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The present study aimed to determine the effects of Tianxiangdan Granule on nuclear factor (NF)-κB p65 and p38 mitogen-activated protein kinase (MAPK) inflammatory signaling pathways, and explored the possible mechanism underlying the effects of Tianxiangdan Granule on prevention and treatment of atherosclerosis. A total of 48 apolipoprotein E-/- mice (age, 8 weeks) were selected and divided into two groups: The normal control group (n=12) and the modeling group (n=36). In the modeling group, mice were fed a high-fat diet and were maintained in an artificial climate box, in order to stimulate the climate and eating habit characteristics of Xinjiang. Every morning, ApoE-/- mice in the modeling group were placed in the artificial climate box at 10:00 am and were taken out at 09:00 pm and placed back in the room temperature environment. The temperature of the artificial climate box was set at 6±2°C, relative humidity was controlled at 25-32.8% and the light-dark cycle was 12 h/day. The purpose of this method was to establish the Huizhuo Tanzu type atherosclerosis model. Following successful generation of the model, mice in the modeling group were randomly divided into three groups: Model group (n=10), Tianxiangdan group (n=10) and atorvastatin group (n=10). After 12 weeks, mice were sacrificed and the serum levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α in each group were detected. Furthermore, the expression levels of NF-κB p65 and p38 MAPK in aortic tissue were detected. The results indicated that the concentrations of IL-1β and TNF-α were significantly higher in mice in the model group compared with in the normal control group (P<0.01), whereas the concentrations of IL-1β and TNF-α were lower in the Tianxiangdan and atorvastatin groups compared with in the model group (P<0.01). Furthermore, the protein expression levels of phosphorylated (p)-NF-κB p65 and p-p38 MAPK protein were higher in aortic tissues from the model group compared with in the normal control group (P<0.01), p-NF-κB p65 and p-p38 MAPK protein expression was reduced in the atorvastatin and Tianxiangdan groups compared with in the model group. The present study indicated that the mechanism underlying the effects of Tianxiangdan Granule on the prevention and treatment of atherosclerosis may be as follows: Tianxiangdan Granule may decrease the expression of the inflammatory cytokines IL-1β and TNF-α, and suppress activation of the NF-κB p65 and p38 MAPK signaling pathways. [ABSTRACT FROM AUTHOR]