Glibenclamide, a diabetic drug, prevents acute radiation-induced liver injury of mice via up-regulating intracellular ROS and subsequently activating Akt-NF-κB pathway

Liu, Hu; Wang, Qianqian; Zhao, Weihong; Huang, Ziyun; Chen, Wei You; Yang, Yue; Cui, Jianguo; Liu, Cong; Zhao, Hainan; Guo, Jiaming; Zhang, Pei; Fu, Guosheng; Li, Bailong; Cai, Jianming

doi:10.18632/oncotarget.16501

Cited by 21 publications

(12 citation statements)

References 24 publications

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“…Oxidative stress is an important factor causing mitochondrial dysfunction 34 . Moreover, reactive oxygen species (ROS) play a key role in cell apoptosis 35 . Therefore, we examined the effect of Glaucocalyxin A on ROS generation in HOS and MG-63 cells.…”

Section: Resultsmentioning

confidence: 99%

Glaucocalyxin A exerts anticancer effect on osteosarcoma by inhibiting GLI1 nuclear translocation via regulating PI3K/Akt pathway

et al. 2018

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Osteosarcoma, the most common malignant bone tumor with recurring disease or lung metastases, has become one of the leading causes of death in humans. In the current study, we made an investigation on the anticancer effect of glaucocalyxin A, a bioactive ent-kauranoid diterpenoid isolated from Rabdosia japonica var., and unraveled the underlying mechanisms. Here, we found that Glaucocalyxin A inhibited the cell viability of numerous osteosarcoma cells. Our results showed that Glaucocalyxin A exerted the pro-apoptotic effect on human osteosarcoma cells, MG-63 and HOS cells. Glaucocalyxin A induced apoptosis by mitochondrial apoptotic pathway through several steps including increasing the Bax/Bcl-2 ratio, triggering the intracellular reactive oxygen species (ROS) generation, reducing mitochondrial membrane potential (MMP), and inducing cleavage of caspase-9 and caspase-3. We demonstrated that Glaucocalyxin A induced apoptosis via inhibiting Five-zinc finger Glis 1 (GLI1) activation by overexpression and knockdown of GLI1 in vitro. We also found that Glaucocalyxin A inhibited GLI1 activation via regulating phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling pathway. We further confirmed our findings by using PI3K activator and inhibitor to verify the inhibitory effect of Glaucocalyxin A on PI3K/Akt/GLI1 pathway. Moreover, our in vivo study revealed that glaucocalyxin A possessed a remarkable antitumor effect with no toxicity in the xenograft model inoculated with HOS tumor through the same mechanisms as in vitro. In conclusion, our results suggested that Glaucocalyxin A induced apoptosis in osteosarcoma by inhibiting nuclear translocation of GLI1 via regulating PI3K/Akt signaling pathway. Thus, Glaucocalyxin A might be a potential candidate for human osteosarcoma in the future.

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Section: Resultsmentioning

confidence: 99%

Glaucocalyxin A exerts anticancer effect on osteosarcoma by inhibiting GLI1 nuclear translocation via regulating PI3K/Akt pathway

et al. 2018

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“…31 Glibenclamide is had antioxidant properties and has the hepatoprotective and neuroprotective effects that are mediated through upregulation of intracellular reactive oxygen species and inhibit of apoptosis pathway, respectively. 32,33 Diabetic animals showed increases in the levels of serum sodium levels that indicating the risk of development of renal failure. 34 The animals treated with MECZ, showed a significant reduction in serum sodium level compared with diabetic animals, which indicates that this plant has a nephroprotective effect.…”

Section: Discussionmentioning

confidence: 99%

Antioxidant and Antidiabetic Activities of Methanolic extract of Bark of Cinnamomum zeylanicum in Diabetic Rats

Singh

Parasuraman

Kathiresan

2020

FRA

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Background: Cinnamomum zeylanicum or Ceylon cinnamon is used for the management of dyspepsia, dysmenorrhea, memory loss and tremor. It is also traditionally recommended for the management of diabetes. Further studies are required to explore the antioxidant and antidiabetic activity of various extracts of bark of C. zeylanicum. Hence, the present study is planned to investigate the antioxidant and antidiabetic activities of methanolic extract of barks of C. zeylanicum. Methods: Bark of C. zeylanicum was extracted with methanol, ethanol and acetone and its antioxidant activity was studied using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) free radical scavenging assays. Acute toxic effect of methanolic extract of C. zeylanicum (MECZ) studied as per the method described in OECD Guideline for testing of chemicals (Test Guideline 423). MECZ was studied for its antidiabetic effect using streptozotocin-induced diabetic rats. Results: In both DPPH and ABTS free radical scavenging assay, methanolic and acetone extracts exhibited free radical scavenging activity, respectively. In acute toxicity testing, MECZ did not show any significant toxic signs up to 2000 mg/kg, hence the antidiabetic activity of MECZ was carried out at the dose levels of 125, 250 and 500 mg/kg. MECZ showed antidiabetic activity from 2 nd week of the experiment onward. In the biochemical analysis, MECZ treated animals showed significant decreases in the levels of ALP and urea when compared with control. In lipid profile analysis, diabetic animals and diabetic animals treated glibenclamide showed significant increases in the levels of total cholesterol when compared with normal control and MECZ prevented the STZ-induced hyperlipidemia. At the end of the study, diabetic animals and diabetic animals treated with glibenclamide and MECZ showed significant decreases in the level of insulin when compared with the control group. In the histopathological analysis, sections from the liver, pancreas and kidney of the diabetic animals showed mid-to-moderate toxic effects and glibenclamide and MECZ 500 mg/kg prevented the STZ-induced cellular changes. Conclusion: The MECZ exhibited significant antioxidant and antidiabetic activities.

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“…22 Radiation-induced liver damage severely restricts the increase of the tumor radiotherapy dose and the reirradiation of hepatobiliary tumors. 23 The irradiation techniques used in previous reports were mostly 2-dimensional block or 3-dimensional conformal, and almost all of the liver is irradiated, 24,25 which makes it difficult to compare irradiated and nonirradiated areas in 1 animal. Limitations of irradiation technology, and liver movement due to diaphragmatic movement and gastrointestinal motility, easily lead to poor irradiation accuracy.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Analysis of Radiation-Induced Acute Liver Damage in a Rabbit Model

et al. 2019

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Radiation-induced liver damage (RILD) has become a limitation in radiotherapy for hepatocellular carcinoma. We established a rabbit model of RILD by CyberKnife. Electron microscopy analysis revealed obvious nuclear atrophy and disposition of fat in the nucleus after irradiation. We then utilized a mass spectrometry-based label-free relative quantitative proteomics approach to compare global proteomic changes of rabbit liver in response to radiation. In total, 2365 proteins were identified, including 338 proteins that were significantly dysregulated between irradiated and nonirradiated liver tissues. These differentially expressed proteins included USP47, POLR2A, CSTB, MCFD2, and CSNK2A1. Real-time polymerase chain reaction confirmed that USP47 and CABLES1 transcripts were significantly higher in irradiated liver tissues, whereas MCFD2 and CSNK2A1 expressions were significantly reduced. In Clusters of Orthologous Groups of proteins analysis, differentially expressed proteins were annotated and divided into 24 categories, including posttranslational modification, protein turnover, and chaperones. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the enriched pathways in dysregulated proteins included the vascular endothelial growth factors (VEGF) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, and the adipocytokine signaling pathway. The identification of proteins and pathways is crucial toward elucidating the radiation response process of the liver, which may facilitate the discovery of novel therapeutic targets.

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Glibenclamide, a diabetic drug, prevents acute radiation-induced liver injury of mice via up-regulating intracellular ROS and subsequently activating Akt-NF-κB pathway

Cited by 21 publications

References 24 publications

Glaucocalyxin A exerts anticancer effect on osteosarcoma by inhibiting GLI1 nuclear translocation via regulating PI3K/Akt pathway

Glaucocalyxin A exerts anticancer effect on osteosarcoma by inhibiting GLI1 nuclear translocation via regulating PI3K/Akt pathway

Antioxidant and Antidiabetic Activities of Methanolic extract of Bark of Cinnamomum zeylanicum in Diabetic Rats

Proteomic Analysis of Radiation-Induced Acute Liver Damage in a Rabbit Model

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