Tilianin extracted from Xiangqinglan () inhibits apoptosis induced by mitochondrial pathway and endoplasmic reticulum stress in H9c2 cells after oxygen-glucose deprivation/reoxygenation.
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Mitochondrial apoptosis-induced channel
Fleischer
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The membrane of the endoplasmic reticulum (ER) of a cell forms contacts directly with mitochondria whereby the contact is referred to as the mitochondrion-associated ER membrane or the MAM. Here we found that the MAM regulates cellular survival via an MAM-residing ER chaperone the sigma-1 receptor (Sig-1R) in that the Sig-1R chaperones the ER stress sensor IRE1 to facilitate inter-organelle signaling for survival. IRE1 is found in this study to be enriched at the MAM in CHO cells. We found that IRE1 is stabilized at the MAM by Sig-1Rs when cells are under ER stress. Sig-1Rs stabilize IRE1 and thus allow for conformationally correct IRE1 to dimerize into the long-lasting, activated endonuclease. The IRE1 at the MAM also responds to reactive oxygen species derived from mitochondria. Therefore, the ER-mitochondrion interface serves as an important subcellular entity in the regulation of cellular survival by enhancing the stress-responding signaling between mitochondria, ER, and nucleus.
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Sigma-1 Receptor
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Objective To investigate the effects of the unfolded protein response(UPR) in endoplasmic reticulum stress on apoptosis of human lens epithelial cells(hLECs) and the relationship between UPR and cataract formation.Methods Cultured hLECs were divided into the control group and stimulated groups A,B,C and D, which were cultured in 1640 with homocysteine(1,2,5 and 10 mmol/L) for 24 h.Inhibition of the cell proliferation was determined by MTT assay;cell apoptosis was determined by Hoechst staining;free glutathione was determined using a Glutathione Quantigication Kit;the levels of cytosolic ROS were determined by adding H2-DCFH-DA for 20 to 30min followed by imaging with a fluorescent microscope;and the expressions of Bip/GRP78 and Caspase-12 in stimulated cells were determined by Western blot.Results After being exposed to differentconcentrations of Hcy,LECs showed a dose-dependent decrease in cell vitality: 48.2% declined at 5 mmol/L concentration of Hcy and 57.7% declined at 10 mmol/L concentration of Hcy, which showed significant differences compared with the control group(P0.01). Also significant apoptotic cells were determined.Compared with the control group,the level of ROS increased in a dose-dependent manner and of GSH was decreased in the C and D groups(P0.05),also the expressions of GRP78 and Caspase-12 were significantly increased in the C and D groups(P0.05).Conclusions High concentration of endoplasmic reticulum stressors can induce the endoplasmic reticulum and induce apoptosis of LECs through UPR.The conclusion can be drawn that UPR is probably one of the initiating factors of cataracts.
Caspase 12
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Abstract The endoplasmic reticulum (ER) and mitochondria form close physical associations to facilitate calcium transfer, thereby regulating mitochondrial function and dynamics. For neurons with high metabolic demands, such as sensory hair cells, precise regulation of ER-mitochondria associations is especially critical for cell survival. We previously identified the secreted metalloprotease Pregnancy associated plasma protein-aa (Pappaa) as a novel regulator of mitochondrial function in zebrafish lateral line hair cells (Alassaf et al., 2019). Here, we show that pappaa mutant hair cells exhibit excessive and abnormally close ER-mitochondria associations, suggesting increased ER-mitochondria calcium transfer. Indeed, we find that pappaa mutant hair cells are more vulnerable to pharmacological induction of ER-calcium release. Additionally, pappaa mutant hair cells display ER stress and dysfunctional downstream processes of the ER-mitochondria axis including mitochondrial fragmentation and autophagy. Together our results support a model in which Pappaa regulates mitochondrial function, at least in part, by regulating ER-mitochondria associations.
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The endoplasmic reticulum(ER) is a major site for protein processing and Ca2+ storage and it is extremely sensitive to the stress.In the state of dysfunction,unfolded or misfolded protein accumulation and Ca2+ disbalance occur,known as endoplasmic reticulum stress(ERS).Reactive oxygen species(ROS),as a second messenger plays an important role in the regulation of biological function in cells.Intracellular changes in redox state promote the generation of ROS and the activation of apoptosis inducing factor,leading to apoptosis which in turn exacerbate the intracellular redox state change.Recent studies have found that intracellular redox changes in the level of ERS mediated apoptosis assumes an important role in the process,and it is speculated that ROS is the upstream signal molecule in ERS-mediated apoptosis pathway.This paper provides a review of the relationship between ROS and ERS.
Second messenger system
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Objective To investigate the effects of the unfolded proteinresponse(UPR) in endoplasmic reticulum stress on apoptosis of human lens epithelialcells (hLECs) and the relationship between the UPR and cataract formation. Methods Cultured hLECs were divided into control group and stimulated groups-A, B, C, D, whictwere cultured in 1640 with homocysteine( 1, 2, 5, IOmmol/L) for 24h. Inhibition of cell proliferation was determined by MTT assay; cell apoptosis was detected byHoechst staining;flee glutathione was determined using a Glutathione QuantificationKit; levels of cytusolic ROS were assessed by adding H2-DCFH-DA for 20-30min followedby imaging with a fluorescent microscope;expression of Bip/GRP78, caspase-12 instimulated cells was observed by Western blot. Results After exposed to differentconcentration of Hcy, LECs showed dose-dependent decrease in cell vitality, 48.2%decline at 5mmol/L concentration of Hcy and 57.7% decline at IOmmol/L concentratioof Hey, which showed significant difference compared with control group (P <0.01),andsignificant apoptotic cells were detected;the level of ROS increased in adose-dependent manner, GSH were relatively decreased, which showed significantdifference between C,D group and control group(P<0.05); the expression of GR.P78and Caspase-12 were significant increased in C and D groups compared with controlgronp(P <0.05 ).Conclusions Higherconcentration of endoplasmic reticulumstressorscan induce endoplasmic reticulum and induce apoptosis in LECs through UPR. Theconclusion can be &awed that the UPR is probably one of initiating factors ofcataract.
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Cataract; Pathogenesis; Endoplasmic reticulum; Unfoldedproteinrespouse; Apoptosis
Pathogenesis
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SH-SY5Y
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Bax and Bak play a redundant but essential role in apoptosis initiated by the mitochondrial release of apoptogenic factors. In addition to their presence at the mitochondrial outer membrane, Bax and Bak can also localize to the ER. Agents that initiate ER stress responses can induce conformational changes and oligomerization of Bax on the ER as well as on mitochondria. In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax-/-bak-/- cells. In bax-/-bak-/- cells, introduction of Bak mutants selectively targeted to either mitochondria or the ER can induce apoptosis. However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage. In contrast, mitochondria-targeted Bak leads to enhanced caspase 7 and PARP cleavage in comparison with the ER-targeted Bak. These findings demonstrate that in addition to their functions at mitochondria, Bax and Bak also localize to the ER and function to initiate a parallel pathway of caspase activation and apoptosis.
Mitochondrial apoptosis-induced channel
Cleavage (geology)
Bcl-2-associated X protein
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Mitochondrial apoptosis-induced channel
Fragmentation
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