PMID- 34794887
OWN - NLM
STAT- MEDLINE
DCOM- 20220322
LR  - 20220322
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 101
IP  - Pt B
DP  - 2021 Dec
TI  - Recombinant human growth hormone improves the immune status of rats with septic 
      encephalopathy: The role of VEGFR2 in the prevalence of endoplasmic reticulum 
      stress repair module.
PG  - 108370
LID - S1567-5769(21)01006-7 [pii]
LID - 10.1016/j.intimp.2021.108370 [doi]
AB  - Septic encephalopathy results from the intense reaction of the immune system to 
      infection. The role of growth hormone (GH) signaling in maintaining brain 
      function is well established; however, the involvement of the vascular 
      endothelial growth factor receptor-2 (VEGFR2) in the potential modulatory effect 
      of GH on septic encephalopathy-associated endoplasmic reticulum stress (ERS) and 
      blood-brain barrier (BBB) permeability is not well-understood. Therefore, after 
      the induction of mid-grade sepsis by cecal ligation/perforation, rats were 
      subcutaneously injected with recombinant human GH (rhGH)/somatropin alone or 
      preceded by the VEGFR2 antagonist WAG-4S for 7 days. rhGH/somatropin reduced 
      bodyweight loss and plasma endotoxin, maintained the hyperthermic state, and 
      improved motor/memory functions. Additionally, rhGH/somatropin increased the 
      junctional E-cadherin and beta-catenin pool in the cerebral cortex to enhance the 
      BBB competency, effects that were abolished by VEGFR2 blockade. Also, it 
      activated cortical VEGFR2/mammalian target of the Rapamycin (mTOR) axis to 
      mitigate ERS. The latter was reflected by the deactivation of the 
      inositol-requiring enzyme-1alpha (IRE1alpha)/spliced X-box binding protein-1 (XBP1s) 
      trajectory and the reduction in the protein levels of the death markers, C/EBP 
      homologous protein (CHOP)/growth arrest and DNA damage-153 (GADD153), 
      c-jun-N-terminal kinase (JNK), and caspase-3 with the simultaneous augmentation 
      of expression of the unfolded protein response transducer proteinkinaseR-like 
      ERkinase (PERK). Furthermore, rhGH/somatropin suppressed the phosphorylation of 
      eukaryotic initiation factor-2alpha (eIF2alpha), upregulated the gene expression of 
      activating transcription factor-4 (ATF4), GADD34, and glucose-regulated 
      protein-78/binding immunoglobulin (GRP78/Bip). Moreover, it increased the 
      glutathione level and reduced lipid peroxidation in the cerebral cortex. The 
      VEGFR2 antagonist reversed the effect of rhGH/somatropin on PERK and IRE1alpha and 
      boosted the apoptotic markers but neither affected p-eIF2alpha nor GADD34. Hence, we 
      conclude that VEGFR2 activation by rhGH/somatropin plays a crucial role in 
      assembling the BBB adherens junctions via its antioxidant capacity, ERS relief, 
      and reducing endotoxemia in septic encephalopathy.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - Zaky, Doaa A
AU  - Zaky DA
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 
      Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt. Electronic address: 
      doaa.zaky@pharma.cu.edu.eg.
FAU - Eldehna, Wagdy M
AU  - Eldehna WM
AD  - Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh 
      University, P.O. Box 33516, Egypt.
FAU - El Kerdawy, Ahmed M
AU  - El Kerdawy AM
AD  - Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, 
      Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt.
FAU - Abdallah, Dalaal M
AU  - Abdallah DM
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 
      Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt.
FAU - El Abhar, Hanan S
AU  - El Abhar HS
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 
      Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt; Department of Pharmacology & 
      Toxicology, Faculty of Pharmacy, Future University in Egypt, Cairo, P.O. Box 
      11835, Egypt.
FAU - Wadie, Walaa
AU  - Wadie W
AD  - Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, 
      Kasr El-Aini street, Cairo, P.O. Box 11562, Egypt.
LA  - eng
PT  - Journal Article
DEP - 20211115
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (Cytokines)
RN  - 12629-01-5 (Human Growth Hormone)
RN  - EC 2.7.10.1 (Kdr protein, rat)
RN  - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-2)
SB  - IM
MH  - Animals
MH  - Behavior, Animal/drug effects
MH  - Cytokines/genetics/metabolism
MH  - Endoplasmic Reticulum Stress
MH  - Gene Expression Regulation/drug effects
MH  - Human Growth Hormone/*pharmacology
MH  - Male
MH  - Random Allocation
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sepsis/*complications
MH  - Sepsis-Associated Encephalopathy/*drug therapy/immunology
MH  - Vascular Endothelial Growth Factor Receptor-2/genetics/*metabolism
OTO - NOTNLM
OT  - Blood-brain barrier
OT  - Endoplasmic reticulum stress
OT  - Recombinant human growth hormone
OT  - Somatropin
OT  - Unfolded protein response
OT  - Vascular endothelial growth factor receptor-2
EDAT- 2021/11/20 06:00
MHDA- 2022/03/23 06:00
CRDT- 2021/11/19 05:48
PHST- 2021/07/14 00:00 [received]
PHST- 2021/10/31 00:00 [revised]
PHST- 2021/11/09 00:00 [accepted]
PHST- 2021/11/20 06:00 [pubmed]
PHST- 2022/03/23 06:00 [medline]
PHST- 2021/11/19 05:48 [entrez]
AID - S1567-5769(21)01006-7 [pii]
AID - 10.1016/j.intimp.2021.108370 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2021 Dec;101(Pt B):108370. doi: 
      10.1016/j.intimp.2021.108370. Epub 2021 Nov 15.