Adrenomedullin alleviates the pyroptosis of Leydig cells by promoting autophagy via the ROS–AMPK–mTOR axis

Li, Ming-yong; Zhu, Xia-lian; Zhao, Bixia; Shi, Lei; Wang, Wei; Hu, Wei; Qin, Song‐lin; Chen, Binghai; Zhou, Panghu; Qiu, Bo; Gao, Yong; Liu, Bolong

doi:10.1038/s41419-019-1728-5

Cited by 198 publications

(149 citation statements)

References 43 publications

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“…Among them, pyroptosis has recently been discovered as a pro-inflammatory programmed cell death process that plays an important role in cerebral I/R injury (Xia et al, 2018 ; Zhu et al, 2019 ). Recent studies have suggested that activation of autophagy has a potential therapeutic effect on cerebral I/R injury (Yao et al, 2019 ), and the mechanism of autophagy may be related to the inhibition of pyroptosis in some tissue injury (Li et al, 2019 ), which still remains unclear in cerebral I/R injury.…”

Section: Introductionmentioning

confidence: 99%

Exosomes Secreted From Bone Marrow Mesenchymal Stem Cells Attenuate Oxygen-Glucose Deprivation/Reoxygenation-Induced Pyroptosis in PC12 Cells by Promoting AMPK-Dependent Autophagic Flux

Zeng

Zhou

Liang

et al. 2020

Front. Cell. Neurosci.

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Background : Cerebral ischemia–reperfusion (I/R) injury can lead to severe dysfunction, and its treatment is difficult. It is reported that nucleotide-binding domain and leucine-rich repeat family protein 3 (NLRP3) inflammasome-mediated cell pyroptosis is an important part of cerebral I/R injury and the activation of autophagy can inhibit pyroptosis in some tissue injury. Our previous study found that the protective effects of bone marrow mesenchymal stem cells (BMSCs) in cerebral I/R injury may be associated with the regulation of autophagy. Recent studies have demonstrated that exosomes secreted from BMSCs (BMSC-Exos) may play an essential role in the effective biological performance of BMSCs and the protective mechanism of BMSC-Exos is associated with the activation of autophagy and the remission of inflammation, but it has not been reported in studies of cerebral I/R injury. We aimed to investigate the effects of BMSC-Exos on cerebral I/R injury and determine if the mechanism is associated with the regulation of pyroptosis and autophagic flux. Method : PC12 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) to induce cerebral I/R in vitro and were cocultured with BMSC-Exos. Cell viability was determined with CCK-8 and lactate dehydrogenase (LDH) detection kits. Scanning electron microscopy (SEM), Hoechst 33342/propidium iodide (PI) double staining, 2′,7′-dichlorodihydrofluorescein diacetate assay, immunofluorescence, Western blot, and Enzyme-linked immunosorbent assay (ELISA) were used to detect cell pyroptosis. Furthermore, transmission electron microscopy (TEM), GFP-RFP-LC3 adenovirus transfection, and Western blot were used to detect autophagic flux and its influence on pyroptosis. Finally, coimmunoprecipitation was used to detect the binding interaction between NLRP3 and LC3. Results : BMSC-Exos increased cell viability in OGD/R. The inhibitory effect of BMSC-Exos on pyroptosis was comparable to the NLRP3 inhibitor MCC950 and was reversed by NLRP3 overexpression. Furthermore, BMSC-Exos promoted autophagic flux through the AMP-activated kinase (AMPK)/mammalian target of the rapamycin pathway, whereas chloroquine, AMPK silencing, and compound C blocked the inhibitory effect on pyroptosis. Conclusions : BMSC-Exos can protect PC12 cells against OGD/R injury via attenuation of NLRP3 inflammasome-mediated pyroptosis by promoting AMPK-dependent autophagic flux.

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Section: Introductionmentioning

confidence: 99%

Exosomes Secreted From Bone Marrow Mesenchymal Stem Cells Attenuate Oxygen-Glucose Deprivation/Reoxygenation-Induced Pyroptosis in PC12 Cells by Promoting AMPK-Dependent Autophagic Flux

Zeng

Zhou

Liang

et al. 2020

Front. Cell. Neurosci.

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“…Adrenomedullin restored the steroidogenic enzyme expression, including StAR, CYP11A1, 3β-HSD, and CYP17A1, and testosterone production in LPS-induced Leydig cells via activation of the mTOR signaling pathway (Li et al, 2019). Nicotine decreased testosterone synthesis via inhibition of the mTOR signaling pathway in Leydig cells .…”

Section: Discussionmentioning

confidence: 85%

“…The mTOR signaling pathway was involved in the upregulation of the release of both progesterone and testosterone in porcine granulosa cells (Sirotkin et al, 2015). Adrenomedullin restored the steroidogenic enzyme expression, including StAR, CYP11A1, 3β‐HSD, and CYP17A1, and testosterone production in LPS‐induced Leydig cells via activation of the mTOR signaling pathway (Li et al, 2019). Nicotine decreased testosterone synthesis via inhibition of the mTOR signaling pathway in Leydig cells (Zhao et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

ERO1α promotes testosterone secretion in hCG‐stimulated mouse Leydig cells via activation of the PI3K/AKT/mTOR signaling pathway

Chen

Wang

Liu

et al. 2020

Journal Cellular Physiology

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ER oxidoreduclin 1α (ERO1α) is an oxidase, participating in formation of secretory and membrane proteins. However, the other physiological functions ERO1α is not well known. We found that ERO1α is high in the Leydig cells of the testis. Therefore, the purposes of the current study are to explore the role of ERO1α and the possible mechanisms in regulating cell proliferation, apoptosis, and testosterone secretion of Leydig cells. ERO1α was mainly localized in Leydig cells in the adult mice testes by immunofluorescence staining. Western blot analysis showed that ERO1α was higher in Leydig cells than that in the seminiferous tubules. The effect of ERO1α on cell proliferation, apoptosis, and testosterone secretion was detected by transducing ERO1α overexpression and knockdown lentiviruses into cultured primary Leydig cells (PLCs) together with hCG exposure. Flow cytometry analysis showed that ERO1α promoted cell proliferation by increasing cell distribution at the S phase and decreasing that at the G0/G1 phase. Western bolt analysis showed that ERO1α increased CDK2 and CDK6 expression. Cell apoptosis determination found that ERO1α inhibited PLC apoptosis. Western bolt analysis showed that ERO1α increased the ratio of BCL‐2/BAX, and decreased BAD and Caspase‐3 expression. Enzyme‐linked immunosorbent assay analysis demonstrated that ERO1α enhanced testosterone secretion. Western bolt analysis found that ERO1α increased StAR, 3β‐HSD, and CYP17A1 expression. Furthermore, ERO1α could activate the PI3K/AKT/mTOR signaling pathway. In summary, these results suggest that ERO1α might play proliferation promotion and antiapoptotic roles and enhance testosterone secretion in PLC, at least partly, via activation of the PI3K/AKT/mTOR signaling pathway.

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“…Similarly, Q10 reduced the level of ROS to protect astrocytes from oxidative stress (Jing et al 2015). ROS induced autophagy that was associated with the ROS-AMPK-mTOR pathway (Li et al 2019;Yang et al 2019).…”

Section: Discussionmentioning

confidence: 99%

Co-enzyme Q10 protects primary chicken myocardial cells from heat stress by upregulating autophagy and suppressing the PI3K/AKT/mTOR pathway

Huang

Tang

et al. 2019

Cell Stress and Chaperones

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In this study, we investigated the function of co-enzyme Q10 (Q10) in autophagy of primary chicken myocardial cells during heat stress. Cells were treated with Q10 (1 μΜ, 10 μΜ, and 20 μM) before exposure to heat stress. Pretreatment of chicken myocardial cells with Q10 suppressed the decline in cell viability during heat stress and suppressed the increase in apoptosis during heat stress. Treatment with 20 μM Q10 upregulated autophagy-associated genes during heat stress. The expression of LC3-II was highest in cells treated with 20 μM Q10. Pretreatment with Q10 decreased reactive oxygen species (ROS) levels during heat stress. The number of autophagosomes was significantly increased by 20 μM Q10 treatment, as demonstrated by electron microscopy or monodansylcadaverine (MDC) fluorescence. SQSTM1 accumulation was diminished by Q10 treatment during heat stress, and the number of LC3II puncta was increased. Treatment with 20 μM Q10 also decreased the activation of the PI3K/Akt/mTOR pathway. Our results showed that co-enzyme Q10 can protect primary chicken myocardial cells by upregulating autophagy and suppressing the PI3K/Akt/mTOR pathway during heat stress.

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Adrenomedullin alleviates the pyroptosis of Leydig cells by promoting autophagy via the ROS–AMPK–mTOR axis

Cited by 198 publications

References 43 publications

Exosomes Secreted From Bone Marrow Mesenchymal Stem Cells Attenuate Oxygen-Glucose Deprivation/Reoxygenation-Induced Pyroptosis in PC12 Cells by Promoting AMPK-Dependent Autophagic Flux

Exosomes Secreted From Bone Marrow Mesenchymal Stem Cells Attenuate Oxygen-Glucose Deprivation/Reoxygenation-Induced Pyroptosis in PC12 Cells by Promoting AMPK-Dependent Autophagic Flux

ERO1α promotes testosterone secretion in hCG‐stimulated mouse Leydig cells via activation of the PI3K/AKT/mTOR signaling pathway

Co-enzyme Q10 protects primary chicken myocardial cells from heat stress by upregulating autophagy and suppressing the PI3K/AKT/mTOR pathway

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