RESUMEN
Altered lipid metabolism is a hallmark of hepatocellular carcinoma (HCC), a common malignancy with a dismal prognosis against which there is a lack of effective therapeutic strategies. Bufalin, a classical Na[Formula: see text]-K[Formula: see text]-ATPase (NKA) inhibitor, shows a potent antitumor effect against HCC. However, the role of bufalin in regulating lipid metabolism-related pathways of HCC remains unclear. In this study, we examined the interaction between bufalin and its target molecule, ATP1A1/CA2, in vitro and in vivo and explored the intersected downstream pathways in silico. A multi-omics analysis of transcriptomics and metabolomics was employed to screen for potential action targets. The results were verified and correlated with the downstream lipid de novo synthesis pathway and the bufalin/ATP1A1/CA2 axis. We found that bufalin suppressed the ATP1A1/CA2 ratio in the treated HCC cells and showed a negative correlation with bufalin drug sensitivity. Functionally, ATP1A1 overexpression and CA2 down-regulation inhibited the bufalin-suppressed HCC proliferation and metastasis. Furthermore, down-regulation of CA2 induced epithelial-mesenchymal transition and bufalin resistance in HCC cells by up-regulating ATP1A1. Mechanistically, lipid metabolism-related signaling pathways were enriched in low ATP1A1 and high CA2 expression subgroups in GSEA. The multi-omics analysis also showed that bufalin was closely related to lipid metabolism. We demonstrated that bufalin inhibits lipogenesis and tumorigenesis by down-regulating SREBP-1/FASN/ACLY via modulating the ATP1A1/CA2 axis in HCC.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Lipogénesis/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Proliferación Celular/genética , Transformación Celular Neoplásica , Carcinogénesis/genética , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
Background: Aging may result in autonomic nervous dysfunction. Heart rate variability (HRV) is a non-invasive method to measure autonomic nervous activities. Many studies have shown that HRV contributes to the risk assessment of diseases. A Polar V800 heart rate monitor is a wearable device that measures R-R intervals, but has only been validated in younger adults under limited testing conditions. There is no validation of the V800 under mental stress or in dual task testing conditions. Therefore, this study investigated the validity of the Polar V800 heart rate monitor for assessing R-R intervals and evaluated if there were differences on HRV parameters under different situations in community-dwelling elderly adults. Methods: Forty community-dwelling elderly adults were recruited. Heart rates were recorded via electrocardiogram (ECG) and the V800 under sitting, during an arithmetic test, during a naming test, a self-selected walking velocity test (SSWV), and dual tasks (SSWV performing mental arithmetic test and SSWV performing naming test). Indices of time and frequency domains of HRV were calculated afterwards. The intra-class correlation coefficient (ICC) analysis and effect size were calculated to examine the concurrent validity between the V800 and the ECG. Results: All HRV indices from the V800 were highly correlated with the ECG under all tested conditions (ICC = 0.995-1.000, p < 0.001) and the effect size of bias was small (<0.1). Conclusion: Overall, the V800 has good validity on the assessment of HRV in community-dwelling elderly adults during sitting, mental arithmetic test, naming test, SSWV, and dual tasks.