Effects of Photoperiod on Acetaminophen-Induced Hepatotoxicity in Mice

Lü, Jing; Wang, Hu; Zhang, Rumeng; Wan, Zhikang; Gao, Hang; Cai, Jie; Cheng, Yun; Dong, Ping; Lin, Tengfei; Fan, Chenyu; Sun, Ying

doi:10.1007/s10620-019-05749-6

Cited by 8 publications

(7 citation statements)

References 26 publications

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“…Tissues were fixed in 4% formaldehyde and embedded in paraffin. Sections with a thickness of 4 mm were stained with hematoxylin-eosin (Beyotime Biotechnology) as described previously (29,31).…”

Section: Histologic Analysismentioning

confidence: 99%

Inhibition of Aurora-A Promotes CD8+ T-Cell Infiltration by Mediating IL10 Production in Cancer Cells

Han

Jiang

Wang

et al. 2020

Molecular Cancer Research

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Intratumoral tumor-specific activated CD8 þ T cells with functions in antitumor immune surveillance predict metastasis and clinical outcome in human colorectal cancer. Intratumoral CD8 þ T cells also affect treatment with immune checkpoint inhibitors. Interestingly, inhibition of Aurora kinase A (Aurora-A) by its selective inhibitor alisertib obviously induced infiltration of CD8 þ T cells. However, the mechanisms by which inhibition of Aurora-A promotes infiltration of intratumoral CD8 þ T cells remain unclear. Our recent results demonstrated that conditional deletion of the AURKA gene or blockade of Aurora-A by alisertib slowed tumor growth in association with an increase in the infiltration of intratumoral CD8 þ T cells as well as the mRNA levels of their IL10 receptor a (IL10Ra). The antitumor effects of targeting Aurora-A were attenuated in the absence of CD8 þ T cells. In addition, antibody-mediated blockade of IL10Ra dramatically decreased the percentage of intratumoral CD8 þ T cells. In further experiments, we found that the levels of IL10 were elevated in the serum of azoxymethane/dextran sodium sulfate-treated AURKA flox/þ ; VillinCre þ mice. Unexpectedly, we found that in addition to Aurora-A's mitotic role, inhibition of Aurora-A elevated IL10 transcription, which in turn increased the IL10Ra mRNA levels in CD8 þ T cells. Thus, inhibition of Aurora-A could be a useful treatment strategy for recruiting tumor-specific intratumoral CD8 þ T cells.Implications: Understanding the mechanisms by which inhibition of Aurora-A promotes CD8 þ T-cell infiltration and activation, as mediated by the IL10 pathway could provide a potential strategy for tumor immunotherapy.

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Section: Histologic Analysismentioning

confidence: 99%

Inhibition of Aurora-A Promotes CD8+ T-Cell Infiltration by Mediating IL10 Production in Cancer Cells

Han

Jiang

Wang

et al. 2020

Molecular Cancer Research

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“…For H&E staining, the histological sections were deparaffinized and hydrated through a series of decreasing concentrations of ethanol (100-80%), then stained with H&E (Beyotime, Shanghai, China), and covered with synthetic resin. Samples were observed by light microscopy using an Eclipse E400 microscope (Nikon, Tokyo, Japan) as described previously [16].…”

Section: Haematoxylin and Eosin (Hande) And Immunofluorescence Stainingmentioning

confidence: 99%

Inhibition of Aurora-A improves insulin resistance by ameliorating islet inflammation and controlling interleukin-6 in a diabetic mouse model

et al. 2020

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Aurora-A kinase, a serine/threonine mitotic kinase, is reportedly upregulated in skin tissues of individuals with type 2 diabetes mellitus , although its function in diabetes is unclear. C57BL/6 J mice were utilized to establish a type 2 diabetic model and explore the functions of Aurora-A in diabetes. Aurora-A was highly expressed in the pancreas of the diabetic mice as confirmed by western blot. Inhibition of Aurora-A did not affect fasting blood glucose and body weight, but did improve insulin resistance, as indicated by improved oral glucose tolerance, insulin tolerance, and the Homoeostasis Model Assessment-Insulin Resistance index. Blockade of Aurora-A dramatically decreased the number of infiltrating macrophages in the pancreas in parallel with decreases in the levels of serum insulin and interleukin-6 (IL-6) mRNA. The levels of phosphorylated forms of protein kinase B, which are the key mediators of in insulin resistance, were not induced in liver, adipocyte tissues, and skeletal muscle by alisertib treatment. Our findings indicate that suppression of Aurora-A could at least partially enhance insulin sensitivity by decreasing the number of infiltrating macrophages and IL-6 level in a type 2 diabetic mouse model.

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“…The effect of alisertib on Aurora A and the Jak/STATs signaling pathways was assessed by immunoblotting, as described previously 21 , 23 , using the following phospho-specific antibodies: p-Aurora A/B/C (Cell Signaling Technology, #2914), Aurora A (35C1) (Abcam, ab13824), p-Jak1 (T1022/1023) (Cell Signaling Technology, #3331), Jak1 (6G4) (Cell Signaling Technology, #3344), p-Jak2 (T1007/1008) (Cell Signaling Technology, #3776), Jak2 (D2E12) (Cell Signaling Technology, #3230), p-STAT1 (T701) (Cell Signaling Technology, #7649), STAT1 (D1K9Y) (Cell Signaling Technology, #14994), p-STAT2 (T690) (Cell Signaling Technology, #4441), STAT2 (D9J7L) (Cell Signaling Technology, #72604), PARP (46D11) (Cell Signaling Technology, #9532), DNMT3B (D7070) (Cell Signaling Technology, #67259), DNMT1 (Proteintech., 24206-1-AP), DNMT3A (Proteintech., 19366-1-AP), ubiquitin (Proteintech., 10201-1-AP), UHRF1(Proteintech., 21402-1-AP), flag (Abmart, M20008L) and β-actin (Proteintech.,66009-1-Ig).…”

Section: Methodsmentioning

confidence: 99%

“…The effect of alisertib on Aurora A and the Jak/STATs signaling pathways was assessed by immunoblotting, as described previously [21,23], using the following phospho-specific antibodies: p-Aurora A/B/C (Cell Signaling Technology, #2914), Aurora A (35C1) (Abcam, ab13824), p-Jak1 (T1022/1023) (Cell Signaling Technology, #3331), Jak1 (6G4) (Cell Signaling Technology, #3344), p-Jak2 (T1007/1008) (Cell Signaling Technology, #3776), Jak2…”

Section: Immunoblottingmentioning

confidence: 99%

Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1

Han

Chen

et al. 2021

Int. J. Med. Sci.

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Aurora-A has attracted a great deal of interest as a potential therapeutic target for patients with CRC. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis behind the ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1 mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of CpG islands of STAT1 promoter and STAT1 overexpression. Simultaneous silencing Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting Aurora-A and UHRF1 can be a promising therapeutic strategy for CRC.

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Effects of Photoperiod on Acetaminophen-Induced Hepatotoxicity in Mice

Cited by 8 publications

References 26 publications

Inhibition of Aurora-A Promotes CD8+ T-Cell Infiltration by Mediating IL10 Production in Cancer Cells

Inhibition of Aurora-A Promotes CD8+ T-Cell Infiltration by Mediating IL10 Production in Cancer Cells

Inhibition of Aurora-A improves insulin resistance by ameliorating islet inflammation and controlling interleukin-6 in a diabetic mouse model

Simultaneous silencing Aurora-A and UHRF1 inhibits colorectal cancer cell growth through regulating expression of DNMT1 and STAT1

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