Abstract
Euphorbia kansui stir-fried with vinegar (V-kansui) has promising biological activities toward treating malignant ascites with reduced toxicity compared to crude kansui. But the mechanism concerning promoting the excretion of ascites has not been systematically studied. The purpose of this paper was to investigate the possible mechanism of V-kansui in treating malignant ascites, including metabolic pathways and molecular mechanism using an integrated serum and urine metabolomics coupled with network pharmacology. Serum and urine samples of rats were collected and analyzed by ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). A comparison with crude kansui was also made to demonstrate the feasibility of processing. Principle component analysis (PCA) and orthogonal partial least square discriminate analysis (OPLS-DA) were conducted to discriminate the groups, search important variables and reveal the possible pathways. A compound-target-metabolite network was finally constructed to identify the crucial targets to further understand the molecular mechanism. Sixteen significant metabolites contributing to the discrimination of model and control groups were tentatively screened out. They were mainly involved in the arachidonic acid metabolism, steroid hormone biosynthesis and primary bile acid to possibly reduce inflammatory and modulate the renin-angiotensin-aldosterone system to achieve treating malignant ascites. A bio-network starting from the compounds and ending in the metabolites was constructed to elucidate the molecular mechanism. HSP90AA1, ANXA2, PRDX6, PCNA, SOD2 and ALB were identified as the potential key targets that were responsible for the treatment of malignant ascites by the parameter combining the average shortest path length and betweenness centrality. The correlated 17 compounds were considered as the potential active ingredients in V-kansui. In addition, the metabolomics showed that the effect of V-kansui was almost in accordance with crude kansui. These results systematically revealed the mechanism of V-kansui against malignant ascites for the first time using metabolomics coupled with network pharmacology. V-kansui could be a promising safe and therapeutic medicine for the excretion of ascites.
Highlights
Hepatocellular carcinoma (HCC) is attracting much more attention because it can lead to most malignancies
The representative based peak intensity (BPI) chromatograms of serum and urine are displayed in Figure S1 and Figure S2. 377 and 504 metabolites were detected from serum and urine samples, respectively
In this study, integrated serum and urine metabolomics based on UPLC-Q-TOF-MS coupled with network analysis was used to interpret the mechanism of kansui stir-fried with vinegar in treating malignant ascites
Summary
Hepatocellular carcinoma (HCC) is attracting much more attention because it can lead to most malignancies. Advances have been made in the treatment of HCC, the prognosis of which remains unsatisfactory. Malignant ascites is one of the severe complications of HCC. Current treatments mostly focus on the elimination of ascites, such as salt restriction and peritoneal catheter drainage. Salt restriction has a high risk of protein malnutrition due to the reduced nutrient intake, which may result in sarcopenia and increased mortality. Large volume paracentesis is invasive, requires more time of recovery and leads to bad quality of life. Diuretic therapy after large volume paracentesis is not sufficient to prevent the recurrence of ascites. The results of the above methods are still unfavorable and the treatment of malignant ascites is an urgent problem that need to be solved
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