A new insight into material basis of rhizoma Paridis saponins in alleviating pain.

ETHNOPHARMACOLOGICAL RELEVANCE: Paris polyphylla, as a traditional Chinese herbal medicine, was often used to relieve inflammation and pain. Rhizoma Paridis saponins (RPS) as the main active components of Paris polyphylla have excellent analgesic effects. AIM OF THE STUDY: Determine the analgesic material basis of RPS. MATERIALS AND METHODS: LC-MS/MS was used to analyze RPS, plasma after intravenous injection of RPS, and oral administration of RPS. H22 plantar pain model was established to explore the analgesic material basis of RPS. Moreover, correlation analysis, network pharmacology, RT-PCR and molecular docking were applied in this research. RESULTS: RPS had dose-dependently analgesic effects in acetic acid- and formalin-induced pain models. LC-MS/MS detection indicated that diosgenin as the metabolite of RPS mainly distributed in brain tissues. The addition of antibiotics increased the anti-tumor effect of RPS, but reduced its analgesic effect. Network pharmacology, RT-PCR and molecular docking showed that diosgenin exerted its analgesic effect through SRC and Rap1 signaling pathway. CONCLUSION: Diosgenin exhibited analgesic effects, while saponins had good anti-tumor effects in RPS. This discovery provided a better indication for the later application of RPS in anti-tumor and analgesic settings.

[Advances of Claudin6-targeting drugs in cancer therapy].

CLDN6 is a member of the CLDNs family that is specifically and highly expressed in cancers such as ovarian, testicular, endocervical, liver and lung adenocarcinoma, but hardly expressed in adult normal tissues. CLDN6 is able to activate multiple signaling pathways, which take part in the development and progression of cancer, including promoting tumor growth, migration and invasion, and promoting chemoresistance in cancer. In recent years, CLDN6 has received much attention as a novel target for cancer therapeutics. Many types of anticancer drugs targeting CLDN6 have been developed, including antibody-conjugated drugs (ADC), monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T-cell immunotherapy (CAR-T). This paper briefly summarizes the structure, expression and function of CLDN6 in tumors, and reviews the current status and ideas of developing targeted CLDN6 anticancer drugs.

Q-marker identification of Paris polyphylla var. yunnanensis (Franch.) Hand.-Mazz. in pulmonary metastasis of liver cancer mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Rhizoma Paridis saponins (RPS) as the mainly active components of Paris polyphylla var. yunnanensis (Franch.) Hand.-Mazz., possess tumor therapeutic potential. However, the anti-tumor material basis of RPS in liver cancer pulmonary metastasis remains poorly understood. The objective of this study was to identify the distribution and anti-cancer effects of RPS in liver cancer pulmonary metastatic model. MATERIALS AND METHODS: In this study, a mouse liver cancer pulmonary metastasis model was established to determine the distribution of different saponins in the tissues by UPLC-MS and plasma protein binding rate. RESULTS: As a result, RPS prolonged the survival time and inhibited the pulmonary metastasis in H22 injected mice through its underlying mechanism. UPLC-MS identified saponins from RPS such as PVII, PH, PVI, PII, gracillin and PI in tissues, which may be regarded as the Q-markers in RPS. Surprisingly, the concentration of PI, PII and gracillin as diosgenyl saponins was higher than that of pennogenyl saponins in the liver and lung. Besides, plasma protein binding rate of PII was higher than that of PVII. CONCLUSION: These findings suggested that PVII, PH, PVI, PI, PII and gracillin are regarded as the Q-markers of RPS in liver cancer pulmonary metastasis. The concentration of PI, PII and gracillin as diosgenyl saponins was higher than that of pennogenyl saponins in the liver and lung. It would be helpful for understanding the importance of RPS with anticancer activities in the future.

Tissue distribution, metabolism and absorption of Rhizoma Paridis Saponins in the rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Paris polyphylla var yunnanensis as a traditional Chinese medicine has been used in the treatment of liver disease for thousands of years. Rhizoma Paridis saponins (RPS) were the main active ingredients in Paris polyphylla with an excellent antitumor effect. However, metabolic and distribution of RPS has not been known. AIM OF THE STUDY: The objective of this study was to research metabolic and distribution of RPS. MATERIALS AND METHODS: In this study, the separation and simultaneous determination of RPS in rat plasma and tissues were developed and validated by LC-MS/MS. The permeability and recovery of RPS were tested by Caco-2. S9 assay suggested the metabolic mode of RPS in rats. RESULTS: After oral administration of RPS, the metabolic compound like diosgenin was detected in different tissues although there was none in RPS. The concentration of PI, PII, PVI, PVII, PH and gracillin in the spleen was the highest among these organs. The content of diosgenin were the highest in lung and brain. Caco-2 test indicated that PI, PII, PVI and PVII were low permeability and low recovery. Efflux ratio indicated that PVI should be a potential P-gp substrate. Potential P-gp substrate may be PVI. S9 assay suggested that RPS possess slow metabolic and moderate metabolic compounds. CONCLUSIONS: Integrated LC-MS/MS analysis of serum samples, together with Caco-2 and S9 assays provided a theoretical basis for the application of RPS in the future.

Pharmacokinetics profiles of polyphyllin II and polyphyllin VII in rats by liquid chromatography with tandem mass spectrometry.

Polyphyllin II (PII) and polyphyllin VII (PVII) are the main active ingredients in Paris Polyphylla with an excellent antitumor effect in vitro and in vivo. In this study, a rapid and precise LC-MS/MS method was developed and validated for the separation and simultaneous determination of PII and PVII in rat plasma, tissues, feces and urine using ginsenoside Rg3 as the internal standard. Positive linearity ranged from 1 to 1,000 ng/ml in samples. At the same time, intra- and inter-day precisions were in range of 1.8-12.0%. The accuracy ranged from 95.9 to 100.8%. Mean extraction recoveries of PII and PVII ranged from 86.6 to 96.4%. The analytical method has been successfully applied to the pharmacokinetic studies of PII and PVII in rats after their i.v. administration. After entering systemic circulation, PII and PVII were rapidly distributed in organs, mainly including liver, lung and spleen. Their elimination rate was slow. All of these data provided a theoretical basis for the application of PII and PVII in the treatment of liver- and lung-related diseases.

Xiao Ke Qing improves glycometabolism and ameliorates insulin resistance by regulating the PI3K/Akt pathway in KKAy mice.

Xiao Ke Qing (XKQ) granule has been clinically used to treat type 2 diabetes mellitus (T2DM) for 10 years in Chinese traditional medication. However, its mechanisms against hyperglycemia remain poorly understood. This study aims to investigate XKQ mechanisms on diabetes and diabetic liver disease by using the KKAy mice model. Our results indicate that XKQ can significantly reduce food and water intake. XKQ treatment also remarkably decreases both the fasting blood glucose and blood glucose in the oral glucose tolerance test. Additionally, XKQ can significantly decrease the serum alanine aminotransferase level and liver index and can alleviate the fat degeneration in liver tissues. Moreover, XKQ can ameliorate insulin resistance and upregulate the expression of IRS-1, PI3K (p85), p-Akt, and GLUT4 in the skeletal muscle of KKAy mice. XKQ is an effective drug for T2DM by ameliorating insulin resistance and regulating the PI3K/Akt signaling pathway in the skeletal muscle.