bFGF-Regulating MAPKs Are Involved in High Glucose-Mediated ROS Production and Delay of Vascular Endothelial Cell Migration

Luo, Hua; Cai, Wan Hui; Wang, Tao; Ye, Hong Bo; Zhu, Yu; Li, Sha; Duan, Yuan Meng; Sun, Cong; Xuan, Yuan; Jin, Li

doi:10.1371/journal.pone.0144495

Cited by 22 publications

(22 citation statements)

References 32 publications

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“…Concentration of HG in in vitro fibroblast experiments is typically higher than the glucose levels in physiological levels of glucose in diabetic patients (>11.1 mM); 25-50 mM HG has been used for DM study in previous reports (10,23,24). In the present study, 35 mM HG was used to perform the experiments.…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog‑c‑Jun N‑terminal kinase‑zinc finger protein Gli1 signaling protects against high glucose concentration‑induced reactive oxygen species generation in human fibroblasts

Song

Wang

et al. 2018

Exp Ther Med

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Abstract. Diabetes mellitus (DM) complications affect patients and cause varying damage. Skin ulcers exhibit difficulties in wound healing, and the regulatory basis for this remains unclear. High glucose concentration (HG) was utilized to mimic DM in cultured cells. Reverse transcription-quantitative polymerase chain reaction, western blotting and fluorescence dye analyses were performed to analyze the effects of hedgehog signaling in regulation of HG or diabetes in fibroblasts. HG-stress suppressed hedgehog-signaling gene expression, whereas the apoptosis and inflammatory response markers, Caspase-3 and plasminogen activator inhibitor-1 (PAI1), respectively, were induced. In addition, HG-stress inhibited the fibroblast proliferation rate. In parallel, treatment with Sonic hedgehog (Shh), an activator of hedgehog signaling, together with HG eliminated effects of HG on expression of hedgehog-signaling genes, Caspase-3 and PAI1, and rescued the cell proliferation rate in fibroblasts. In addition, Shh application activated c-Jun N-terminal kinase (JNK), which was inhibited by HG stress. sp600125, a JNK specific inhibitor, treatment inhibited the effect of Shh on fibroblast proliferation and hedgehog-signaling marker gene expression. Furthermore, zinc finger protein Gli1 (Gli1) overexpression partially eliminated the effect of HG and sp600125 on fibroblast proliferation, and reduced HG-induced ROS generation in fibroblasts. Together, these results indicate that HG stress inhibits hedgehog signaling, and Shh-JNK-Gli1 pathway positively regulates HG-induced damage on fibroblasts.

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Section: Discussionmentioning

confidence: 99%

Sonic hedgehog‑c‑Jun N‑terminal kinase‑zinc finger protein Gli1 signaling protects against high glucose concentration‑induced reactive oxygen species generation in human fibroblasts

Song

Wang

et al. 2018

Exp Ther Med

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“…Based on their work with acute myocardial ischemia/reperfusion (I/R) injuries, Wang et al reported that bFGF significantly reduces apoptosis by inhibiting ROS-induced mitochondrial dysfunction through expression of proteins related to the MAPK/ERK and PI3K/AKT signaling pathways [ 48 ]. Furthermore, related studies showed that, in the case of high-glucose-induced ROS generation, cell migration and skin regeneration are promoted by activation of the PI3K-Rac1-JNK pathway and regulation of MAPK family proteins via bFGF signaling [ 49 – 51 ]. This study indicated that treatment of selenium effectively changed the activation of AKT and ERK pathway.…”

Section: Discussionmentioning

confidence: 99%

Additive effect of bFGF and selenium on expansion and paracrine action of human amniotic fluid-derived mesenchymal stem cells

et al. 2018

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BackgroundMesenchymal stem cell-derived conditioned medium (MSC-CM) has emerged as a promising cell-free tool for restoring degenerative diseases and treating traumatic injuries. The present study describes the effect of selenium as a reactive oxygen species (ROS) scavenger and its additive effect with basic fibroblast growth factor (bFGF) on in vitro expansion of amniotic fluid (AF)-MSCs and the paracrine actions of AF-MSC-CM as well as the associated cellular and molecular mechanisms.MethodsIn this study, we obtained CM from human AF-MSCs cultured with selenium. The stemness of selenium-treated AF-MSCs was evaluated by cell growth and differentiation potential. Human fibroblasts were treated with AF-MSC-CM and analyzed for cell signaling changes. For in vivo wound healing assay, ICR mice with a full-thickness skin wound were used.ResultsSelenium played a critical role in in vitro expansion of AF-MSCs through activation of the AKT-ERK1/2, Smad2, and Stat3 signaling pathways along with inactivation of GSK3β. When administered together with bFGF, it showed remarkable effect in inhibiting ROS accumulation and preserving their multipotency. Proliferation and migration of human dermal fibroblasts and in vivo wound healing were improved in the CMs derived from AF-MSCs exposed to selenium and bFGF, which was caused by the Smad2, AKT-MEK1/2-ERK, and NFκB signaling triggered by the paracrine factors of AF-MSCs, such as TGF-β, VEGF, and IL-6. Our results suggest the following: (a) supplementation of selenium in AF-MSC culture contributes to in vitro expansion and preservation of multipotency, (b) ROS accumulation causes progressive losses in proliferative and differentiation potential, (c) the separate activities of bFGF and selenium in MSCs exert an additive effect when used together, and (d) the additive combination improves the therapeutic effects of AF-MSC-derived CMs on tissue repair and regeneration.ConclusionAntioxidants, such as selenium, should be considered as an essential supplement for eliciting the paracrine effects of MSC-CMs.Electronic supplementary materialThe online version of this article (10.1186/s13287-018-1058-z) contains supplementary material, which is available to authorized users.

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“…ERK and JNK are well-known MAPKs, which are involved in diverse aspect of biology, including HG-mediated damage of VECs (9). In fibroblasts, NF-κB signaling was identified to function upstream of JNK (13).…”

Section: Association Between Nf-κb and Erk/jnk Signaling In Vecsmentioning

confidence: 99%

“…Recently, an inhibition phenomenon similar to that in mice was observed in keratinocytes cultured in a high-glucose (HG) environment (8), which suggested that HG has a significant role in delaying wound repair. Mitogen-associated protein kinases (MAPKs) were identified to be involved in reactive oxygen species (ROS) production upon HG stress (9). However, these studies failed to address the detailed cellular regulatory mechanisms involved in this phenomenon.…”

Section: Introductionmentioning

confidence: 99%

Nuclear factor-κB signaling negatively regulates high glucose-induced vascular endothelial cell damage downstream of the extracellular signal-regulated kinase/c-Jun N-terminal kinase pathway

Chen

Guo

Zheng

et al. 2017

Experimental and Therapeutic Medicine

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Abstract. Diabetes mellitus (DM)-induced high blood sugar severely damages vascular endothelial cells (VECs), which are in direct contact with the blood. Diabetic complications cause difficulties in skin wound healing and VECs are important for this process. Previous studies demonstrated that high blood sugar delayed the repair of wounded VECs, but the underlying mechanism has remained elusive. To explore the effects of diabetic conditions on VEC damage, cells were incubated in a medium with high glucose and then subjected to RNA-sequencing based transcriptome analysis. The results revealed that numerous biological processes were altered by HG stress, including extracellular matrix-receptor interaction, NOD-like receptor signaling and the nuclear factor (NF)-κB pathway. HG treatment increased the levels of phosphorylated inhibitor of NF-κB (IκB-α), the key NF-κB signaling regulator as well as the transcripts of plasminogen activator inhibitor-1 and interleukin-8, two inflammatory response markers. Treatment with extracellular signal-regulated kinase (ERK)-and c-Jun N-terminal kinase (JNK)-specific inhibitors U0126 and sp600125, respectively, led to the activation of IκB-α; however, the inhibitor of IκBα phosphorylation Bay11-7082 did not affect ERK and JNK activity, suggesting that ERK/JNK signaling occurs upstream of NF-κB in VECs. The present study provided useful information regarding the effects of diabetes on VECs, which may provide approaches for therapies of diabetes-associated complications in the future.

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bFGF-Regulating MAPKs Are Involved in High Glucose-Mediated ROS Production and Delay of Vascular Endothelial Cell Migration

Cited by 22 publications

References 32 publications

Sonic hedgehog‑c‑Jun N‑terminal kinase‑zinc finger protein Gli1 signaling protects against high glucose concentration‑induced reactive oxygen species generation in human fibroblasts

Sonic hedgehog‑c‑Jun N‑terminal kinase‑zinc finger protein Gli1 signaling protects against high glucose concentration‑induced reactive oxygen species generation in human fibroblasts

Additive effect of bFGF and selenium on expansion and paracrine action of human amniotic fluid-derived mesenchymal stem cells

Nuclear factor-κB signaling negatively regulates high glucose-induced vascular endothelial cell damage downstream of the extracellular signal-regulated kinase/c-Jun N-terminal kinase pathway

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