PM2.5-induced ADRB2 hypermethylation contributed to cardiac dysfunction through cardiomyocytes apoptosis via PI3K/Akt pathway

Yang, Xiaozhe; Zhao, Tong; Lin, Feng; Shi, Yanfeng; Jiang, Jinjin; Liang, Shuang; Sun, Baiyang; Xu, Qing; Duan, Junchao; Sun, Zhiwei

doi:10.1016/j.envint.2019.03.057

Cited by 69 publications

(29 citation statements)

References 52 publications

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“…They regulate not only metabolic processes such as protein synthesis and glycolysis/gluconeogenesis [32,33] but also cell growth, cycle progression and cell division, proliferation, and apoptosis [34][35][36][37]. Currently, the PI3K pathway is receiving increasing attention, and far more significant functions are being revealed [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

Zhang

Wang

et al. 2020

Mol Cancer

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Background: PI3K/AKT is a vital signaling pathway in humans. Recently, several PI3K/AKT inhibitors were reported to have the ability to reverse cancer multidrug resistance (MDR); however, specific targets in the PI3K/AKT pathways and the mechanisms associated with MDR have not been found because many of the inhibitors have multiple targets within a large candidate protein pool. AKT activation is one presumed mechanism by which MDR develops during cancer treatment. Methods: The effects of inhibiting PI3K 110α and 110β by BAY-1082439 treatment and CRISPR/Cas9 knockout were examined to determine the possible functions of BAY-1082439 and the roles of PI3K 110α and 110β in the reversal of MDR that is mediated by the downregulation of P-gp and BCRP. Inhibition of AKT with GSK-2110183 showed that the downregulation of P-gp and BCRP is independent of generalized AKT inactivation. Immunofluorescence, immunoprecipitation, MTT, flow cytometry and JC-1 staining analyses were conducted to study the reversal of MDR that is mediated by P-gp and BCRP in cancer cells. An ATPase assay and a structural analysis were also used to analyze the potential mechanisms by which BAY-1082439 specifically targets PI3K 110α and 110β and nonspecifically influences P-gp and BCRP. Results: By inhibiting the activation of the PI3K 110α and 110β catalytic subunits through both the administration of BAY-1082439 and the CRISPR/Cas9 deletion of Pik3ca and Pik3cb, the ATP-binding cassette transporters P-gp/ ABCB1 and BCRP/ABCG2 were downregulated, thereby reestablishing the drug sensitivity of human epidermoid carcinoma and non-small cell lung cancer (NSCLC) MDR cells. Inhibition of AKT did not reverse the MDR mediated by P-gp or BCRP. The ABC family proteins and AKT may play MDR-enhancing roles independently. Conclusions: The reversal of the dual functions of ABC-transporter-mediated and AKT-activation-enhanced MDR through the inhibition or knockout of PI3K 110α or 110β promises to improve current strategies based on combined drug treatments to overcome MDR challenges.

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Section: Discussionmentioning

confidence: 99%

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

Zhang

Wang

et al. 2020

Mol Cancer

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“…WHO indicated that 92% of the world's population were breathing air which does not meet minimum standards [16]. Earlier studies demonstrated that the exposure of PM 2.5 could lead to increased incidence and mortality from cardiovascular and respiratory diseases [17,18]. Moreover, epidemiological studies have shown that exposure to PM 2.5 may be related to obesity and type 2 diabetes [19,20].…”

Section: Discussionmentioning

confidence: 99%

“…Cell Counting Kit-8 (CCK-8) was usually chosen to detect cell viability after cells were exposed to toxicant [17]. PC12 cells and primary hippocampal neurons were seeded at 1×10 4 cells/well in a 96-well plate for 24 hr.…”

Section: Brain Slice Preparation and Tunel Testmentioning

confidence: 99%

S-adenosylmethionine Decarboxylase 1 Participates in PM2.5 Exposure Induced Neuronal Apoptosis via Mitochondria-Mediated Pathway

Zhu

Shou

et al. 2020

Preprint

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Background: Fine particle (Particulate matter 2.5, PM2.5), as the primary ambient pollutant, is considered harmful to some neurodegenerative diseases, while the specific biochemical mechanism underlying is still unrevealed. Neuronal apoptosis is believed the crucial event in neurodegenerative pathogenesis, but evidence supporting neuronal apoptosis as PM2.5 induced neuronal injury is insufficient. S-adenosylmethionine decarboxylase 1 (AMD1) and its related spermidine synthesis have been shown to participate in cellular apoptosis, but its role in PM2.5 exposure induced neuronal apoptosis was rarely reported. To better understand contribution of AMD1 activity and spermidine in PM2.5 exposure induced neuronal apoptosis, may provide novel therapeutic and preventive targets for air pollution associated neurodegenerative diseases.Methods: In the current work, sixteen C57BL/6 male mice were randomly divided into ambient PM2.5 chamber or filtered air chamber, and the mouse model of whole-body ambient PM2.5 chronic exposure was established. Behavioral and cognitive ability, together with corresponding biomedical index were recorded and tested to evaluated neurotoxicity by PM2.5 exposure in mice. In parallel, PC12 cells and primary hippocampal neurons were applied for PM2.5 treatment to explore the possible cellular and molecular mechanism which may be critically involved in the process. AMD1 activity and cellular spermidine content were modulated by pharmacological approach to examine their participation in PM2.5 triggered neuronal apoptosis, followed by better examination of typical index for mitochondrial membrane potential and mitochondrial-mediated apoptosis pathway signaling.Results: Chronic ambient PM2.5 exposure attenuated spatial learning and memory ability, and triggered neuronal apoptosis together with increased expression of apoptosis-related Bax/Bcl-2 and cleaved caspase-3. PM2.5 exposure impaired AMD1 expression and spermidine synthesis. AMD1 inhibition could mimick PM2.5 exposure induced neuronal apoptosis. Spermidine supplementation rescued against neurotoxicity and inhibited PM2.5 induced apoptosis, in which mitochondrial pathway signaling.Conclusions: Chronic real-time exposure to ambient PM2.5 led to the reduced the ability of spatial learning and memory in mice. Neuronal apoptosis was the key event in the process of neurodegenerative development induced by PM2.5 exposure. AMD1 and spermidine participated in neuronal apoptosis induced by PM2.5 exposure, which was at least partially dependent on mitochondria mediated pathway.

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“…The MAPK signalling pathway has three major regulatory factors: Jun N‐terminal kinase (JNK/SAPK), extracellular signal‐related kinase (ERK1/2) and p38 kinase . The phosphatidylinositol 3‐kinase/protein kinase‐B (PI3K/Akt) signalling pathway is also one of the most important intracellular pathways that regulate cell survival, cell growth, differentiation and the like . It is closely related to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

“…[8,9] The phosphatidylinositol 3-kinase/protein kinase-B (PI3K/Akt) signalling pathway is also one of the most important intracellular pathways that regulate cell survival, cell growth, differentiation and the like. [10][11][12] It is closely related to apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Meriolin1 induces cell cycle arrest, apoptosis, autophagy and targeting the Akt/MAPKs pathways in human neuroblastoma SH-SY5Y cells

Wang

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives Meriolins, a kind of chemical hybrid between meridianins and variolins, have lately been determined as kinase inhibitors and reportedly have antitumour activity. However, there is currently no in‐depth study for the action mechanism. This study aimed to elucidate the potentially antitumour action mechanism of Meriolin1 on human neuroblastoma (SH‐SY5Y) cells. Methods Firstly, cell viability was detected by MTT assay. Secondly, cell cycle, cell apoptosis, cell autophagy, reactive oxygen species and mitochondrial membrane potential (ΔΨm) were measured by flow cytometry. Then, cell cycle‐associated proteins, Bcl‐2 family proteins, Akt/MAPK proteins and autophagy‐associated proteins expressions were evaluated by Western blot. Bcl‐2 and Bax mRNA expressions were also evaluated by qRT‐PCR. Furthermore, cell adhesion assay and Hoechst 33258 fluorescent staining were carried out to detect the effect of Meriolin1 on cell adhesion and morphology. Finally, to gain further insight into mechanism of action of Meriolin1 to CDK protein, the molecular docking study was performed by using the CDOCKER module of DS software. Key findings Meriolin1 could exert the antitumour activity on SH‐SY5Y cells by inducing cell cycle arrest, cell autophagy, the mitochondrion‐dependent cell apoptosis and targeting the Akt/MAPKs signalling pathway. Conclusions Meriolin1 might be a promising therapeutic candidate for neuroblastoma.

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PM2.5-induced ADRB2 hypermethylation contributed to cardiac dysfunction through cardiomyocytes apoptosis via PI3K/Akt pathway

Cited by 69 publications

References 52 publications

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

The PI3K subunits, P110α and P110β are potential targets for overcoming P-gp and BCRP-mediated MDR in cancer

S-adenosylmethionine Decarboxylase 1 Participates in PM2.5 Exposure Induced Neuronal Apoptosis via Mitochondria-Mediated Pathway

Meriolin1 induces cell cycle arrest, apoptosis, autophagy and targeting the Akt/MAPKs pathways in human neuroblastoma SH-SY5Y cells

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