Rapamycin inhibits Erk1/2-mediated neuronal apoptosis caused by cadmium

Xu, Chong; Zhang, Hai; Liu, Chunxiao; Yang, Zhu; Wang, Xiaoxue; Gao, Wei; Huang, Shile; Chen, Long

doi:10.18632/oncotarget.4087

Cited by 11 publications

(10 citation statements)

References 63 publications

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“…Further, because RPM is a famous mTOR inhibitor, we try to assess related proteins in the ERK1/2 and mTOR pathways. Consistent with previous reports ( 28 , 29 ), the results revealed that both p-ERK1/2/ERK1/2 and p-mTOR/mTOR exhibited increased levels following lncRNA SENCR upregulation. Based on the above data and analysis, we conclude the likely mechanism of action of lncRNA SENCR via relieving the inhibitory effect of RPM on ERK1/2 and mTOR pathways and promoting HUVEC proliferation and migration.…”

Section: Discussionsupporting

confidence: 92%

Long non‑coding RNA SENCR alleviates the inhibitory effects of rapamycin on human umbilical vein endothelial cells

2018

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Rapamycin (RPM) is frequently used as the drug coating in drug-eluting stents (DESs) as it can inhibit the growth of smooth muscle cells. However, RPM also inhibits the proliferation and migration of vascular endothelial cells, and impairs reendothelialization in DES implantation. Therefore, the development of a strategy to protect vascular endothelial cells after DES implantation is of great importance. Long non-coding RNAs (lncRNAs) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and smooth muscle and endothelial cell-enriched migration/differentiation-associated lncRNA (SENCR) are able to enhance the proliferation, migration and angiogenesis of endothelial cells, which suggests that they may have potential as antagonists of the adverse effects of RPM in DES. However, the relationship between RPM and lncRNAs in endothelial cells during the intervention is not fully understood at present. The current study investigated the role and potential mechanism of the lncRNA SENCR on the activity of human umbilical vein endothelial cells (HUVECs) after RPM treatment. The proliferation, migration, angiogenic capacity and cell cycle progression of lncRNA SENCR-overexpressing HUVECs following RPM treatment was examined. The proliferation-related proteins of lncRNA SENCR-modified HUVECs were evaluated to understand the mechanism of action. LncRNA SENCR significantly alleviated the inhibition of proliferation, migration, angiogenesis and cell cycle progression of HUVECs caused by RPM by activating extracellular signal-regulated kinase 1/2 and mammalian target of RPM. The lncRNA SENCR could alleviate the inhibitory effects of RPM on HUVECs and may be useful as a new combinative agent to avoid the disadvantages of RPM in DES implantation.

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Section: Discussionsupporting

confidence: 92%

Long non‑coding RNA SENCR alleviates the inhibitory effects of rapamycin on human umbilical vein endothelial cells

2018

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“…Because of the high blood–brain barrier (BBB) permeability of this compound, Cd toxicity is highly significant in the nervous system. Epidemiological and clinical data have shown that Cd exposure severely affects the function of the nervous system and is associated with neurological disorders with symptoms including headache, vertigo, olfactory dysfunction, memory deficits, polyneuropathy, lower attention, and parkinsonism symptoms …”

Section: Introductionmentioning

confidence: 99%

“…Epidemiological and clinical data have shown that Cd exposure severely affects the function of the nervous system and is associated with neurological disorders with symptoms including headache, vertigo, olfactory dysfunction, memory deficits, polyneuropathy, lower attention, and parkinsonism symptoms. [4][5][6] Autophagy is a "self-eating" catabolic process that removes protein aggregates and damaged organelles required to maintain a homeostatic environment within the cell. Depending on the environmental stress and cell type, the autophagy pathway acts as either a survival or death safeguard mechanism.…”

Section: Introductionmentioning

confidence: 99%

Melatonin antagonizes cadmium‐induced neurotoxicity by activating the transcription factor EB‐dependent autophagy–lysosome machinery in mouse neuroblastoma cells

Yang

et al. 2016

Journal of Pineal Research

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Cadmium (Cd), a highly ubiquitous heavy metal, induces neurotoxicity. Melatonin, a major secretory product of the pineal gland, protects against Cd-induced neurotoxicity. However, the mechanism that accounts for this protection remains to be elucidated. Herein, we exposed mouse neuroblastoma cells (Neuro-2a cells) to different concentrations of cadmium chloride (CdCl2 ) (12.5, 25, and 50 μ mol L(-1) ) for 24 hours. We showed that Cd inhibits autophagosome-lysosome fusion and impairs lysosomal function, subsequently leading to nerve cell death. In addition, Cd decreases the level of transcription factor EB (TFEB) but induces the nuclear translocation of TFEB, associated with compromised lysosomal function or a compensatory effect after the impairment of the autophagic flux. Moreover, compared to the 50-μ mol L(-1) Cd group, administration of 1 μ mol L(-1) melatonin increased "TFEB-responsive genes" (P<.05) and the levels of lysosomal-associated membrane protein (0.57±0.06 vs 1.00±0.11, P<.05), preserved lysosomal protease activity (0.52±0.01 vs 0.90±0.02, P<.05), maintained the lysosomal pH level (0.50±0.01 vs 0.87±0.05, P<.01), and enhanced autophagosome-lysosome fusion (0.05±0.00 vs 0.21±0.01, P<.01). Notably, melatonin enhanced TFEB expression (0.37±0.04 vs 0.72±0.07, P<.05) and nuclear translocation (2.81±0.08 vs 3.82±0.05, P<.05). Tfeb siRNA blocked the melatonin-mediated elevation in autophagy-lysosome machinery in Cd-induced neurotoxicity (P<.01). Taken together, these results uncover a potent role for TFEB-mediated autophagy in the pathogenesis of Cd-induced neurotoxicity, suggesting that control of the autophagic pathway by melatonin might provide an important clue for exploring potential targets for novel therapeutics of Cd-induced neurotoxicity.

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“…In apoptotic cells, caspase-9 is activated [15] , and this leads to the activation and cleavage of executioner caspases-3 and -7 [16,17] . The critical downstream protein PARP is cleaved in this process [18] .…”

Section: Introductionmentioning

confidence: 99%

Emodin attenuates TNF-α-induced apoptosis and autophagy in mouse C2C12 myoblasts though the phosphorylation of Akt

Chen

Liu

et al. 2016

International Immunopharmacology

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Emodin, a major component of Rheum palmatum, has been reported to significantly protect neural tissue against apoptosis and autophagy. However, the effects and underlying mechanisms of action of emodin in muscle atrophy are still poorly defined. In this study, we investigated the protective effects and the underlying mechanisms by which emodin acts on tumor necrosis factor alpha (TNF-α)-induced apoptosis and autophagy in mouse C2C12 myoblasts. Emodin, at various concentrations, decreased TNF-α-induced apoptosis in C2C12 myoblasts, which were analyzed by Hoechst 33342 staining and annexin V/PI analysis. Emodin also inhibited the collapse of the mitochondrial membrane potential and the generation of reactive oxygen species in TNF-α-stimulated C2C12 myoblasts. Consistent with these results, the expression of Bcl-2 was increased, whereas the expression of Bax, cleaved-caspase 3 and cleaved-PARP was decreased after emodin treatment. These data demonstrate that emodin attenuated apoptosis in TNF-α-stimulated C2C12 myoblasts through mitochondrial signaling pathways. In addition, emodin inhibited autophagy in TNF-α-stimulated C2C12 myoblasts by suppressing the expression of LC3-II, Beclin-1 and Atg7. Emodin also resulted in the upregulation of the phosphorylated forms of Akt. Taken together, these results suggest that emodin inhibited apoptosis and autophagy in TNF-α-induced C2C12 myoblasts, possibly through the activation of phosphorylated Akt. Our findings suggest that emodin could be a potential therapeutic agent in the treatment of muscle atrophy.

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Rapamycin inhibits Erk1/2-mediated neuronal apoptosis caused by cadmium

Cited by 11 publications

References 63 publications

Long non‑coding RNA SENCR alleviates the inhibitory effects of rapamycin on human umbilical vein endothelial cells

Long non‑coding RNA SENCR alleviates the inhibitory effects of rapamycin on human umbilical vein endothelial cells

Melatonin antagonizes cadmium‐induced neurotoxicity by activating the transcription factor EB‐dependent autophagy–lysosome machinery in mouse neuroblastoma cells

Emodin attenuates TNF-α-induced apoptosis and autophagy in mouse C2C12 myoblasts though the phosphorylation of Akt

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