Inhibition of Nasopharyngeal Carcinoma by Beta-Lapachone Occurs by Targeting the Mammalian Target of Rapamycin (mTOR)/PI3K/AKT Pathway, Reactive Oxygen Species (ROS) Production, and Autophagy Induction

Abstract Mechanisms governing stress-induced hematopoietic progenitor cell mobilization are not fully deciphered. We report that during granulocyte colony-stimulating factor–induced mobilization c-Met expression and signaling are up-regulated on immature bone marrow progenitors. Interestingly, stromal cell–derived factor 1/CXC chemokine receptor-4 signaling induced hepatocyte growth factor production and c-Met activation. We found that c-Met inhibition reduced mobilization of both immature progenitors and the more primitive Sca-1+/c-Kit+/Lin− cells and interfered with their enhanced chemotactic migration to stromal cell–derived factor 1. c-Met activation resulted in cellular accumulation of reactive oxygen species by mammalian target of rapamycin inhibition of Forkhead Box, subclass O3a. Blockage of mammalian target of rapamycin inhibition or reactive oxygen species signaling impaired c-Met–mediated mobilization. Our data show dynamic c-Met expression and function in the bone marrow and show that enhanced c-Met signaling is crucial to facilitate stress-induced mobilization of progenitor cells as part of host defense and repair mechanisms.

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3,5,3′-Triiodothyronine (T3) stimulates cell proliferation through the activation of the PI3K/Akt pathway and reactive oxygen species (ROS) production in chick embryo hepatocytes

Steroids ◽

10.1016/j.steroids.2012.01.022 ◽

2012 ◽

Vol 77 (6) ◽

pp. 589-595 ◽

Cited By ~ 15

Author(s):

Davide Gnocchi ◽

Silvia Leoni ◽

Sandra Incerpi ◽

Giovannella Bruscalupi

Keyword(s):

Reactive Oxygen Species ◽

Cell Proliferation ◽

Chick Embryo ◽

Reactive Oxygen ◽

Akt Pathway ◽

Ros Production ◽

Oxygen Species

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Activation of Autophagic Flux against Xenoestrogen Bisphenol-A-induced Hippocampal Neurodegeneration via AMP kinase (AMPK)/Mammalian Target of Rapamycin (mTOR) Pathways

Journal of Biological Chemistry ◽

10.1074/jbc.m115.648998 ◽

2015 ◽

Vol 290 (34) ◽

pp. 21163-21184 ◽

Cited By ~ 52

Author(s):

Swati Agarwal ◽

Shashi Kant Tiwari ◽

Brashket Seth ◽

Anuradha Yadav ◽

Anshuman Singh ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Bisphenol A ◽

Mammalian Target Of Rapamycin ◽

Reactive Oxygen ◽

Target Of Rapamycin ◽

Autophagic Flux ◽

Compensatory Mechanism ◽

Oxygen Species ◽

Amp Kinase

The human health hazards related to persisting use of bisphenol-A (BPA) are well documented. BPA-induced neurotoxicity occurs with the generation of oxidative stress, neurodegeneration, and cognitive dysfunctions. However, the cellular and molecular mechanism(s) of the effects of BPA on autophagy and association with oxidative stress and apoptosis are still elusive. We observed that BPA exposure during the early postnatal period enhanced the expression and the levels of autophagy genes/proteins. BPA treatment in the presence of bafilomycin A1 increased the levels of LC3-II and SQSTM1 and also potentiated GFP-LC3 puncta index in GFP-LC3-transfected hippocampal neural stem cell-derived neurons. BPA-induced generation of reactive oxygen species and apoptosis were mitigated by a pharmacological activator of autophagy (rapamycin). Pharmacological (wortmannin and bafilomycin A1) and genetic (beclin siRNA) inhibition of autophagy aggravated BPA neurotoxicity. Activation of autophagy against BPA resulted in intracellular energy sensor AMP kinase (AMPK) activation, increased phosphorylation of raptor and acetyl-CoA carboxylase, and decreased phosphorylation of ULK1 (Ser-757), and silencing of AMPK exacerbated BPA neurotoxicity. Conversely, BPA exposure down-regulated the mammalian target of rapamycin (mTOR) pathway by phosphorylation of raptor as a transient cell's compensatory mechanism to preserve cellular energy pool. Moreover, silencing of mTOR enhanced autophagy, which further alleviated BPA-induced reactive oxygen species generation and apoptosis. BPA-mediated neurotoxicity also resulted in mitochondrial loss, bioenergetic deficits, and increased PARKIN mitochondrial translocation, suggesting enhanced mitophagy. These results suggest implication of autophagy against BPA-mediated neurodegeneration through involvement of AMPK and mTOR pathways. Hence, autophagy, which arbitrates cell survival and demise during stress conditions, requires further assessment to be established as a biomarker of xenoestrogen exposure.

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Mammalian target of rapamycin mediates the angiogenic effects of leptin in human hepatic stellate cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00047.2010 ◽

2011 ◽

Vol 301 (2) ◽

pp. G210-G219 ◽

Cited By ~ 22

Author(s):

Sara Aleffi ◽

Nadia Navari ◽

Wanda Delogu ◽

Sara Galastri ◽

Erica Novo ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Hepatic Stellate Cells ◽

Molecular Mechanisms ◽

Umbilical Vein ◽

Mammalian Target Of Rapamycin ◽

Reactive Oxygen ◽

Stellate Cells ◽

Target Of Rapamycin ◽

Oxygen Species ◽

Diphenylene Iodonium

Leptin modulates the angiogenic properties of hepatic stellate cells (HSC), but the molecular mechanisms involved are poorly understood. We investigated the pathways regulating hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in leptin-stimulated myofibroblastic HSC. Exposure to leptin enhanced the phosphorylation of TSC2 on T1462 residues and of p70 S6 kinase and the translational inhibitor 4E-binding protein-1, indicating the ability of leptin to activate the mammalian target of rapamycin (mTOR) pathway. Similar findings were observed when HSC were exposed to PDGF. Both leptin and PDGF increased the expression of HIF-1α and VEGF in HSC. In the presence of rapamycin, a specific mTOR inhibitor, leptin and PDGF were no longer able to activate mTOR, and expression of VEGF was reduced, whereas HIF-1α abundance was not affected. Moreover, knockdown of Raptor, a component of the mTORC1 complex, reduced the ability of leptin to increase VEGF. mTOR was also necessary for leptin- and PDGF-dependent increase in HSC migration. Leptin increased the generation of reactive oxygen species in HSC, which was reduced by NADP(H) oxidase inhibitors. Both N-acetyl cysteine and diphenylene iodonium, a NADP(H) inhibitor, inhibited the expression of HIF-1α and VEGF stimulated by leptin or PDGF. Finally, conditioned media from HSC treated with leptin or PDGF induced tube formation in cultured human umbilical vein endothelial cells. In conclusion, in HSC exposed to leptin or PDGF, increased expression of VEGF requires both activation of mTOR and generation of reactive oxygen species via NADPH-oxidase. Induction of HIF-1α requires NADP(H) oxidase but not mTOR activation.

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Nanotechnologies. 5-(and 6)-Chloromethyl-2',7' Dichlorodihydrofluorescein diacetate (CM-H2DCF- DA) assay for evaluating nanoparticle-induced intracellular reactive oxygen species (ROS) production in RAW 264.7 macrophage cell line

10.3403/30284328u ◽

2016 ◽

Keyword(s):

Reactive Oxygen Species ◽

Cell Line ◽

Reactive Oxygen ◽

Intracellular Reactive Oxygen Species ◽

Raw 264.7 ◽

Ros Production ◽

Oxygen Species ◽

Macrophage Cell Line ◽

Macrophage Cell ◽

Raw 264.7 Macrophage

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Reactive Oxygen Species in Host Plant Are Required for an Early Defense Response against Attack of Stagonospora nodorum Berk. Necrotrophic Effectors SnTox

Plants ◽

10.3390/plants10081586 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1586

Author(s):

Svetlana Veselova ◽

Tatyana Nuzhnaya ◽

Guzel Burkhanova ◽

Sergey Rumyantsev ◽

Igor Maksimov

Keyword(s):

Reactive Oxygen Species ◽

Early Stage ◽

Reactive Oxygen ◽

Triticum Aestivum L ◽

Redox Status ◽

Stagonospora Nodorum ◽

Ros Generation ◽

Ros Production ◽

Oxygen Species ◽

Necrotrophic Effectors

Reactive oxygen species (ROS) play a central role in plant immune responses. The most important virulence factors of the Stagonospora nodorum Berk. are multiple fungal necrotrophic effectors (NEs) (SnTox) that affect the redox-status and cause necrosis and/or chlorosis in wheat lines possessing dominant susceptibility genes (Snn). However, the effect of NEs on ROS generation at the early stages of infection has not been studied. We studied the early stage of infection of various wheat genotypes with S nodorum isolates -Sn4VD, SnB, and Sn9MN, carrying a different set of NE genes. Our results indicate that all three NEs of SnToxA, SnTox1, SnTox3 significantly contributed to cause disease, and the virulence of the isolates depended on their differential expression in plants (Triticum aestivum L.). The Tsn1–SnToxA, Snn1–SnTox1and Snn3–SnTox3 interactions played an important role in inhibition ROS production at the initial stage of infection. The Snn3–SnTox3 inhibited ROS production in wheat by affecting NADPH-oxidases, peroxidases, superoxide dismutase and catalase. The Tsn1–SnToxA inhibited ROS production in wheat by affecting peroxidases and catalase. The Snn1–SnTox1 inhibited the production of ROS in wheat by mainly affecting a peroxidase. Collectively, these results show that the inverse gene-for gene interactions between effector of pathogen and product of host sensitivity gene suppress the host’s own PAMP-triggered immunity pathway, resulting in NE-triggered susceptibility (NETS). These results are fundamentally changing our understanding of the development of this economical important wheat disease.

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