Minocycline prevents paraquat-induced cell death through attenuating endoplasmic reticulum stress and mitochondrial dysfunction

Huang, Chuen Lin; Lee, Yi Chao; Yang, Ying; Kuo, Tsun Yung; Huang, Nai Kuei

doi:10.1016/j.toxlet.2011.12.021

Cited by 44 publications

(20 citation statements)

References 55 publications

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“…Thus, 50 µM rotenone was used to induce cellular damage for further analysis. Consistent with previous studies, we observed significant decreases in cell viability following paraquat or 6-OHDA treatments at different time points [33][34][35]. It is suggested that performing dose-response studies while studying, particularly, rotenone-induced neurotoxicity is very important before investigating molecular responses of neurotoxins.…”

Section: Discussionsupporting

confidence: 90%

The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

Kaftan¹,

Armağan²,

Dağcı³

2020

jrp

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Programmed cell death (apoptosis) is mainly responsible for neuronal damage in neurodegenerative diseases. Thus, inhibition of apoptosis could represent an effective strategy in the prevention of these diseases. In this study, we aimed to compare the apoptotic responses of neurotoxins that are widely used to induce neuronal damage in cell culture studies and help to decide the most suitable experimental model for drug studies that target apoptosis. Cell viability analyses were performed by MTT assay following 1-methyl-4-phenylpyridinium (MPP +), 6-hydroxydopamine (6-OHDA), rotenone and paraquat treatments at three different time points (12, 24, 48h). Pro-apoptotic (Bax, Bad, Bak), anti-apoptotic (Bcl-2, Bcl-xl) protein levels and total caspase-3 protein levels were determined by Western Blotting technique following treatments. As expected, all neurotoxins managed to trigger cell death and apoptotic pathway. On the other hand, each neurotoxin was found to enhance and/or reduce the levels of different proteins that are associated with apoptosis. Due to different responses of apoptosis related proteins to neurotoxins, it can be concluded that the determination of target proteins with a number of protein-binding assays prior to cell culture studies and then deciding an in vitro model are essential while screening newly synthesized drugs that target apoptosis.

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Section: Discussionsupporting

confidence: 90%

The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

Kaftan¹,

Armağan²,

Dağcı³

2020

jrp

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“…Acute kidney dysfunction leads to paraquat accumulation in the body and contributes to toxic injury in other organs [52, 53]. Paraquat can cause mitochondrial cytopathy by triggering the MPT pore opening in multiple organ systems, including brain, liver and kidney [54-57]. As the renal proximal tubule is a major site for the excretion of xenobiotics and is highly dependent on oxidative mitochondrial metabolism for ATP production, it is particularly vulnerable to deleterious effects of toxins targeting mitochondria [18, 58].…”

Section: Discussionmentioning

confidence: 99%

Redox-sensitive glycogen synthase kinase 3β-directed control of mitochondrial permeability transition: rheostatic regulation of acute kidney injury

Wang

Bao

et al. 2013

Free Radical Biology and Medicine

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Mitochondrial dysfunction plays a pivotal role in necroapoptotic cell death and in the development of acute kidney injury (AKI). Evidence suggests that glycogen synthase kinase (GSK) 3β resides at the nexus of multiple signaling pathways implicated in the regulation of mitochondrial permeability transition (MPT). In cultured renal tubular epithelial cells, a discrete pool of GSK3β was detected in mitochondria. Co-immunoprecipitation assay confirmed that GSK3β physically interacts with cyclophilin F and voltage-dependent anion channel (VDAC), key MPT regulators that possess multiple GSK3β phosphorylation consensus motifs, suggesting that GSK3β has a direct control of MPT. Upon a strong burst of reactive oxygen species elicited by the pro-oxidant herbicide paraquat, the activity of the redox-sensitive GSK3β was drastically enhanced. This was accompanied by augmented phosphorylation of cyclophilin F and VDAC, associated with MPT and cell death. Inhibition of GSK3β by either the selective inhibitor 4-Benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione(TDZD-8) or forced expression of a kinase-dead mutant obliterated paraquat-induced phosphorylation of cyclophilin F and VDAC, prevented MPT and improved cellular viability. Conversely, ectopic expression of a constitutively active GSK3β amplified the effect of paraquat on cyclophilin F and VDAC phosphorylation and sensitized cells to paraquat induced MPT and death. In vivo, paraquat injection elicited marked oxidant stress in the kidney and resulted in acute kidney dysfunction and massive tubular apoptosis and necrosis. Consistent with in vitro findings, the activity of GSK3β was augmented in the kidney following paraquat injury, associated with increased phosphorylation of cyclophilin F and VDAC and sensitized MPT. TDZD-8 blocked GSK3β activity in the kidney, intercepted cyclophilin F and VDAC phosphorylation, prevented MPT, attenuated tubular cell death and ameliorated paraquat-induced AKI. Our data suggests that the redox-sensitive GSK3β regulates renal tubular injury in AKI via controlling the activity of MPT regulators.

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“…The generation of mitochondrial ROS was analyzed by flow cytometry using the dye MitoSOX Red18. In brief, cells were stained with 5 μM MitoSOX Red for 10 min and the fluorescence intensity represents the mitochondrial ROS.…”

Section: Methodsmentioning

confidence: 99%

Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells

Shi

et al. 2016

Sci Rep

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Hypoxia-inducible factor-1 (HIF-1) is an important transcription factor that induces adaptive responses upon low oxygen conditions in human cancers and triggers off a poor prognostic outcome of conventional treatments. In this study, we discovered for the first time that brusatol (BRU), a quassinoid extracted from Brucea Esters, has the capability to inhibit HIF-1 signaling pathway. We found that BRU concentration-dependently down-regulated HIF-1α protein levels under hypoxia or CoCl2-induced mimic hypoxia in HCT116 cells without causing significant cytotoxicity. Besides, the transactivation activity of HIF-1 was suppressed by BRU under hypoxic conditions, as well as the expression of HIF-1 target genes, including VEGF, GLUT1, HK2 and LDHA. In addition, BRU can also decrease glucose consumption under hypoxia through inhibition of HIF-1 signaling pathway. Further studies revealed that the inhibitory effect of BRU on HIF-1 signaling pathway might be attributed to promoting degradation of HIF-1α. Interestingly, intracellular reactive oxygen species (ROS) levels and mitochondrial ROS level were both decreased by BRU treatment, indicating the involvment of mitochondrial ROS regulation in the action of BRU. Taken together, these results provided clear evidence for BRU-mediated HIF-1α regulation and suggested its therapeutic potential in colon tumors.

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Minocycline prevents paraquat-induced cell death through attenuating endoplasmic reticulum stress and mitochondrial dysfunction

Cited by 44 publications

References 55 publications

The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

The comparison of apoptosis-related protein expressions in neurotoxin-based in vitro Parkinson s Disease models

Redox-sensitive glycogen synthase kinase 3β-directed control of mitochondrial permeability transition: rheostatic regulation of acute kidney injury

Brusatol inhibits HIF-1 signaling pathway and suppresses glucose uptake under hypoxic conditions in HCT116 cells

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