7,8-Dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cell death through modulating PI3K/Akt and JNK pathways

Han, Xiaohua; Cheng, Meng-Nan; Chen, Lei; Fang, Hui; Wang, Limin; Li, Xueting; Qu, Zhe

doi:10.1016/j.neulet.2014.08.016

Cited by 21 publications

(21 citation statements)

References 22 publications

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“…It has been reported that the cytoprotective effects of TrkB agonist 7,8-DHF are mediated by activation of PI3K/AKT signaling [19, 25, 26, 36, 37]. First we found that TrkB is expressed in the HK-2 cells (Figure S1 in Supplementary Material available online at http://dx.doi.org/10.1155/2016/5029797).…”

Section: Discussionmentioning

confidence: 61%

7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells

Zhang

Liu

et al. 2016

BioMed Research International

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Acute kidney injury (AKI) is a common syndrome which is strongly linked to high morbidity and mortality. Hypoxia is the leading cause of AKI and the proximal renal tubular cells are the most damaged part in the kidney during this period. It has been observed that 7,8-dihydroxyflavone (7,8-DHF) plays a protective role by acting on antiapoptosis and antioxidative stress. In this study we explored functions of 7,8-DHF in protecting human proximal tubular cell line HK-2 from hypoxia insults. We observed that treatment of 7,8-DHF could improve the viability of ischemic cell. Mechanistically, we found that 7,8-DHF could elevate the expression of cysteine-rich protein 61 (Cyr61), a protective immediate early gene in AKI. In addition, treatment of 7,8-DHF decreased CCAAT/enhancer-binding protein homologous protein (CHOP) expression, which is a marker protein during endoplasmic reticulum (ER) stress activation. Intriguingly, overexpression of Cyr61 significantly reduced CHOP expression. Taken together, our results provide novel insights into the possible protective role of 7,8-DHF by activating Cyr61 signaling and suppressing ER stress in hypoxic HK-2 cells which have potential clinical implications for the treatment of AKI.

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Section: Discussionmentioning

confidence: 61%

7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells

Zhang

Liu

et al. 2016

BioMed Research International

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“…Zhang et al (15) demonstrated that 7,8-DHF exerts cytoprotective effects against oxidative stress by scavenging intracellular ROS and enhancing PI3K/Akt signaling in lung fibroblasts. Han et al (16) also indicated that 7,8-DHF prevents hydroxydopamine-induced DNA damage and apoptosis by directly scavenging intracellular ROS in PC12 pheochromocytoma cells. Recently, 7,8-DHF has been shown to activate the ERK-and Akt-Nrf2 signaling cascades in cultured human HaCaT keratinocytes, leading to the upregulation of HO-1 and cytoprotection against oxidative stress (19).…”

Section: Discussionmentioning

confidence: 99%

“…The flavone derivative 7,8-dihydroxyflavone (7, has been identified as a selective agonist for tyrosine receptor kinase B (TrkB) and activates its downstream signaling cascade (11), thereby exerting potent neuroprotective and neurotrophic effects against Parkinson's disease and other neurological disorders (12). Previous studies have demonstrated that 7,8-DHF is a potent antioxidant and that it protects cells against oxidative stress-induced damage by reducing ROS production (13)(14)(15)(16). In our previous studies, we demonstrated that due to its anti-inflammatory properties 7,8-DHF may be used in the treatment of inflammatory and neurodegenerative diseases (17,18).…”

Section: The Cytoprotective Effects Of 78-dihydroxyflavone Against Omentioning

confidence: 92%

The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K/Akt and ERK pathways in C2C12 myoblasts

Kang

Choi

Han

et al. 2015

International Journal of Molecular Medicine

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Recent studies have demonstrated that 7,8-dihydroxyflavone (7,8-DHF), a newly identified tyrosine kinase receptor B agonist, is a potent antioxidant agent. The present study was designed to confirm the cytoprotective effects of 7,8-DHF against oxidative stress-induced cellular damage and to further elucidate the underlying mechanisms in C2C12 myoblasts. We found that 7,8-DHF attenuated hydrogen peroxide (H2O2)-induced growth inhibition and exhibited scavenging activity against intracellular reactive oxygen species (ROS) that were induced by H2O2. We also observed that 7,8-DHF significantly attenuated H2O2-induced comet tail formation, and decreased the phosphorylation levels of the histone, H2AX, as well as the number of Annexin V-positive cells, suggesting that 7,8-DHF prevents H2O2-induced DNA damage and cell apoptosis. Furthermore, 7,8-DHF increased the levels of heme oxygenase-1 (HO-1), which is a potent antioxidant enzyme associated with the induction and phosphorylation of nuclear factor-erythroid 2-related factor 2 (Nrf2), as well as the translocation of Nrf2 from the cytosol to the nucleus. However, the protective effects of 7,8-DHF against H2O2 -induced ROS generation and growth inhibition were significantly diminished by zinc protoporphyrin IX, an HO-1 competitive inhibitor. Moreover, the potential of 7,8-DHF to mediate HO-1 induction and protect the cells against H2O2 -mediated growth inhibition was abrogated by transient transfection with Nrf2-specific small interfering RNA (siRNA). In addition, 7,8-DHF induced the activation of Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K), and also that of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK), while specific inhibitors of PI3K and ERK, but not a p38 MAPK inhibitor, abolished the 7,8-DHF induced HO-1 upregulation and Nrf2 induction and phosphorylation. Collectively, these results demonstrate that 7,8-DHF augments the cellular antioxidant defense capacity through activation of the Nrf2/HO-1 pathway, which also involves the activation of the PI3K/Akt and ERK pathways, thereby protecting C2C12 myoblasts from H2O2-induced oxidative cytotoxicity.

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“…Since studies have shown that 7,8‐DHF can specifically activate TrkB to function by way of activating PLC, PI3K/Akt and ERK1/2, in our studies, we have benefited from the wide use of the antagonists to these signaling factors, that is U73122 for PLC‐γ, LY294002 for PI3K/Akt and PD98059 for ERK1/2 …”

Section: Introductionmentioning

confidence: 99%

7,8‐dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression

Tian

et al. 2018

Clin Exp Pharma Physio

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Although 7,8-dihydroxyflavone (7,8-DHF), a synthetic agonist specific for tyrosine kinase receptor B (TrkB), has been reported to promote intestinal dynamics, its effect on gastric dynamics has not been studied as yet. In this study, we explored how 7,8-DHF affected the carbachol (CCh)-induced contraction of rat gastric muscle by way of measuring the contractile tension of muscular strips. We found that although 7,8-DHF did not directly cause contraction of gastric muscle, it enhanced CCh-induced, instead of substance P- or high K -induced, contraction. The enhancing role of 7,8-DHF was partially blocked by ANA-12, a blocker specific for TrkB the activation of which in the gastric strips was evidenced by its phosphorylation. Although 7,8-DHF alone did not activate : phospholipase C (PLC)-γ in gastric muscle, CCh did, and importantly, the combined treatment with CCh + 7,8-DHF activated more PLC-γ. U73122, an antagonist to PLC-γ blocked both the CCh-induced and the 7,8-DHF-enhanced/CCh-induced contraction by ~30%. To pursue how 7,8-DHF could augment CCh-activated PLC-γ phosphorylation, we first examined the effect of 7,8-DHF on the expression of muscarinic receptors in gastric muscle and found that 7,8-DHF specifically increased M3 but not M2 receptor expression possibly through TrkB/Akt (protein kinase B) pathway because the Akt antagonist, LY294002 significantly suppressed the 7,8-DHF-augmemted M3 expression and completely blocked the 7,8-DHF-enhanced cholinergic contraction. Supporting the result, Akt phosphorylation in the gastric muscle was enhanced by 7,8-DHF treatment. The in vivo experiment showed that orally fed 7,8-DHF increased gastric emptying rate. The results imply a possibility that 7,8-DHF may be developed into a drug in the future for enhancing gastric dynamics.

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7,8-Dihydroxyflavone protects PC12 cells against 6-hydroxydopamine-induced cell death through modulating PI3K/Akt and JNK pathways

Cited by 21 publications

References 22 publications

7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells

7,8-DHF Treatment Induces Cyr61 Expression to Suppress Hypoxia Induced ER Stress in HK-2 Cells

The cytoprotective effects of 7,8-dihydroxyflavone against oxidative stress are mediated by the upregulation of Nrf2-dependent HO-1 expression through the activation of the PI3K/Akt and ERK pathways in C2C12 myoblasts

7,8‐dihydroxyflavone enhanced cholinergic contraction of rat gastric smooth muscle via augmenting muscarinic M3 receptor expression

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