Poly(ADP-ribosyl)ated PXR is a critical regulator of acetaminophen-induced hepatotoxicity

Wang, Cheng; Xu, Wenjing; Zhang, Yanqing; Huang, Dan

doi:10.1038/s41419-018-0875-4

Cited by 24 publications

(20 citation statements)

References 42 publications

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“…Acetaminophen is a widely used drug to relieve pain and reduced fever however its higher doses could led to acute liver failure and critical health problems (13). Many studies also reported that it induces the apoptosis and inhibits cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Effect of Acetaminophen on Viability of HeLa Cells

Görgişen¹,

Gülaçar²,

Oksuz³

2019

Eastern J Med

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Acetaminophen is a widely used analgesic to release pain and reduce fever. Overdose medication could lead to serious medical conditions such as hepatotoxicity and liver failure. In addition to its cytotoxicity effects, it has an anti-proliferative effect in human cancer cells. In this study it is aimed to determine the apoptotic effect of acetaminophen in HeLa cells. In this perspective, HeLa cells were treated with different concentrations of acetaminophen at three different exposure times. Cell viability was determined by MTT analysis. Results showed that acetaminophen inhibited viability of HeLa cells. Its cytotoxic effect depends on exposure time and concentration. Prolonged exposure of acetaminophen led to decrease in cell survival even at minimum concentrations.

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Section: Discussionmentioning

confidence: 99%

Effect of Acetaminophen on Viability of HeLa Cells

Görgişen¹,

Gülaçar²,

Oksuz³

2019

Eastern J Med

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“…Co-Immunoprecipitation: Co-IP assay was performed as previously reported, [36,37] with antibodies specific for Myc (Cell Signaling Technology, 2276), Flag (Cell Signaling Technology; 14793). The bead bound proteins were released and analyzed by Western blot.…”

Section: Methodsmentioning

confidence: 99%

E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis

Wang

Chao

et al. 2020

Advanced Science

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Chronic low-grade inflammation orchestrated by macrophages plays a critical role in metabolic chronic diseases, like obesity and atherosclerosis. However, the underlying mechanism remains to be elucidated. Here, the E3 ubiquitin ligase F-box/WD Repeat-Containing Protein 2 (FBXW2), the substrate-binding subunit of E3 ubiquitin ligase SCF (a complex of FBXW2, SKP1, and cullin-1), as an inflammatory mediator in macrophages, is identified. Myeloid-specific FBXW2 gene deficiency improves both obesity-associated with insulin resistance and atherosclerosis in murine models. The beneficial effects by FBXW2 knockout are accompanied by decreased proinflammatory responses and macrophage infiltration in the microenvironment. Mechanistically, it is identified that KH-type splicing regulatory protein (KSRP) is a new bona fide ubiquitin substrate of SCF FBXW2. Inhibition of KSRP prevents FBXW2-deficient macrophages from exerting a protective effect on inflammatory reactions, insulin resistance and plaque formation. Furthermore, it is demonstrated that the C-terminus (P3) of FBXW2 competitively ablates the function of FBXW2 in KSRP degradation and serves as an effective inhibitor of obesity and atherogenesis progression. Thus, the data strongly suggest that SCF FBXW2 is an important mediator in the context of metabolic diseases. The development of FBXW2 (P3)-mimicking inhibitors and small-molecular drugs specifically abrogating KSRP ubiquitination-dependent inflammatory responses are viable approaches for obesity and atherosclerosis treatment.

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“…Western blot analysis was performed to detect the related protein levels [19,20]. Tissues or cells were homogenized, boiled, separated by SDS-PAGE electrophoresis and transferred to PVDF membranes.…”

Section: Methodsmentioning

confidence: 99%

Endothelial FAM3A positively regulates post-ischaemic angiogenesis

Liang

Zhang

et al. 2019

EBioMedicine

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Background Angiogenesis improves reperfusion to the ischaemic tissue after vascular obstruction. The underlying molecular mechanisms of post-ischaemic angiogenesis are not clear. FAM3A belongs to the family with sequence similarity 3 (FAM3) genes, but its biological function in endothelial cells in regards to vascular diseases is not well understood. Methods Gain- and loss-of-function methods by adenovirus or associated-adenovirus (AAV) in different models were applied to investigate the effects of FAM3A on endothelial angiogenesis. Endothelial angiogenesis was analysed by tube formation, migration and proliferation in vitro, and the blood flow and capillary density in a hind limb ischaemic model in vivo. Findings Endothelial FAM3A expression is downregulated under hypoxic conditions. Overexpression of FAM3A promotes, but depletion of FAM3A suppresses, endothelial tube formation, proliferation and migration. Utilizing the mouse hind limb ischaemia model, we also observe that FAM3A overexpression can improve blood perfusion and increase capillary density, whereas FAM3A knockdown has the opposite effects. Mechanistically, mitochondrial FAM3A increases adenosine triphosphate (ATP) production and secretion; ATP binds to P2 receptors and then upregulates cytosolic free Ca 2+ levels. Increased intracellular Ca 2+ levels enhance phosphorylation of the transcriptional factor cAMP response element binding protein (CREB) and its recruitment to the VEGFA promoter, thus activating VEGFA transcription and the final endothelial angiogenesis. Interpretation In summary, our data demonstrate that FAM3A positively regulates angiogenesis through activation of VEGFA transcription, suggesting that FAM3A may constitute a novel molecular therapeutic target for ischaemic vascular disease.

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Poly(ADP-ribosyl)ated PXR is a critical regulator of acetaminophen-induced hepatotoxicity

Cited by 24 publications

References 42 publications

Effect of Acetaminophen on Viability of HeLa Cells

Effect of Acetaminophen on Viability of HeLa Cells

E3 Ligase FBXW2 Is a New Therapeutic Target in Obesity and Atherosclerosis

Endothelial FAM3A positively regulates post-ischaemic angiogenesis

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