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.

Diosgenin relieves oxaliplatin-induced pain by affecting TLR4/NF-κB inflammatory signaling and the gut microbiota.

Diosgenin extracted from fenugreek, yam and other foods exhibits a wide range of pharmacological activities, especially for the treatment of pain and other nervous system diseases. However, its role in oxaliplatin-induced peripheral neuropathy (OIPN) is unclear. To explore its detailed mechanism on the pain caused by chemotherapy, we carried out this experiment. In this study, the effects of diosgenin on injured PC12 cells and OIPN mice were examined. The results showed that diosgenin not only protected PC12 from injury, but also reduced the mechanical withdrawal threshold and cold hyperalgesia in OIPN mice. Diosgenin inhibited oxidative stress, the cell glial fibrillary acidic protein, and the pro-inflammatory cytokines such as tumor necrosis factor-α, toll-like receptor 4 and nuclear factor-κB in the brain. Furthermore, the fecal microbiota transplantation experiment indicated that diosgenin improved OIPN through regulation of the gut microbiota. All in all, diosgenin ameliorates peripheral neuropathy and is worthy of further study in the treatment of neuropathic pain.

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.

Effects of the polysaccharides extracted from Chinese yam (Dioscorea opposita Thunb.) on cancer-related fatigue in mice.

The aim of this study was to investigate the anti-fatigue activity of Chinese Yam polysaccharides (CYPs). The structural characterization of CYPs was conducted using Fourier transform-infrared spectroscopy, nuclear magnetic resonance spectroscopy, gel permeation chromatography-light scattering-refractive index, and ion chromatography. The weight-loaded swimming capability, behavior performance, tumor growth, content of adenosine triphosphate (ATP), and biochemical markers of CYP in a cancer-related fatigue mouse model were tested. The results showed that CYP is a mixture with an average Mw of 75.57 kDa and is mainly composed of rhamnose, glucuronic acid, glucose, galactose, and arabinose with a molar ratio of 0.01 : 0.06 : 1.00 : 0.17 : 0.01. CYP increased the exhausting swimming time, which was decreased in the cisplatin (DDP) control group and the model group. CYP also increased the content of ATP in musculus gastrocnemius, which was down-regulated by DDP; the DDP had significantly enhanced the contents of interleukin-1ß (IL-lß), malondialdehyde (MDA), blood urea nitrogen (BUN) and lactic dehydrogenase (LDH) and inhibited the activity of superoxide dismutase (SOD) in the muscle. Administration of CYP decreased the levels of IL-lß, MDA, BUN and LDH, and up-regulated the SOD activity. The DDP + CYP group presented a decreased tumor volume and a lower tumor weight as compared with the model group. Moreover, the mice in the CYP or DDP + CYP groups had heavier body weights than the mice in the model group and DDP group. These results suggest that CYP should improve cancer-related fatigue via the regulation of inflammatory responses, oxidative stress and increase in energy supplementation.

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.

The Effects of B1344, a Novel Fibroblast Growth Factor 21 Analog, on Nonalcoholic Steatohepatitis in Nonhuman Primates.

Nonalcoholic steatohepatitis has emerged as a major cause of liver diseases with no effective therapies. Here, we evaluate the efficacies and pharmacokinetics of B1344, a long-acting polyethylene glycolylated (PEGylated) fibroblast growth factor 21 analog, in a nongenetically modified nonhuman primate species that underwent liver biopsy and demonstrate the potential for efficacies in humans. B1344 is sufficient to selectively activate signaling from the ßKlotho/FGFR1c receptor complex. In cynomolgus monkeys with nonalcoholic fatty liver disease (NAFLD), administration of B1344 via subcutaneous injection for 11 weeks caused a profound reduction of hepatic steatosis, inflammation, and fibrosis, along with amelioration of liver injury and hepatocyte death, as evidenced by liver biopsy specimen and biochemical analysis. Moreover, improvement of metabolic parameters was observed in the monkeys, including reduction of body weight and improvement of lipid profiles and glycemic control. To determine the role of B1344 in the progression of murine NAFLD independent of obesity, B1344 was administered to mice fed a methionine- and choline-deficient diet. Consistently, B1344 administration prevented the mice from lipotoxicity damage and nonalcoholic steatohepatitis in a dose-dependent manner. These results provide preclinical validation for an innovative therapeutic approach to NAFLD and support further clinical testing of B1344 for treating nonalcoholic steatohepatitis and other metabolic diseases in humans.

UFLC-MS/MS Determination and Population Pharmacokinetic Study of Tanshinol, Ginsenoside Rb1 and Rg1 in Rat Plasma After Oral Administration of Compound Danshen Dripping Pills.

BACKGROUND AND OBJECTIVES: As a traditional Chinese Materia Medica (CMM), the Compound Danshen Dripping Pill (CDDP) is widely used for the treatments of cardiovascular diseases. In view of its undefined applicable population and dosage, a population pharmacokinetic (PPK) study is required. The objective of this study was to explore the feasibility of multi-component CMM PPK in rat plasma after oral administration of CDDP based on sparse sampling. METHODS: In this research, a simple, rapid and highly sensitive UFLC-MS/MS method for the simultaneous determination of tanshinol (TSL), ginsenoside Rb1 (GRb1) and ginsenoside Rg1 (GRg1) has been successfully developed in rat plasma. Moreover, the validated method has been applied to a PPK study of CDDP based on sparse data. We established the PPK models for these three main active constituents using a nonlinear mixed-effects model, taking into account of factors such as gender, age in weeks and weight. RESULTS: The PPK models of TSL and GRb1 were best described by a one-compartment model with linear elimination and first-order absorption. The model of GRg1 was best described by a two-compartment model with first-order absorption. Bootstrap validation and a visual predictive check confirmed the predictive ability, the model stability and the precision of the parameter estimates from these models. CONCLUSION: As a preliminary exploration toward the clinical population pharmacokinetic research, this study provides a reference for the population pharmacokinetic study of traditional CMM.

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.

Effect of Rhizoma Paridis saponin on the pain behavior in a mouse model of cancer pain.

Rhizoma Paridis saponins (RPS) as active parts of P. polyphylla Smith var. yunnanensis has been used as an anti-cancer drug in traditional Chinese medicine. In this study, RPS was first found to demonstrate a potent effect on markedly reducing the pain induced by cancer. Therefore, the aim of this study was to further explore the analgesic effect of RPS and its possible reaction pathway on H22 hepatocarcinoma cells inoculated in the hind right paw of mice. Cancer-induced pain model mice were randomly divided into 5 groups (n = 10) and orally administered with RPS (50-200 mg kg-1) for 2 weeks. On the last day of treatment, the pain behavior of mice was measured using hot-plate test and open field test, and brain tissues were sampled for detection of biochemical indices, malondialdehyde (MDA), superoxide dismutase (SOD), prostaglandin E2 (PGE2), serotonin (5-HT) and ß-endorphin (ß-EP). Moreover, the concentrations of NF-κB and IL-1ß in the blood serum were measured by ELISA reagent kits. In addition, naloxone, the non-selective antagonist of opioid receptors, was used to identify the opioid receptors involved in RPS's action. It has been found that RPS alleviates cancer pain mainly via the suppression of inflammatory pain induced by oxidative damage, such as decreasing MDA and PGE2 levels, renewing activity of SOD, as well as increasing 5-HT and ß-EP in the brain and suppressing the expression of NF-κB and IL-1ß in the serum in a concentration-dependent manner. Overall, the current study highlights that RPS has widespread potential antinociceptive effects on a mouse model of chronic cancer pain, which may be associated with the peripheral nervous system and the central nervous system.