RESUMO
The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation.
Assuntos
Neoplasias Colorretais/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Metformina/farmacologia , Putrescina/biossíntese , Ureia/metabolismo , Animais , Biomarcadores , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Expressão Gênica , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
OBJECTIVE: To evaluate the immediate effect of moxibustion at Shenshu (BL 23) on renal hemodynamics in patients with chronic kidney disease(CKD)ï¼. METHODS: Thirty-two non-dialysis patients with CKD were recruited in this study. Moxibustion was applied at bilateral BL 23 for 30 min. The peak systolic velocity (PSV), end diastolic velocity (EDV) of the interlobar renal artery were measured by Doppler ultrasonography (US) before, and 0 and 15 min after moxibustion. The renal resistance index (RI) was equal to (PSVï¼EDV)/PSV. The body temperature (T), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) were also monitored at the same time points. RESULTS: After moxibustion, the EVD level at 15 min after moxibustion was significantly increased (P<0.05), and the renal RI levels at 0 and 15 min after moxibustion were significantly down-regulated in comparison with their own pre-treatment (P<0.01). No significant changes were found in the levels of PSV, T, SBP, DBP and HR after moxibustion (P>0.05). CONCLUSION: Moxibustion at BL 23 can increase EDV and reduce renal RI of the interlobar renal artery in patients with CKD, which may be useful in relieving kidney disorders by improving renal blood flow.