Cyclo‐glycylproline attenuates hydrogen peroxide‐induced cellular damage mediated by the MDM2‐p53 pathway in human neural stem cells

Abstract

Cyclo‐glycylproline (cGP), a cyclic dipeptide containing a condensation bond between glycine and proline, is produced by the cyclization of the N‐terminal tripeptide of insulin‐like growth factor‐1. Previous studies have shown that cGP administration exerts a neuroprotective effect and enhances the regenerative ability in rats with ischemic brain injury. The efficacy of cGP is medicated by regulating the bioavailability of insulin‐like growth factor‐1 (IGF‐1), however, the molecular mechanisms underlying the neuroprotective effects of cGP on brain damage remains to be elucidated. In the current study, we investigated the cGP‐mediated molecular mechanism in human fetal neural stem cells (hfNSCs) exposed to oxidative stress, which is a key factor affecting the development of several brain diseases, including traumatic brain injury and Parkinson's disease. We found that cGP treatment attenuated oxidative stress‐induced cell death in cultured hfNSCs in a dose‐dependent manner. Transcriptome analysis revealed that under oxidative stress conditions, p53‐mediated signaling was activated, accompanied by upregulation of mouse double minute 2 homolog (MDM2), a p53‐specific E3 ubiquitin ligase, in cGP‐treated hfNSCs. By using a comprehensive protein phosphorylation array, we found that cGP induced the activation of Akt signaling pathway, which enhanced the expression of MDM2, in hfNSCs exposed to oxidative stress. Moreover, the MDM2 inhibitor nutlin‐3 inhibited the protective effect of cGP on oxidative stress‐induced cell death and apoptosis. Therefore, cGP attenuates oxidative stress‐induced cell death mediated by the interplay between IGF‐1 signaling and the MDM2‐p53 pathway in human NSCs. We revealed the molecular mechanism underlying cGP‐induced neuroprotective properties in a model of brain damage.

Metabolic profiling of Mytilus coruscus mantle in response of shell repairing under acute acidification

“…For example, glycylproline, spicamycin, and 2-aminoheptanoic acid (2-AHA) were up-regulated in DN vs. CN comparison. Glycylproline belongs to the family of proline-containing peptides [53], and previous studies have confirmed the protective role of this dipeptide during the cellular damage process through wound healing, and cell and tissue regeneration [54][55][56]. Spicamycin is a nucleoside antibiotic containing fatty acids of various chain lengths (C12-C18), and shows potent antitumor activity against certain human tumor cell lines in vitro [57,58].…”

A systematic exploration of unexploited genes for oxidative stress in Parkinson’s disease

“…A transcriptomic meta-analysis was conducted on 122 paired RNA sequencing (RNA-seq) datasets [26][27][28][29][30][31][32][33] from cultured human cells related to brain to identify DEGs associated with OS. Each pair comprised an OS sample and a matched normal condition sample from the same original study.…”

Exploring Sources, Biological Functions, and Potential Applications of the Ubiquitous Marine Cyclic Dipeptide: A Concise Review of Cyclic Glycine-Proline

“…The cyclic dipeptide maintains IGF-1 homeostasis, activates Akt signalling, and enhances MDM2 E3 ubiquitin ligase expression. This regulation influences the interaction between IGF-1 signalling and MDM2-p53 pathways, resulting in a dose-dependent reduction in hfNSC cell death and apoptosis ( Figure 7 a) [ 67 ]. Importantly, cGP mimics the pharmacological effects of pramiracetam, including enhanced cognition [ 48 , 68 ], reduced anxiety [ 69 ], neuroprotection [ 51 ], analgesia [ 70 ], and antidepressant properties [ 71 ].…”

“… Proposed mechanisms for the effects of cyclic glycine-proline: ( a ) induction of apoptosis in human foetal neural stem cells; ( b ) regulation of IGF-1 homeostasis in the circulatory system and brain tissue. Akt, protein kinase B; cGP , cyclic glycine-proline; ERK, extracellular signal-regulated kinase; IGF-1 or IGF1, insulin-like growth factor 1; IGFBP-3 or IGFBP 3 , insulin-like growth factor-binding protein 3; IGF-1R, insulin-like growth factor 1 receptor; MDM2, mouse double minute 2 homologous protein (Note: Redrawn graphics are based on original artwork by Murotomi [ 67 ] and Guan [ 74 ]. The red arrows on the left indicate the up-regulated levels of related proteins, while the red arrows on the right indicate changes in their relative amounts).…”