Salidroside and FG-4592 ameliorate high glucose-induced glomerular endothelial cells injury via HIF upregulation

Xie, Ruiyan; Fang, Xue-ling; Zheng, Xiaobin; Lv, Weize; Li, Yijie; Rage, Hamze Ibrahim; He, Qiao-lan; Zhu, Weiping; Cui, Tongxia

doi:10.1016/j.biopha.2019.109175

Cited by 31 publications

(28 citation statements)

References 35 publications

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“…As shown in Fig. 6a, after FG-4592 treatment (50 μM) [35,36], the expression of HIF-1α, PPAR-γ and PKM2 were all up-regulated; however, in the Sora + Sim group, the up-regulation after FG-4592 treatment was reversed. However, after application of the HIF-1α inhibitor BAY87-2243 (10 mM) [37], the expression of HIF-1α, PPAR-γ and PKM2 were all down-regulated.…”

Section: Sim Enhances the Sensitivity Of Sora By Down-regulating The mentioning

confidence: 87%

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

150

127

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Background: Hepatocellular carcinoma (HCC) is a common primary malignant tumor which usually progresses to an advanced stage because of late diagnosis. Sorafenib (Sora) is a first line medicine for advanced stage HCC; however, it has been faced with enormous resistance. Simvastatin (Sim) is a cholesterol-lowering drug and has been reported to inhibit tumor growth. The present study aims to determine whether Sora and Sim co-treatment can improve Sora resistance in HCC. Methods: The HCC cell line LM3 and an established Sora-resistant LM3 cell line (LM3-SR) were used to study the relationship between Sora resistance and aerobic glycolysis. Cell proliferation, apoptosis and glycolysis levels were analyzed by western blotting, flow cytometry analysis and biomedical tests. A xenograft model was also used to examine the effect of Sim in vivo. Detailed mechanistic studies were also undertaken by the use of activators and inhibitors, and lentivirus transfections.Results: Our results demonstrated that the resistance to Sora was associated with enhanced aerobic glycolysis levels. Furthermore, LM3-SR cells were more sensitive to Sim than LM3 cells, suggesting that combined treatment with both Sora and Sim could enhance the sensitivity of LM3-SR cells to Sora. This finding may be due to the suppression of the HIF-1α/PPAR-γ/PKM2 axis. Conclusions: Simvastatin can inhibit the HIF-1α/PPAR-γ/PKM2 axis, by suppressing PKM2-mediated glycolysis, resulting in decreased proliferation and increased apoptosis in HCC cells, and re-sensitizing HCC cells to Sora.

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Section: Sim Enhances the Sensitivity Of Sora By Down-regulating The mentioning

confidence: 87%

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Jiao

Dai

Mao

et al. 2020

J Exp Clin Cancer Res

150

127

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“…Xie et al recently demonstrated that the inhibition of PDH activity ameliorated glomerular endothelial cells (GECs) injury associated with diabetic nephropathy. This effect was related to the glucose metabolism increase due to the HIF1-αmediated transcription of genes associated with glycolysis [ 136 ]. Anemia is one of the consequences of advanced CKD.…”

Section: Dual Role Of Hypoxia In Acute and Chronic Disease Conditimentioning

confidence: 99%

Hypoxia and HIF Signaling: One Axis with Divergent Effects

Corrado

Fontana

2020

IJMS

122

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The correct concentration of oxygen in all tissues is a hallmark of cellular wellness, and the negative regulation of oxygen homeostasis is able to affect the cells and tissues of the whole organism. The cellular response to hypoxia is characterized by the activation of multiple genes involved in many biological processes. Among them, hypoxia-inducible factor (HIF) represents the master regulator of the hypoxia response. The active heterodimeric complex HIF α/β, binding to hypoxia-responsive elements (HREs), determines the induction of at least 100 target genes to restore tissue homeostasis. A growing body of evidence demonstrates that hypoxia signaling can act by generating contrasting responses in cells and tissues. Here, this dual and controversial role of hypoxia and the HIF signaling pathway is discussed, with particular reference to the effects induced on the complex activities of the immune system and on mechanisms determining cell and tissue responses after an injury in both acute and chronic human diseases related to the heart, lung, liver, and kidney.

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“…In addition, one recent study showed FG-4592 ameliorated the cisplatin-induced acute kidney injury through regulating apoptosis and inflammation (Yang et al, 2018). FG-4592 also had protective effects against atherosclerosis and high glucose-induced glomerular endothelial cells injury through upregulating HIF (Xie et al, 2019;Zhang et al, 2019). For cancer cells, HIFs increases the proliferation and metastasis of cancer cells by regulating the expression of some target genes (Keith et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

Long

Chen

et al. 2020

Front. Pharmacol.

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Doxorubicin (DOX) is broadly used in treating various malignant tumors. However, its cardiotoxicity limits its clinical use. Roxadustat (FG-4592) is a new hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) inhibitor and has been approved for treating anemia in chronic kidney diseases (CKD) patients. However, the role of FG-4592 in DOX-induced cardiotoxicity remains unknown. In this study, mouse cardiac function was evaluated by echocardiography, plasma LDH/CK-MB, and heart HE staining. Cell viability, apoptosis, oxidative stress, inflammation, and HIF-target genes were evaluated in mouse cardiac tissue and cardiac cells exposed to DOX with FG-4592 pretreatment. DOX-sensitive HepG2 and MCF-7 cell lines were used to evaluate FG-4592 effect on the anticancer activity of DOX. We found that FG-4592 alleviated DOX-induced cardiotoxicity shown by the protection against cardiac dysfunction, cardiac apoptosis, and oxidative stress without the effect on inflammatory response. FG-4592 alone did not change the cardiac function, cardiomyocyte morphology, oxidative stress, and inflammation in vivo. FG-4592 could protect cardiomyocytes against DOX-induced apoptosis and ROS production in line with the upregulation of HIF-1a and its target genes of Bcl-2 and SOD2. Importantly, FG-4592 displayed anticancer property in cancer cells treated with or without DOX. These findings highlighted the protective effect of FG-4592 on DOX-induced cardiotoxicity possibly through upregulating HIF-1a and its target genes antagonizing apoptosis and oxidative stress.

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Salidroside and FG-4592 ameliorate high glucose-induced glomerular endothelial cells injury via HIF upregulation

Cited by 31 publications

References 35 publications

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

Hypoxia and HIF Signaling: One Axis with Divergent Effects

Antianemia Drug Roxadustat (FG-4592) Protects Against Doxorubicin-Induced Cardiotoxicity by Targeting Antiapoptotic and Antioxidative Pathways

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