Induction of Mitochondrial Dysfunction by Poly(ADP-Ribose) Polymer: Implication for Neuronal Cell Death

Baek, Seung Hoon; Bae, Ok Nam; Kim, Eun Kyoung; Yu, Sebastian

doi:10.1007/s10059-013-0172-0

Cited by 27 publications

(20 citation statements)

References 28 publications

(32 reference statements)

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“…Since cytochrome C and AIF are released from mitochondria to the cytosol during mitochondrial damage, 32,41 these results were consistent with mitochondrial dysfunction. Carnosine potently inhibited the release of AIF and cytochrome C, demonstrating its protective activity on mitochondrial damage (Fig.…”

Section: Resultssupporting

confidence: 59%

Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage

Baek

Noh

Kim

et al. 2014

Stroke

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150

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Background and Purpose Despite the rapidly increasing global burden of ischemic stroke, no therapeutic options for neuroprotection against stroke currently exist. Recent studies have shown that autophagy plays a key role in ischemic neuronal death and treatments that target autophagy may represent a novel strategy in neuroprotection. We investigated whether autophagy is regulated by carnosine, an endogenous pleiotropic dipeptide which has robust neuroprotective activity against ischemic brain damage. Methods We examined the effect of carnosine on mitochondrial dysfunction and autophagic processes in rat focal ischemia and in neuronal cultures. Results Autophagic pathways such as reduction of phosphorylated mTOR/p70S6K and the conversion of LC3-I to LC3-II were enhanced in the ischemic brain. However, treatment with carnosine significantly attenuated autophagic signaling in the ischemic brain, with improvement of brain mitochondrial function and mitophagy signaling. The protective effect of carnosine against autophagy was also confirmed in primary cortical neurons. Conclusion Taken together, our data suggest that the neuroprotective effect of carnosine is at least partially mediated by mitochondrial protection, and attenuation of deleterious autophagic processes. Our findings shed new light on the mechanistic pathways that this exciting neuroprotective agent influences.

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Section: Resultssupporting

confidence: 59%

Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage

Baek

Noh

Kim

et al. 2014

Stroke

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150

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“…Anticancer drugs may induce mitochondrial dysfunction in cells via dissipation of ΔΨm leading to liberation of numerous cell death proteins from the mitochondria (24). Therefore, it was reported that the intrinsic pathway depends on the dysfunction of the mitochondria resulting from an increase in the ratio of Bak:Bcl-2 which is caused by anticancer drugs thus leading to AIF and Endo G release from the mitochondria before inducing apoptosis (25)(26)(27) which is termed caspase-independent pathways or alternatively causing cytochrome c release, activation of caspase-9 and -3 resulting in apoptosis termed the caspase-dependent pathway (28). Our results showed that DMC induced mitochondrial dysfunction (decreased levels of ΔΨm) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Demethoxycurcumin induces the apoptosis of human lung cancer NCI-H460 cells through the mitochondrial-dependent pathway

Lien

Liu

et al. 2015

Oncology Reports

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Abstract. Lung cancer is the most common cause of cancerrelated mortality in the US as well as other regions of the world. Curcumin, demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are the major components of Curcuma longa L. It has been reported that curcumin inhibits the growth of various types of cancer cells in vitro and in vivo. However, the mechanisms involved in the inhibition of cell growth and induced apoptosis by DMC in human lung cancer cells remain unclear. In the present study, we investigated the effect of DMC on cell death via the induction of apoptosis in NCI-H460 human lung cancer cells. Flow cytometric assay was used to examine the total percentage of viable cells, the population of cells in the sub-G1 phase of the cell cycle, the level of reactive oxygen species (ROS), Ca 2+ production, mitochondrial membrane potential (ΔΨm) and caspase activity. Western blotting was used to examine the changes in the expression of cell cycle-and apoptosis-associated proteins. Confocal microscopy was used to examine the translocation of apoptosis-associated proteins. The results indicated that DMC significantly induced cell morphological changes and decreased the percentage of viable NCI-H460 cells and DMC induced apoptosis based on the cell distribution in the sub-G1 phase. Moreover, DMC promoted ROS and Ca 2+ production and decreased the level of ΔΨm and promoted the activities of caspase-3, -8 and -9. The Western blotting results showed that DMC promoted the expression of AIF, Endo G and PARP. The levels of Fas ligand (Fas L) and Fas were also upregulated. Furthermore, DMC promoted expression of ER stress-associated proteins such as GRP78, GADD153, IRE1β, ATF-6α, ATF-6β and caspase-4. Based on the findings, we suggest that DMC may be used as a novel anticancer agent for the treatment of lung cancer in the future.

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“…38 However, it did not provide any neuronal protection as assessed by PI labeling (n ¼ 17, p ¼ 0.173, Supplemental Figure 5b). Thus, it seems unlikely that PARP contributes to cell death in this thrombin-induced ex vivo model.…”

Section: Ep3r Inhibition Improves Neuronal Survival In Organotypic Himentioning

confidence: 93%

Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury

Han

Lan

et al. 2015

J Cereb Blood Flow Metab

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Prostaglandin E 2 EP3 receptor is the only prostaglandin E 2 receptor that couples to multiple G-proteins, but its role in thrombin-induced brain injury is unclear. In the present study, we exposed mouse hippocampal slice cultures to thrombin in vitro and injected mice with intrastriatal thrombin in vivo to investigate the role of EP3 receptor in thrombin-induced brain injury and explore its underlying cellular and molecular mechanisms. In vitro, EP3 receptor inhibition reduced thrombin-induced hippocampal CA1 cell death. In vivo, EP3 receptor was expressed in astrocytes and microglia in the perilesional region. EP3 receptor inhibition reduced lesion volume, neurologic deficit, cell death, matrix metalloproteinase-9 activity, neutrophil infiltration, and the number of CD68 þ microglia, but increased the number of Ym-1 þ M2 microglia. RhoA-Rho kinase levels were increased after thrombin injection and were decreased by EP3 receptor inhibition. In mice that received an intrastriatal injection of autologous arterial blood, inhibition of thrombin activity with hirudin decreased RhoA expression compared with that in vehicle-treated mice. However, EP3 receptor activation reversed this effect of hirudin. These findings show that prostaglandin E 2 EP3 receptor contributes to thrombin-induced brain damage via Rho-Rho kinase-mediated cytotoxicity and proinflammatory responses.

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Induction of Mitochondrial Dysfunction by Poly(ADP-Ribose) Polymer: Implication for Neuronal Cell Death

Cited by 27 publications

References 28 publications

Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage

Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage

Demethoxycurcumin induces the apoptosis of human lung cancer NCI-H460 cells through the mitochondrial-dependent pathway

Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury

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Induction of Mitochondrial Dysfunction by Poly(ADP-Ribose) Polymer: Implication for Neuronal Cell Death

Cited by 27 publications

References 28 publications

Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage

Modulation of Mitochondrial Function and Autophagy Mediates Carnosine Neuroprotection Against Ischemic Brain Damage

Demethoxycurcumin induces the apoptosis of human lung cancer NCI-H460 cells through the mitochondrial-dependent pathway

Inhibition of prostaglandin E2 receptor EP3 mitigates thrombin-induced brain injury

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Inhibition of prostaglandin E₂ receptor EP3 mitigates thrombin-induced brain injury