Neural stem cells injured by oxidative stress can be rejuvenated by GV1001, a novel peptide, through scavenging free radicals and enhancing survival signals

Park, Hyun Hee; Yu, Hyun Jung; Kim, Sangjae; Kim, Gabseok; Choi, Na Young; Lee, Eun Hye; Lee, Young Joo; Yoon, Mi Young; Lee, Kyu Yong; Koh, Seong‐Ho

doi:10.1016/j.neuro.2016.05.022

Cited by 37 publications

(27 citation statements)

References 34 publications

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“…This was evidenced as the increased level of p-Akt (Ser473), which has been shown to regulate cellular radioprotection against IR ( 29 , 34 ), and reduced level of active p53/p21WAF1 proteins in the NHOKs treated with GV1001. This was in accordance with an earlier report showing the protective effects of GV1001 against oxidative stress in neural stem cells, allowing for continued cell proliferation and reduced cell death following exposure to H 2 O 2 ( 35 ). Further investigations aim to elucidate the detailed mechanism by which GV1001 modulates the genotoxic effects of IR.…”

Section: Discussionsupporting

confidence: 93%

hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic effects through suppression of TGF‑β signaling

Chen¹,

Shin²,

Kim

et al. 2018

Int J Mol Med

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GV1001 is a 16-amino acid peptide derived from the human telomerase reverse transcriptase (hTERT) protein (616–626; EARPALLTSRLRFIPK), which lies within the reverse transcriptase domain. Originally developed as an anticancer vaccine, GV1001 demonstrates diverse cellular effects, including anti-inflammatory, tumor suppressive and antiviral effects. In the present study, the radioprotective and antifibrotic effects of GV1001 were demonstrated through suppressing transforming growth factor-β (TGF-β) signaling. Proliferating human keratinocytes underwent premature senescence upon exposure to ionizing radiation (IR), however, treatment of cells with GV1001 allowed the cells to proliferate and showed a reduction in senescent phenotype. GV1001 treatment notably increased the levels of Grainyhead-like 2 and phosphorylated (p-)Akt (Ser473), and reduced the activation of p53 and the level of p21/WAF1 in irradiated keratinocytes. It also markedly suppressed the level of TGF-β signaling molecules, including p-small mothers against decapentaplegic (Smad)2/3 and Smad4, and TGF-β target genes, including zinc finger E-box binding homeobox 1, fibronectin, N-cadharin and Snail, in irradiated keratinocytes. Furthermore, GV1001 suppressed TGF-β signaling in primary human fibroblasts and inhibited myofibroblast differentiation. Chromatin immunoprecipitation revealed that GV1001 suppressed the binding of Smad2 on the promoter regions of collagen type III α1 chain (Col3a1) and Col1a1. In a dermal fibrosis model in vivo, GV1001 treatment notably reduced the thickness of fibrotic lesions and the synthesis of Col3a1. These data indicated that GV1001 ameliorated the IR-induced senescence phenotype and tissue fibrosis by inhibiting TGF-β signaling and may have therapeutic effects on radiation-induced tissue damage.

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Section: Discussionsupporting

confidence: 93%

hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic effects through suppression of TGF‑β signaling

Chen¹,

Shin²,

Kim

et al. 2018

Int J Mol Med

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“…We conducted proteomics analyses as reported by our previous study 17. Cultured NSC pellets were washed twice with ice-cold PBS and sonicated for 10 s with a Sonoplus (Bandelin Electronics, Berlin, Germany) in a sample lysis solution composed of 7 M urea and 2 M thiourea with 4% (w/v) 3-[(3-cholamidopropyl) dimethy-lammonio]-1-propanesulfonate (CHAPS), 1% (w/v) dithiothreitol (DTT), 2% (v/v) pharmalyte, and 1 mM benzamidine.…”

Section: Methodsmentioning

confidence: 99%

Neural Stem Cell Death Mechanisms Induced by Amyloid Beta

Lee

Park

Koh

et al. 2017

Dement Neurocognitive Disord

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Background and Purpose Amyloid beta (Aβ) is the main component of amyloid plaques, which are deposited in the brains of patients with Alzheimer' s disease (AD). Biochemical and animal studies support the central role of Aβ in AD pathogenesis. Despite several investigations focused on the pathogenic mechanisms of Aβ, it is still unclear how Aβ accumulates in the central nervous system and subsequently initiates the disease at the cellular level. In this study, we investigated the pathogenic mechanisms of Aβ using proteomics and antibody microarrays. Methods To evaluate the effect of Aβ on neural stem cells (NSCs), we treated primary cultured cortical NSCs with several doses of Aβ for 48 h. A 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay, trypan blue staining, and bromodeoxyuridine cell proliferation assay were performed. We detected several intracellular proteins that may be associated with Aβ by proteomics and Western blotting analysis. Results Various viability tests showed that Aβ decreased NSCs viability and cell proliferation in a concentration-dependent manner. Aβ treatment significantly decreased lactate dehydrogenase B, high-mobility group box 1, aldolase C, Ezrin, and survival signals including phosphorylated phosphoinositide 3-kinase, Akt, and glycogen synthase kinase-3β. Conclusions These results suggest that several factors determined by proteomics and Western blot hold the clue to Aβ pathogenesis. Further studies are required to investigate the role of these factors.Key Words amyloid beta, neural stem cells, proteomics.

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“…GV1001, a novel cell-penetrating peptide (16-amino-acid sequence) derived from human telomerase reverse transcriptase, has been implicated to have anticancer, antioxidant, anti-inflammatory, and antiapoptotic effects in kidney; it prevents myocardial ischemia-reperfusion injury; stimulates neural stem cell; and is active against various cancer types [7][8][9][10][11]. Moreover, our previous studies revealed that GV1001 significantly attenuated hearing threshold shift and cochlear outer hair cell (OHC) damage in kanamycin-induced ototoxicity mouse model [12,13].…”

Section: Introductionmentioning

confidence: 99%

Outcomes of Peptide Vaccine GV1001 Treatment in a Murine Model of Acute Noise-Induced Hearing Loss

et al. 2020

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Noise-induced hearing loss (NIHL) is primarily caused by damage to cochlear hair cells, associated with synaptopathy. The novel cell-penetrating peptide GV1001, an antitumor agent, also has antioxidant and anti-inflammatory effects, and is otoprotective in a murine model of kanamycin-induced ototoxicity. Here, we explored whether GV1001 attenuated NIHL, and the underlying mechanism at play. We established an NIHL model by exposing 4- to 6-week-old C57/BL6 mice to white noise at 120 dB SPL for 2 h, resulting in a significant permanent threshold shift (PTS). We then subcutaneously injected saline (control), GV1001, or dexamethasone immediately after cessation of PTS-noise exposure and evaluated the threshold shifts, structural damages to outer hair cells (OHCs), and ribbon synapses. We also verified whether GV1001 attenuates oxidative stress at the level of lipid peroxidation or protein nitration in OHCs 1 h after exposure to white noise at 120 dB SPL. GV1001-treated mice exhibited significantly less hearing threshold shifts over 2 weeks and preserved OHCs and ribbon synapses compared with controls. Similarly, dexamethasone-treated mice showed comparable protection against NIHL. Importantly, GV1001 markedly attenuated oxidative stress in OHCs. Our findings suggest that GV1001 may protect against NIHL by lowering oxidative stress and may serve as preventive or adjuvant treatment.

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Neural stem cells injured by oxidative stress can be rejuvenated by GV1001, a novel peptide, through scavenging free radicals and enhancing survival signals

Cited by 37 publications

References 34 publications

hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic effects through suppression of TGF‑β signaling

hTERT peptide fragment GV1001 demonstrates radioprotective and antifibrotic effects through suppression of TGF‑β signaling

Neural Stem Cell Death Mechanisms Induced by Amyloid Beta

Outcomes of Peptide Vaccine GV1001 Treatment in a Murine Model of Acute Noise-Induced Hearing Loss

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