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
Guidelines for clinical trials of acupuncture are scarce, particularly in their guidance on choosing an adequate control in an acupuncture trial. This guideline was developed to address the research methodology for clinical research in acupuncture which contains the essential elements to be considered in the design, preparation and reporting of an acupuncture RCT. Particularly, investigators focused on the control design because of the unique feature of acupuncture. As one size does not fit all, one single design cannot answer all research questions. Therefore, we recommend that the clinical questions be answered in different stages of trials by choosing the appropriate control or comparator. This concept is adapted from classical drug trials developed by the Food and Drug Administration (FDA) of USA in which trials are staged in four phages in order to address different research questions. From the points listed above, this guideline offers the specific recommendations in an acupuncture RCT.
Asunto(s)
Terapia por Acupuntura , Guías de Práctica Clínica como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Terapia por Acupuntura/métodos , Humanos , Proyectos de InvestigaciónRESUMEN
Analgesic effects of acupuncture have been extensively studied in various clinical trials. However, the conclusion remains controversial, even among large scale randomized controlled trials. This study aimed to evaluate the association between the conclusion of the trials and the types of control used in those trials via systematic review. Published randomized controlled trials of acupuncture for pain were retrieved from electronic databases (Medline, AMED, Cochrane libraries, EMBASE, PsycINFO, Clinicaltrials.gov, and CAB Abstracts) using a prespecified search strategy. One hundred and thirty-nine studies leading to 166 pairs of acupuncture-control treatment effect comparisons (26 studies comprised of 53 intervention-control pairs) were analyzed based on the proportion of positive conclusions in different control designs. We found that treatment effects of acupuncture compared with nontreatment controls had the highest tendency to yield a positive conclusion (84.3%), compared with nonneedle-insertion controls (53.3%). Whereas with needle-insertion controls, the lowest tendency of positive conclusions was observed (37.8%). Consistently, in studies reporting successful blinding, a higher tendency of positive findings on the treatment effect of acupuncture was found in the noninsertion sham controls compared with that in the insertion sham controls. We conclude that the type of control is likely to affect the conclusion in acupuncture analgesic trials. Appropriate control should be chosen according to the aims of studies.