Endosulfan induces autophagy and endothelial dysfunction via the AMPK/mTOR signaling pathway triggered by oxidative stress

Zhang, Lianshuang; Wei, Jialin; Ren, Lihua; Zhang, Jin; Ji, Wang; Li, Jing; Yang, Man; Yu, Yang; Sun, Zhiwei; Zhou, Xianqing

doi:10.1016/j.envpol.2016.10.067

Cited by 37 publications

(25 citation statements)

References 35 publications

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“…More importantly, the effects of BCAA on ROS generation, NF‐κB activation, inflammatory genes expression and leucocytes adhesion to ECs, were blunted by rapamycin. This highlights the pivotal role of mTORC1 in mediating pro‐oxidant and pro‐inflammatory effects of BCAA on ECs, and it might be in agreement with the role of the overactivation of Akt‐mTORC1 axis and the progression of the metabolic syndrome, future development of T2DM and the associated endothelial cell activation and endothelial dysfunction 37, 38, 39. The molecular mechanisms responsible for the mTOR‐dependent activation of NOX and NF‐κB in response to BCAA are unknown and this is a limitation of our study.…”

Section: Discussionsupporting

confidence: 77%

“…This highlights the pivotal role of mTORC1 in mediating prooxidant and pro-inflammatory effects of BCAA on ECs, and it might be in agreement with the role of the overactivation of Akt-mTORC1 axis and the progression of the metabolic syndrome, future development of T2DM and the associated endothelial cell activation and endothelial dysfunction. [37][38][39] The molecular mechanisms responsible for the mTOR-dependent activation of NOX and NF-κB in response to BCAA are unknown and this is a limitation of our study. However, other authors have also found a role for mTOR in oxidative stress generation 40,41 or NF-κB activation in response to different stimuli or pathological conditions.…”

Section: Discussionmentioning

confidence: 97%

“…to promote cell growth, proliferation, migration, inflammation and oxidative stress in cancer cells 27,37 and PBMC. 22 We found that in ECs BCAA also promoted concentration-dependent phosphorylation of mTORC1 and activation of Akt.…”

Section: Discussionmentioning

confidence: 99%

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Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

Zhenyukh

González‐Amor

Rodrigues-Díez

et al. 2018

J Cellular Molecular Medi

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Branched‐chain amino acids (BCAA: leucine, isoleucine and valine) are essential amino acids implicated in glucose metabolism and maintenance of correct brain function. Elevated BCAA levels can promote an inflammatory response in peripheral blood mononuclear cells. However, there are no studies analysing the direct effects of BCAA on endothelial cells (ECs) and its possible modulation of vascular function. In vitro and ex vivo studies were performed in human ECs and aorta from male C57BL/6J mice, respectively. In ECs, BCAA (6 mmol/L) increased eNOS expression, reactive oxygen species production by mitochondria and NADPH oxidases, peroxynitrite formation and nitrotyrosine expression. Moreover, BCAA induced pro‐inflammatory responses through the transcription factor NF‐κB that resulted in the release of intracellular adhesion molecule‐1 and E‐selectin conferring endothelial activation and adhesion capacity to inflammatory cells. Pharmacological inhibition of mTORC1 intracellular signalling pathway decreased BCAA‐induced pro‐oxidant and pro‐inflammatory effects in ECs. In isolated murine aorta, BCAA elicited vasoconstrictor responses, particularly in pre‐contracted vessels and after NO synthase blockade, and triggered endothelial dysfunction, effects that were inhibited by different antioxidants, further demonstrating the potential of BCAA to induce oxidative stress with functional impact. In summary, we demonstrate that elevated BCAA levels generate inflammation and oxidative stress in ECs, thereby facilitating inflammatory cells adhesion and endothelial dysfunction. This might contribute to the increased cardiovascular risk observed in patients with elevated BCAA blood levels.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 97%

See 1 more Smart Citation

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

Zhenyukh

González‐Amor

Rodrigues-Díez

et al. 2018

J Cellular Molecular Medi

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“…Several pesticides exert cellular toxicity via the triggering of oxidative stress, such as organophosphorus insecticides (35), organochlorine insecticides (36), pyrethroid insecticides (37), and fungicides (38), but the mechanisms by which FEN induces oxidative hepatic damage are still poorly understood. Therefore, we first profiled hepatic gene expression in FEN-exposed rats.…”

Section: Discussionmentioning

confidence: 99%

Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF‐κB pathway

et al. 2018

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Fenvalerate (FEN), a mainstream pyrethroid pesticide, was initially recommended as a low‐toxicity agent for controlling agricultural and domestic pests. Despite the widespread use of FEN worldwide, little data are available on FEN‐induced hepatic lesions and molecular mechanisms. In the present study, we first performed an occupational cross‐sectional study on FEN factory workers and found that the levels of serum alanine aminotransferase (ALT) and total antioxidant capacity increased, whereas malondialdehyde decreased in laborers in the working areas where the levels of airborne FEN were much higher compared with the office area. The results were then confirmed by animal experiments that abnormal hepatic histology, increased ALT level, and compromised hepatic oxidative capability were observed in rats exposed to a high concentration of FEN. Furthermore, the bioinformatics analysis of gene microarray in rat liver tissue showed that FEN significantly changed the expressions of genes related to the regulation of intracellular calcium ion homeostasis and the calcium signal pathway. Finally, the functional experiments in Buffalo rat liver (BRL) cells demonstrated that FEN first activated ERK MAPK, followed by IKK and NF‐κB, which triggered the transcription of genes responsible for accelerating an overload of intracellular calcium ions, prompted reactive oxygen species generation in the mitochondria, and finally, induced hepatic cellular apoptosis. The calcium signaling pathway and in particular, an overload of intracellular calcium play a critical role in this pathophysiological process via the ERK/IKK/NF‐κB pathway. Our study furthers the understanding of the mechanism of FEN‐induced hepatic injuries and may have implications in the prevention and control of liver diseases induced by environmental pesticides.—Qiu, L.‐L., Wang, C., Yao, S., Li, N., Hu, Y., Yu, Y., Xia, R., Zhu, J., Ji, M., Zhang, Z., Wang, S.‐L. Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF‐κB pathway. FASEB J. 33, 2782–2795 (2019). http://www.fasebj.org

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“…mTOR molecularly interacts with AMPK, constituting the operated switch of catabolism and anabolism [42]. Particularly, under the condition of adequate nutrition, the increased synthesis of ATP stimulates the activity of mTOR, which further promotes protein synthesis and lipogenesis [28].…”

Section: Discussionmentioning

confidence: 99%

Antifatigue Effects of Antrodia cinnamomea Cultured Mycelium via Modulation of Oxidative Stress Signaling in a Mouse Model

Liu

et al. 2017

BioMed Research International

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Antrodia cinnamomea, a folk medicinal mushroom, has numerous biological effects. In this study, we aim to assess whether the antifatigue effects of A. cinnamomea mycelia (AC) and its underlying mechanisms are related to oxidative stress signaling using behavioral mouse models and biochemical indices detection. Mice were orally treated with AC at doses of 0.1, 0.3, and 0.9 g/kg for three weeks. AC had no effect on the spontaneous activities of mice indicating its safety on central nervous system. Furthermore, results obtained from weight-loaded forced swimming test, rotary rod test, and exhausted running test confirmed that AC significantly enhanced exercise tolerance of mice. Biochemical indices levels showed that these effects were closely correlated with inhibiting the depletion of glycogen and adenosine triphosphate stores, regulating oxidative stress-related parameters (superoxide dismutase, glutathione peroxidase, reactive oxygen species, and malondialdehyde) in serum, skeletal muscle, and liver of mice. Moreover, the effects of AC may be related with its regulation on the activations of AMP-activated protein kinase, protein kinase B, and mammalian target of rapamycin in liver and skeletal muscle of mice. Altogether, our data suggest that the antifatigue properties of AC may be one such modulation mechanism via oxidative stress-related signaling in mice.

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Endosulfan induces autophagy and endothelial dysfunction via the AMPK/mTOR signaling pathway triggered by oxidative stress

Cited by 37 publications

References 35 publications

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

Branched‐chain amino acids promote endothelial dysfunction through increased reactive oxygen species generation and inflammation

Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF‐κB pathway

Antifatigue Effects of Antrodia cinnamomea Cultured Mycelium via Modulation of Oxidative Stress Signaling in a Mouse Model

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