression of ERK1/2MAPK/Akt/tuberin-mTOR/IRF3, inflammatory mediators, and 
      attenuated apoptosis in keratinocytes. Together, our results indicated that 
      excess production of RNS in HG environment triggered inflammation and apoptosis, 
      mediated by activation of ERK1/2MAPK/Akt/tuberin-mTOR/IRF3 signaling cascades in 
      keratinocytes.
CI  - Copyright (c) 2022. Published by Elsevier Inc.
FAU - Rizwan, Huma
AU  - Rizwan H
AD  - School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 
      751024, India.
FAU - Kumar, Sonu
AU  - Kumar S
AD  - Department of Zoology, School of Life Sciences, Mahatma Gandhi Central 
      University, Motihari, Bihar 845401, India.
FAU - Kumari, Golden
AU  - Kumari G
AD  - Department of Zoology, School of Life Sciences, Mahatma Gandhi Central 
      University, Motihari, Bihar 845401, India.
FAU - Pal, Arttatrana
AU  - Pal A
AD  - School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar 
      751024, India; Department of Zoology, School of Life Sciences, Mahatma Gandhi 
      Central University, Motihari, Bihar 845401, India. Electronic address: 
      arttatranapal@mgcub.ac.in.
LA  - eng
PT  - Journal Article
DEP - 20221123
PL  - Netherlands
TA  - Life Sci
JT  - Life sciences
JID - 0375521
RN  - 0 (Reactive Nitrogen Species)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - 0 (Reactive Oxygen Species)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Antioxidants)
RN  - 0 (Inflammation Mediators)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Humans
MH  - *Reactive Nitrogen Species/metabolism
MH  - Tuberous Sclerosis Complex 2 Protein/metabolism
MH  - *Proto-Oncogene Proteins c-akt/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - Oxidative Stress
MH  - Apoptosis
MH  - Inflammation/metabolism
MH  - Keratinocytes/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - Mitochondria/metabolism
MH  - Antioxidants/pharmacology
MH  - Inflammation Mediators/metabolism
MH  - Glucose/pharmacology/metabolism
OTO - NOTNLM
OT  - Apoptosis
OT  - High glucose
OT  - Inflammation
OT  - Mitochondrial dysfunction
OT  - RNS
COIS- Declaration of competing interest All authors have declared that no potential 
      conflicts of interest relevant to this article were reported.
EDAT- 2022/11/26 06:00
MHDA- 2022/12/20 06:00
CRDT- 2022/11/25 19:23
PHST- 2022/08/12 00:00 [received]
PHST- 2022/11/12 00:00 [revised]
PHST- 2022/11/15 00:00 [accepted]
PHST- 2022/11/26 06:00 [pubmed]
PHST- 2022/12/20 06:00 [medline]
PHST- 2022/11/25 19:23 [entrez]
AID - S0024-3205(22)00908-0 [pii]
AID - 10.1016/j.lfs.2022.121208 [doi]
PST - ppublish
SO  - Life Sci. 2023 Jan 1;312:121208. doi: 10.1016/j.lfs.2022.121208. Epub 2022 Nov 
      23.