Brusatol inhibits the response of cultured beta-cells to pro-inflammatory cytokines in vitro

Turpaev, Kyril; Welsh, Nils

doi:10.1016/j.bbrc.2015.03.124

Cited by 22 publications

(14 citation statements)

References 21 publications

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“…extract improved glucose homeostasis in a streptozotocininjected diabetic rat model (31). As brusatol improved b-cell function in HFD-treated mice, and as brusatol protected pancreatic b cells against the deleterious action of proinflammatory cytokines in vitro (16), the present study was focused on effects of brusatol on islet cells, with particular emphasis on the possibility that brusatol affects protein synthesis (15) and the hypusinated translation initiation factor eIF5A. Indeed, we observed that brusatol reduced hypusination of eIF5A in HFD-fed mice, both in islet endocrine and endothelial cells, suggesting that a decrease of hypusination may mediate a beneficial effect of brusatol on islet function in vivo.…”

Section: Discussionmentioning

confidence: 94%

“…We have recently observed that brusatol has a remarkable efficacy in protecting rat insulin-producing b cells against dysfunction and destruction induced by the proinflammatory cytokines IL-1b and IFN-g, and that this possibly occurred via inhibition of iNOS induction by a posttranscriptional mechanism (16). The biosynthesis of certain proteins is controlled by the translation factor eukaryotic initiation factor 5A (eIF5A) (17).…”

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confidence: 99%

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The protein synthesis inhibitor brusatol normalizes high‐fat diet‐induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination

et al. 2018

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The naturally occurring quassinoid compound brusatol improves the survival of insulin‐producing cells when exposed to the proinflammatory cytokines IL‐1β and IFN‐γ in vitro. The aim of the present study was to investigate whether brusatol also promotes beneficial effects in mice fed a high‐fat diet (HFD), and if so, to study the mechanisms by which brusatol acts. In vivo, we observed that the impaired glucose tolerance of HFD‐fed male C57BL/6 mice was counteracted by a 2 wk treatment with brusatol. Brusatol treatment improved both β‐cell function and peripheral insulin sensitivity of HFD‐fed mice. In vitro, brusatol inhibited β‐cell total protein and proinsulin biosynthesis, with an ED50 of ∼40 nM. In line with this, brusatol blocked cytokine‐induced iNOS protein expression via inhibition of iNOS mRNA translation. Brusatol may have affected protein synthesis, at least in part, via inhibition of eukaryotic initiation factor 5A (eIF5A) hypusination, as eIF5A spermidine association and hypusination in RIN‐5AH cells was reduced in a dose‐ and time‐dependent manner. The eIF5A hypusination inhibitor GC7 promoted a similar effect. Both brusatol and GC7 protected rat RIN‐5AH cells against cytokine‐induced cell death. Brusatol reduced eIF5A hypusination and cytokine‐induced cell death in EndoC‐βHl cells as well. Finally, hypusinated eIF5A was reduced in vivo by brusatol in islet endocrine and endothelial islet cells of mice fed an HFD. The results of the present study suggest that brusatol improves glucose intolerance in mice fed an HFD, possibly by inhibiting protein biosynthesis and eIF5A hypusination.—Turpaev, K., Krizhanovskii, C., Wang, X., Sargsyan, E., Bergsten, P., Welsh, N. The protein synthesis inhibitor brusatol normalizes high‐fat diet‐induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination. FASEB J. 33, 3510–3522 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 94%

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confidence: 99%

The protein synthesis inhibitor brusatol normalizes high‐fat diet‐induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination

et al. 2018

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“…Brusatol is a type of quassinoid obtained from Brucea javanica , an evergreen shrub grown in Southeast Asia 1 . It is known that brusatol and structurally related molecules, including bruceantin, bruceoside and bruceins, are capable of inducing an array of biological responses, exerting anti-inflammatory, antileukemia, and anticancer activities 1 , 2 . The major mechanism responsible for the anticancer activity of brusatol at high micromolar concentrations is inhibition of protein synthesis 1 - 4 .…”

Section: Introductionmentioning

confidence: 99%

“…It is known that brusatol and structurally related molecules, including bruceantin, bruceoside and bruceins, are capable of inducing an array of biological responses, exerting anti-inflammatory, antileukemia, and anticancer activities 1 , 2 . The major mechanism responsible for the anticancer activity of brusatol at high micromolar concentrations is inhibition of protein synthesis 1 - 4 . Importantly, diverse protein targets of brusatol have recently been reported to be involved in its anticancer activity.…”

Section: Introductionmentioning

confidence: 99%

Brusatol-Mediated Inhibition of c-Myc Increases HIF-1α Degradation and Causes Cell Death in Colorectal Cancer under Hypoxia

Kim

et al. 2017

Theranostics

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HIF-1 (hypoxia-inducible factor-1) regulates the expression of ~100 genes involved in angiogenesis, metastasis, tumor growth, chemoresistance and radioresistance, underscoring the growing interest in targeting HIF-1 for cancer control. In the present study, we investigated the molecular mechanisms underlying brusatol-induced HIF-1α degradation and cell death in colorectal cancer under hypoxia (0.5% O2). Under hypoxia, pretreatment of cancer cells with brusatol increased HIF-1α degradation and cancer cell death in a dose-dependent manner. This effect was mediated by activation of prolyl hydroxylases (PHDs), as evidenced by the block of brusatol-induced HIF-1α degradation and cancer cell death by both pharmacological inhibition and siRNA-mediated knockdown of PHDs. In addition, a ferrous iron chelator (2,2'-bypyridyl) blocked brusatol-induced degradation of HIF-1α and cancer cell death in hypoxia by inhibiting PHD activation. We further found that brusatol inhibited c-Myc expression, and showed that overexpression of c-Myc prevented brusatol-induced degradation of HIF-1α and cancer cell death by increasing mitochondrial ROS production and subsequent ROS-mediated transition of ferrous iron to ferric iron. Consistent with these results, treatment of tumor-bearing mice with brusatol significantly suppressed tumor growth by promoting PHD-mediated HIF-1α degradation. Collectively, our results suggest that brusatol-mediated inhibition of c-Myc/ROS signaling pathway increases HIF-1α degradation by promoting PHD activity and induces cell death in colorectal cancer under hypoxia

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“…Brusatol from the seeds of Brucea sumatrana can inhibit the response of cultured beta-cells to pro-inflammatory cytokines in vitro [116]. Brusatol (2 µM) can inhibit the EMT of pancreatic cancer cells [117].…”

Section: Reversal Of Emt By Anti-inflammatory Natural Compoundsmentioning

confidence: 99%

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

Lee

2019

Cancers

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Epithelial mesenchymal transition (EMT) is a key process in the progression of malignant cancer. Therefore, blocking the EMT can be a critical fast track for the development of anticancer drugs. In this paper, we update recent research output of EMT and we explore suppression of EMT by natural anti-inflammatory compounds and pro-resolving lipids.A typical signaling pathway of EMT is the transforming growth factor-β1 (TGF-β1) pathway. TGF-β1 induces EMT via SMAD-dependent or non-SMAD signaling pathway [7]. Growth factors including FGF, HGF, IGF1, EGF, and PDGF via receptor tyrosine kinase can induce EMT via signaling pathway of PI3K-AKT and ERK MAPK [8][9][10][11]. Wnt signaling, hedgehog signaling, Notch signaling, hypoxia, and inflammatory tumor microenvironment also involves in EMT [5]. Recently, it has been shown that hippo signaling is also involved in EMT [12]. YAP and TAZ can enhance EMT through upregulation of EMT transcription factors such as forkhead box C2 (FOXC2), snail family zinc finger 1/2 (SNAIL1, SLUG), twist-related protein 1 (TWIST1), and ZEB1 [12-15]. Transcription Factors Involved in EMTNovel players are newly recognized as regulatory transcription factor in the EMT. Brachyury, the T-box transcription factor, is a novel transcription factor implicated in the EMT of cancer cells [16]. Brachyury is known as the target gene of WNT, one of the m ajor signaling pathways of EMT [17]. Foxq1, one of forkhead transcription factor, has also regarded as a novel transcription factor mediating the EMT of gastric cancer [6,18]. Runt-related transcription factor 2 (Runx2) belongs to the runt-related transcription factor family [19]. Runx2 plays a key role in EMT of hepatocellular carcinoma (HCC) [20]. GATA transcription factors are also implicated in the EMT of cancer cells [21].A typical signaling pathway of EMT is the transforming growth factor-β1 (TGF-β1) pathway. TGF-β1 induces EMT via SMAD-dependent or non-SMAD signaling pathway [7]. Growth factors including FGF, HGF, IGF1, EGF, and PDGF via receptor tyrosine kinase can induce EMT via signaling pathway of PI3K-AKT and ERK MAPK [8][9][10][11]. Wnt signaling, hedgehog signaling, Notch signaling, hypoxia, and inflammatory tumor microenvironment also involves in EMT [5]. Recently, it has been shown that hippo signaling is also involved in EMT [12]. YAP and TAZ can enhance EMT through upregulation of EMT transcription factors such as forkhead box C2 (FOXC2), snail family zinc finger 1/2 (SNAIL1, SLUG), twist-related protein 1 (TWIST1), and ZEB1 [12-15]. Transcription Factors Involved in EMTNovel players are newly recognized as regulatory transcription factor in the EMT. Brachyury, the T-box transcription factor, is a novel transcription factor implicated in the EMT of cancer cells [16]. Brachyury is known as the target gene of WNT, one of the major signaling pathways of EMT [17]. Foxq1, one of forkhead transcription factor, has also regarded as a novel transcription factor mediating the EMT of gastric cancer [6,18]. Runt-related transcription factor 2 (Runx2...

show abstract

Brusatol inhibits the response of cultured beta-cells to pro-inflammatory cytokines in vitro

Cited by 22 publications

References 21 publications

The protein synthesis inhibitor brusatol normalizes high‐fat diet‐induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination

The protein synthesis inhibitor brusatol normalizes high‐fat diet‐induced glucose intolerance in male C57BL/6 mice: role of translation factor eIF5A hypusination

Brusatol-Mediated Inhibition of c-Myc Increases HIF-1α Degradation and Causes Cell Death in Colorectal Cancer under Hypoxia

Reversal of Epithelial–Mesenchymal Transition by Natural Anti-Inflammatory and Pro-Resolving Lipids

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