Ghrelin ameliorates A549 cell apoptosis caused by paraquat via p38-MAPK regulated mitochondrial apoptotic pathway

Cui, Shuqing; Nian, Qing; Chen, Gang; Wang, Xingyong; Zhang, Jinying; Qiu, Jian; Zhang, Zhiqiang

doi:10.1016/j.tox.2019.152267

Cited by 33 publications

(15 citation statements)

References 41 publications

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“…We observed that mitochondrial morphological characteristics induced by PQ did not quite fit that description. Previous studies had shown that PQ could induce cellular apoptosis [52,53]. Our data suggested that there was some cross-talk between apoptosis and ferroptosis.…”

Section: Discussionsupporting

confidence: 62%

Ferritinophagy‐Mediated Ferroptosis Involved in Paraquat‐Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD

Zuo

Jinhong

et al. 2021

Oxidative Medicine and Cellular Longevity

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Parkinson’s disease (PD) is a progressive nervous system disorder. Until now, the molecular mechanism of its occurrence is not fully understood. Paraquat (PQ) was identified as a neurotoxicant and is linked to increased PD risk and PD-like neuropathology. Ferroptosis is recognized as a new form of regulated cell death. Here, we revealed a new underlying mechanism by which ferritinophagy-mediated ferroptosis is involved in PD induced by PQ. The effect of PQ on movement injury in mice was investigated by the bar fatigue and pole-climbing test. SH-SY5Y human neuroblastoma cells were used to evaluate the mechanism of ferroptosis. Our results showed that PQ induced movement injury by causing the decrease in tyrosine hydroxylase in mice. In vitro, PQ significantly caused the iron accumulation in cytoplasm and mitochondria through ferritinophagy pathway induced by NCOA4. Iron overload initiated lipid peroxidation through 12Lox, further inducing ferroptosis by producing lipid ROS. PQ downregulated SLC7A11 and GPX4 expression and upregulated Cox2 expression significantly, which were important markers in ferroptosis. Fer-1, an inhibitor of ferroptosis, could significantly ameliorate the ferroptosis induced by PQ. Meanwhile, Bcl2, Bax, and p-38 were involved in apoptosis induced by PQ. In conclusion, ferritinophagy-mediated ferroptosis pathway played an important role in PD occurrence. Bcl2/Bax and P-p38/p38 pathways mediated the cross-talk between ferroptosis and apoptosis induced by PQ. These data further demonstrated the complexity of PD occurrence. The inhibition of the ferroptosis and apoptosis together may be a new strategy for the prevention of neurotoxicity or PD in the future.

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Section: Discussionsupporting

confidence: 62%

Ferritinophagy‐Mediated Ferroptosis Involved in Paraquat‐Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD

Zuo

Jinhong

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Our study on the anti-inflammatory and antiapoptosis mechanisms of KL demonstrated that KL treatment could inhibit P38-MAPK activation post PQ exposure. It is reported that MAPKs perform a significant function in regulating oxidative stress-related signaling and participate in the pathogenesis of PQ-induced ALI [43]. MAPKs are involved in regulating a variety of physiological processes in cells, including proliferation, differentiation, and apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK-Regulated Inflammatory Responses and Apoptosis

Zhang

Nian

Chen

et al. 2020

Oxidative Medicine and Cellular Longevity

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Acute lung injury (ALI) induced by paraquat (PQ) progresses rapidly with high mortality; however, there is no effective treatment, and the specific mechanism is not well understood. The antiaging protein klotho (KL) has multiple functions and exerts significant influences on various pathophysiological processes. This work evaluated the impact of KL on PQ-induced ALI and investigated its underlying mechanisms. As for in vivo research, C57BL/6 mice were treated with PQ (30 mg/kg) intraperitoneal (IP) injection to create a toxicity model of ALI (PQ group). The mice were divided into control group, KL group, PQ group, and PQ+KL group. For in vitro experiment, A549 cells were incubated with or without KL and then treated in the presence or absence of PQ for 24 h. In vivo result indicated that KL reduced the mortality, reduced IL-1β and IL-6 in the bronchoalveolar lavage fluid (BALF), attenuated ALI, and decreased apoptosis in situ. In vitro result revealed that KL significantly improved cell viability, reduced the levels of IL-1β and IL-6 in culture supernatants, suppressed cell apoptosis, inhibited caspase-3 activation, and enhanced mitochondrial membrane potential (ΔΨm) after PQ treatment. Besides, KL effectively abated reactive oxygen species (ROS) production, improved GSH content, and lowered lipid peroxidation in PQ-exposed A549 cells. Further experiments indicated that phosphorylated JNK and P38 MAPK was increased after PQ treatment; however, KL pretreatment could significantly lower the phosphorylation of P38 MAPK. Suppression of P38 MAPK improved cell viability, alleviated inflammatory response, and reduced apoptosis-related signals; however, it had no obvious effect on the production of ROS. Treatment with N-acetylcysteine (NAC), a classic ROS scavenger, could suppress ROS production and P38 MAPK activation. These findings suggested that KL could alleviate PQ-caused ALI via inhibiting ROS/P38 MAPK signaling-regulated inflammatory responses and mitochondria-dependent apoptosis.

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“…The lung is a principle target organ because paraquat is effectively taken up by the alveolar epithelium, which causes pneumonic damage by intense inebriation or long haul collection. [3][4][5] The paraquat toxicity mechanism includes a progression of cyclic reduction-oxidation responses instigating numerous inflammatory agents, which in the long run become progressive lung fibrosis; this mechanism assumes a basic role in delivering deadly hypoxemia after paraquat poisoning. [6][7][8][9] 2,5-Dihydroxy-3-undecyl-1,4-benzoquinone is a chemical name of Embelin.…”

Section: Introductionmentioning

confidence: 99%

Embelin impact on paraquat‐induced lung injury through suppressing oxidative stress, inflammatory cascade, and MAPK/NF‐κB signaling pathway

Sreeharsha

2020

J Biochem & Molecular Tox

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The current examination was intended to observe the defensive impacts of embelin against paraquat‐incited lung damage in relationship with its antioxidant and anti‐inflammatory action. Oxidative stress marker, like malondialdehyde (MDA), antioxidative enzymes, for example, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH Px), inflammatory cytokines, such as interleukin‐1β (IL‐1β), tumor necrosis factor‐α, and IL‐6, histological examination, and nuclear factor kappa B/mitogen‐activated protein kinase (NF‐κB/MAPK) gene expression were evaluated in lung tissue. Embelin treatment significantly decreased MDA and increased SOD, CAT, and GSH Px. Embelin significantly reduced levels of inflammatory cytokines in paraquat‐administered and paraquat‐intoxicated rats. In addition, embelin suggestively decreased relative protein expression of nuclear NF‐κB p65, p‐NF‐κBp65, p38 MAPK, and p‐p38 MAPKs in paraquat‐intoxicated rats. The outcomes show the impact of embelin inhibitory action on NF‐κB and MAPK and inflammatory cytokines release, and the decrease of lung tissue damage caused by paraquat.

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Ghrelin ameliorates A549 cell apoptosis caused by paraquat via p38-MAPK regulated mitochondrial apoptotic pathway

Cited by 33 publications

References 41 publications

Ferritinophagy‐Mediated Ferroptosis Involved in Paraquat‐Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD

Ferritinophagy‐Mediated Ferroptosis Involved in Paraquat‐Induced Neurotoxicity of Dopaminergic Neurons: Implication for Neurotoxicity in PD

Klotho Alleviates Lung Injury Caused by Paraquat via Suppressing ROS/P38 MAPK-Regulated Inflammatory Responses and Apoptosis

Embelin impact on paraquat‐induced lung injury through suppressing oxidative stress, inflammatory cascade, and MAPK/NF‐κB signaling pathway

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