The Neuroprotection of Liraglutide Against Ischaemia-induced Apoptosis through the Activation of the PI3K/AKT and MAPK Pathways

Zhu, Huili; Zhang, Yusheng; Shi, Zhongshan; Lu, Dan; Li, Tingting; Ding, Yan; Ruan, Yiwen; Xu, Anding

doi:10.1038/srep26859

Cited by 148 publications

(133 citation statements)

References 40 publications

(42 reference statements)

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“…Indeed, GLP-1 antagonized the senescence of endothelial cells evoked by 5FU. ERK1/2 was required for this protective effect of GLP-1 against 5FU-triggered senescence and eNOS downregulation, consistent with the previous data reporting the positioning this kinase downstream of GLP-1 (Favaro et al, 2012;Kang et al, 2015;Zhu et al, 2016). Experiments with multiple signalling inhibitors also suggested that the effect of GLP-1's action was secondary to PKA and PI3K, which have both been shown to mediate GLP-1's effects previously (Erdogdu et al, 2010;Oeseburg et al, 2010;Favaro et al, 2012;Chien et al, 2014;Zhu et al, 2016).…”

Section: Figuresupporting

confidence: 77%

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5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Altieri

Murialdo

Barisione

et al. 2017

British J Pharmacology

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BACKGROUND AND PURPOSE5-fluorouracil (5FU) and its prodrug, capecitabine, can damage endothelial cells, whilst endothelial integrity is preserved by glucagon-like peptide 1 (GLP-1). Here, we studied the effect of 5FU on endothelial senescence and whether GLP-1 antagonizes it. EXPERIMENTAL APPROACHEA.hy926 cells were exposed to 5FU or sera from patients taking capecitabine, with or without pre-incubation with GLP-1. Senescence was identified by expression of senescence-associated β-galactosidase and p16INK4a and reduced cell proliferation. Soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1) and CD146 (marker of endothelial injury) were measured by ELISA before and at completion of capecitabine chemotherapy. RT-PCR, western blotting, functional experiments with signalling inhibitors and ERK1/2 silencing were performed to characterize 5FU-induced phenotype and elucidate the pathways underlying 5FU and GLP-1 activity. KEY RESULTSBoth 5FU and sera from capecitabine-treated patients stimulated endothelial cell senescence. 5FU-elicited senescence occurred via activation of p38 and JNK, and was associated with decreased eNOS and SIRT-1 levels. Furthermore, 5FU up-regulated VCAM1 and TYMP (encodes enzyme activating capecitabine and 5FU), and sVCAM-1 and CD146 concentrations were higher after than before capecitabine chemotherapy. A non-significant trend for higher ICAM1 levels was also observed. GLP-1 counteracted 5FU-initiated senescence and reduced eNOS and SIRT-1 expression, this protection being mediated by GLP-1 receptor, ERK1/2 and, possibly, PKA and PI3K. CONCLUSIONS AND IMPLICATIONS5FU causes endothelial cell senescence and dysfunction, which may contribute to its cardiovascular side effects. 5FU-triggered senescence was prevented by GLP-1, raising the possibility of using GLP-1 analogues and degradation inhibitors to treat 5FU and capecitabine vascular toxicity.

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Section: Figuresupporting

confidence: 77%

“…Given the established role of ERK1/2 in GLP-1 signalling (Favaro et al, 2012;Kang et al, 2015;Zhu et al, 2016), we explored the effect of silencing ERK1/2 on the protective effect of GLP-1. ERK1/2 silencing prevented the GLP-1-induced inhibition of 5FU-induced senescence ( Figure 6A).…”

Section: Bjp P Altieri Et Almentioning

confidence: 99%

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Altieri

Murialdo

Barisione

et al. 2017

British J Pharmacology

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“…Activation of the PI3K/AKT pathway has been demonstrated to have neuroprotective effects against ischemia-induced neuron apoptosis (36). The Jak2/Stat3 cascade has been documented to be regulated by the PI3K/AKT pathway, mediating the functions in regulation of cell proliferation, anti-apoptosis and anti-senescence, cancer generation and migration, tissue development and memory formation (15)(16)(17).…”

Section: Discussionmentioning

confidence: 99%

“…The PI3K/AKT pathway is critically important in multiple physiological and pathological processes by regulating various downstream signaling molecules (36). Activation of the PI3K/AKT pathway has been demonstrated to have neuroprotective effects against ischemia-induced neuron apoptosis (36).…”

Section: Discussionmentioning

confidence: 99%

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

Gao

Zhai

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Stroke, characterized by a disruption of blood supply to the brain, is a major cause of morbidity and mortality worldwide. Although humanin, a 24-amino acid polypeptide, has been identified to have multiple neuroprotective functions, the level of humanin in plasma has been demonstrated to decrease with age, which likely limits the effects against stroke injury. A potent humanin analogue, S14G-humanin (HNG), generated by replacement of Ser14 with glycine, has been demonstrated to have 1,000-fold stronger biological activity than humanin. The present study established an in vitro oxygen glucose deprivation/reoxygenation (OGD/R) model using SH-SY5Y neuroblastoma cells to mimic the in vivo ischemia/reperfusion injury in stroke. Adding HNG (0-10 µg/l) to SH-SY5Y cells to different extents blocked OGD/R-induced reduction of cell viability and antioxidative capacity, as well as decreased the elevated apoptosis rate induced by OGD/R, with the most evident effects at 1 µg/l HNG. Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (Stat3) signaling was attenuated in OGD/R processes, yet reactivated with HNG treatment. FLLL32 (5 µM), a specific inhibitor of the signal, abolished effects of HNG on anti-apoptosis and antioxidation in OGD/R processes. Co-treatment with HNG and FLLL32 failed to interrupt upregulation of cytochrome c, B-cell lymphoma 2-associated X protein and cleaved caspase-3 provoked by OGD/R. Similar to FLLL32, Jak2/Stat3 signaling activated by HNG was also repressed by inhibitor of phosphoinositide 3-kinase (PI3K; 10 µM LY294002) or protein kinase B (AKT; 5 µM MK-2206 2HCl). These data collectively indicated that HNG has neuroprotective effects against OGD/R by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway, suggesting that HNG may be a promising agent in the management of stroke.

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“…Ayrıca diğer çalışmalarda da orta serebral arter oklüzyonu sonrasında kan dolaşımını antioksidant etkisiyle artırdığı gösterilmiştir. Bu yararlı etkiler serbest oksijen radikallerinin azaltılması ve PI3K/Akt ve MAPK yolu ile ortaya çıktığı bildirilmektedir (21). Ob/ob, db/db farelerde ve yüksek yağ ile beslenen farelerde dentat girusdaki projentör hücre çoğalmasını artırarak nörogenezisi sağladığı gösterilmiştir (22) Parkinson hastalığının deneysel modellerinde ise eksendin-4 uygulamasının nörogenezisi, substantia nigradaki dopaminerjik nöron miktarını artırdığı gösterilmiştir (23).…”

Section: Glp-1'in Santral Sinirunclassified

The Effects of Glucagon Like Peptid-1 on Nervous System and Appetite

Özaçmak¹,

Bayraktaroğlu²

2017

Turk J Diab Obes

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ÖZET ABSTRACTGlucagon-like peptide-1(GLP-1) is a gut hormone secreted from L cells of the small intestine in response to food ingestion, and facilitates glucose-dependent insülin secretion. GLP-1 is also a neurotransmitter synthesized by a small population of neurons in the nucleus of the solitary tract in the caudal brainstem. Currently, the GLP-1 receptor agonists exendin-4, liraglutide and lixisenatide are approved for treatment of Type 2 diabetes mellitus (T2DM). The distribution of GLP-1 receptors in the brain suggests they play a central role in the regulation of neuronal activity and protect the brain tissue. Several studies have demonstrated the therapeutic effect of GLP-1 analog on animal models of Alzheimer disease, Parkinson disease and stroke. GLP-1 acts as a growth factor in the brain, and has been shown to induce neurite outgrowth and to protect against oxidative stress and reduces apoptosis. GLP-1 receptor agonists that cross the bloodbrain barrier can directly impact brain function independent of vagal afferent stimulation. It is clear that the central GLP-1 system plays a role in the regulation of food intake. Increasing evidence shows that central or peripheral GLP-1 administration reduces food intake in rodents and man. Furthermore, because of the suppression of appetite also induced by GLP-1 and the subsequent bodyweight loss in response to the prolonged administration of the peptide, GLP-1-derivative drugs have also been approved for the treatment of obesity. In this review, the neuroprotective effects of GLP-1 in the nervous system and central effects on appetite were discussed.

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The Neuroprotection of Liraglutide Against Ischaemia-induced Apoptosis through the Activation of the PI3K/AKT and MAPK Pathways

Cited by 148 publications

References 40 publications

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

5‐fluorouracil causes endothelial cell senescence: potential protective role of glucagon‐like peptide 1

Humanin analogue, S14G-humanin, has neuroprotective effects against oxygen glucose deprivation/reoxygenation by reactivating Jak2/Stat3 signaling through the PI3K/AKT pathway

The Effects of Glucagon Like Peptid-1 on Nervous System and Appetite

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