Periplcymarin targets glycolysis and mitochondrial oxidative phosphorylation of esophageal squamous cell carcinoma: Implication in anti-cancer therapy.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype of esophageal cancer (EC) in China, and demonstrates varying levels of resistance to multiple chemotherapeutic agents. Our previous studies have proved that periplocin (CPP), derived from the extract of cortex periplocae, exhibiting the capacity to hinder proliferation and induce apoptosis in ESCC cells. Several studies have identified additional anti-cancer constituents in the extract of cortex periplocae, named periplcymarin (PPM), sharing similar compound structure with CPP. Nevertheless, the inhibitory effects of PPM on ESCC and their underlying mechanisms remain to be further elucidated. PURPOSE: The aim of this study was to investigate function of PPM inhibiting the growth of ESCC in vivo and in vitro and to explore its underlying mechanism, providing the potential anti-tumor drug for ESCC. METHODS: Initially, a comparative analysis was conducted on the inhibitory activity of three naturally compounds obtained from the extract of cortex periplocae on ESCC cells. Among these compounds, PPM was chosen for subsequent investigation owing to its comparatively structure and anti-tumor activity simultaneously. Subsequently, a series of biological functional experiments were carried out to assess the impact of PPM on the proliferation, apoptosis and cell cycle arrest of ESCC cells in vitro. In order to elucidate the molecular mechanism of PPM, various methodologies were employed, including bioinformatics analyses and mechanistic experiments such as high-performance liquid chromatography combined with mass spectrometry (HPLC-MS), cell glycolysis pressure and mitochondrial pressure test. Additionally, the anti-tumor effects of PPM on ESCC cells and potential toxic side effects were evaluated in vivo using the nude mice xenograft assay. RESULTS: Our study revealed that PPM possesses the ability to impede the proliferation of ESCC cells, induce apoptosis, and arrest the cell cycle of ESCC cells in the G2/M phase in vitro. Mechanistically, PPM exerted its effects by modulating glycolysis and mitochondrial oxidative phosphorylation (OXPHOS), as confirmed by glycolysis pressure and mitochondrial pressure tests. Moreover, rescue assays demonstrated that PPM inhibits glycolysis and OXPHOS in ESCC cells through the PI3K/AKT and MAPK/ERK signaling pathways. Additionally, we substantiated that PPM effectively suppresses the growth of ESCC cells in vivo, with only modest potential toxic side effects. CONCLUSION: Our study provides novel evidence that PPM has the potential to simultaneously target glycolysis and mitochondrial OXPHOS in ESCC cells. This finding highlights the need for further investigation into PPM as a promising therapeutic agent that targets the tumor glucose metabolism pathway in ESCC.

Research on fuzi based on animal thermotropism behavior to discover if it has fewer "hot" characteristics without Ganjiang.

OBJECTIVE: To investigate whether fuzi (Radix Aconiti Praeparata) has fewer "hot" characteristics when administered without Ganjiang (Rhizoma Zingiberis). METHODS: Differences in the thermotropism behaviors of mice treated either with fuzi (Radix Aconiti Praeparata), Ganjiang (Rhizoma Zingiberis) or the combination of the two given intragastrically were investigated using the Animal Thermotropism Behavior Surveillance System. The water intake volume, oxygen consumption volume, adenosine triphosphatase (ATPase) activity, total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) activity were determined during the investigation. RESULTS: When fuzi and ganjiang were administered together, the rate at which mice remained on a warm plate ("remaining rate") and the times and distances of their movement were all significantly reduced (P < 0.05). Compared with the Normal group, the reduction was 55.1%, 48.3% and 44.8%, while compared with the Fuzi group, the reduction was 57.6%, 34.3% and 36.0%, indicating that "cold" tropism was significantly increased. Compared with the normal and fuzi groups, the ATPase activity and the respiratory oxygen consumption volume of the fuzi + ganjiang group were significantly increased (P < 0.05), suggesting an improvement in energy metabolism and showing a "hot" characteristic when Fuzi and Ganjiang are present together. Additionally, the T-AOC and T-SOD activity were significantly enhanced (P < 0.05). CONCLUSION: The behavior of mice tending toward "cold" tropism can be regarded as a quantitative reflection of Fuzi having fewer characteristics consistent with a "hot" nature when not used with Ganjiang, the functional mechanism of which may be a change in the ATPase activity in liver tissue.

Comparative pharmacokinetic study of paeoniflorin and albiflorin after oral administration of Radix Paeoniae Rubra in normal rats and the acute cholestasis hepatitis rats.

A comparative study was designed and conducted to compare the pharmacokinetic difference of paeoniflorin and albiflorin after oral administration of Radix Paeoniae Rubra to normal rats and the acute cholestasis hepatitis rats induced by alpha-naphthylisothiocyanate (ANIT). UPLC-ESI-MS/MS method was employed to determine the level of paeoniflorin and albiflorin in rat plasma using geniposide as the internal standard (IS). Unpaired Student's t-test was used for the statistical comparison. The investigation showed that there were significant differences between the normal rats and the acute cholestasis hepatitis rat groups in calculated parameters, such as AUC(0-t), AUC(0-∞), T(max) and CLz/F. The results indicated that acute liver injury in rats could alter the pharmacokinetics of drug. Since patients are the final users of the drug, it is essential to investigate the pharmacokinetics of the drug in disease status. Therefore, we used normal rats and the acute cholestasis hepatitis rats to study pharmacokinetics of Radix Paeoniae Rubra with the purpose of examining the influence of disease on the metabolic course.