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Next generation gene sequencing facilitates transcriptome analysis of liver tissue in dexmedetomidine-treated liver resection model mice

ABSTRACT: Purpose: Liver tissue regeneration is vital in the restoration of liver function after hepatectomy and liver transplantation. Dexmedetomidine is a highly selective alpha2-adrenergic receptor (A2R) agonist, whichis regarded as a sedative and analgesic medication that is frequently used intra- and postoperatively in hepatic surgery. Owing to its critical role in the protection of multiple organs, the purpose of this study is to investigate the effects of dexmedetomidine on liver regeneration. Methods:Dexmedetomidine 25 μg.kg-1 was injected intraperitoneally 30 minutes before a 70% hepatectomy performed in mice. Blood and liver samples were obtained for analysis after 48 hours. Mouse primary hepatocytes (MPHMPHs) were incubated with 10 μM dexmedetomidine for 24 hours, then analyzed for cell proliferation from mRNA and protein levels. Transcriptome sequencing revealed the potential mechanism of dexmedetomidine promoting liver regeneration, verified by western blot analysis. Loss of function analysis was performed using the selective corresponding antagonist of Dexmedetomidine . Results:25 μg.kg-1 Ddexmedetomidine significantly promoted mouse liver regeneration in vivo. The liver/body weight ratio was elevated following dexmedetomidine preconditiontreatment. ImmunohistochemistryProliferative markers of Ki67, PCNA and cyclin-D1 suggested more hepatocytes enter a state of proliferatimore cell proliferationon in dexmedetomidine group via immunohistochemistry. These effects were also phenocopied in vitro Incubating withwhere 10 µM dexmedetomidine increased MPH proliferation in vitro, detected by Edu and Ki67 immunofluorescence staining. The expression of cyclins, PCNA mRNA, protein expression levels of cyclins and PCNA were higher with dexmedetomidine treatment in vivo and in vitro. The p-AKT, p-GSK3beta and beta-catenin expression levels were elevated by dexmedetomidine. The effect of dexmedetomidine on MPH proliferation and p-AKT, p-GSK3beta and beta-catenin expressionse phenomenon was blocked by atipamezole (ATI, alpha2 adrenoceptor antagonist) pretreatment. Conclusion:Dexmedetomidine activates AKT/GSK3beta/beta-catenin pathway to promote enhance liver regeneration via binding the alpha-2 adrenoreceptor, which would shed light on a potential therapeutic clinical role to protect liver function in a broad of hepatic surgery.

ORGANISM(S): Mus musculus

PROVIDER: GSE188867 | GEO | 2022/11/01

REPOSITORIES: GEO

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Project description:The existence of a radiation bystander effect, in which non-irradiated cells respond to signals from irradiated cells, is well established. It raises concerns for the interpretation of risks from exposure to low doses of ionizing radiation. Sparse data exists about the bystander signaling mechanisms and the ability to transmit damaging effects both spatially and temporally. To understand early signaling and cellular changes in bystanders, we have measured global gene expression 30 minutes after direct and bystander exposure to alpha particle in primary human lung fibroblasts. Gene ontology and pathway analyses suggested that the earliest measured changes at 30 minutes after treatment are in cell structure, motility and adhesion categories and a significant number of genes belong to the category of inflammation and cell-to-cell communication. We investigated time course gene expression profiles of matrix metalloproteinases 1 and 3 (MMP1 and MMP3), chemokine ligands 2, 3 and 5 (CXCL2, CXCL3 and CXCL5), interleukins 1a, 1b, 6 and 33 (IL1A, IL1B, IL6 and IL33) growth differentiation factor 15 (GDF15) and superoxide dismutase2 (SOD2) by real time quantitative PCR. These encode proteins involved in cellular signaling via the NFkappaB pathway and time course of mRNA levels revealed an increased response at 30 minutes after irradiation followed by another wave at 4 to 6 hours. We also investigated protein modifications in the AKT-GSK-3 signaling pathway and found that in irradiated cells AKT and GSK3beta are hyper-phosphorylated at 30 minutes and this effect is maintained until 4 hours after exposure. In bystanders there is a similar response with a delay of 30 minutes. In irradiated cells, inactivated GSK3beta led to decreased phosphorylation of beta-catenin. Our results are the first to show that the radiation induced bystander signal can induce a widespread gene expression response as early as 30 minutes after exposure and that these changes are accompanied by protein modification of signaling modules such as AKT and GSK3beta. There are 12 total samples, 4 corresponding biological replicates of IMR90 cells that were not irradiated (control=C), irradiated (alpha=A) and bystander (B), cells were harvested 0.5 hr after treatment

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Next generation gene sequencing facilitates transcriptome analysis of liver tissue in dexmedetomidine-treated liver resection model mice

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