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Polyphyllin Ⅰ(PPⅠ)and polyphyllin Ⅱ(PⅡ)are the main active substances in the Paris polyphylla.However,liver toxicity of these compounds has impeded their clinical application and the potential hepatotoxicity mechanisms remain to be elucidated.In this work,we found that PPⅠ and PⅡ exposure could induce significant hepatotoxicity in human liver cell line L-02 and zebrafish in a dose-dependent manner.The results of the proteomic analysis in L-02 cells and transcriptome in zebrafish indicated that the hepa-totoxicity of PPⅡ and PⅡwas associated with the cholesterol biosynthetic pathway disorders,which were alleviated by the cholesterol biosynthesis inhibitor lovastatin.Additionally,3-hydroxy-3-methy-lglutaryl CoA reductase(HMGCR)and squalene epoxidase(SQLE),the two rate-limiting enzymes in the choles-terol synthesis,selected as the potential targets,were confirmed by the molecular docking,the over-expression,and knockdown of HMGCR or SQLE with siRNA.Finally,the pull-down and surface plasmon resonance technology revealed that PPⅠ could directly bind with SQLE but not with HMGCR.Collectively,these data demonstrated that PPⅠ-induced hepatotoxicity resulted from the direct binding with SQLE protein and impaired the sterol-regulatory element binding protein 2/HMGCR/SQLE/lanosterol synthase pathways,thus disturbing the cholesterol biosynthesis pathway.The findings of this research can contribute to a better understanding of the key role of SQLE as a potential target in drug-induced hepatotoxicity and provide a therapeutic strategy for the prevention of drug toxic effects with similar structures in the future.
ABSTRACT
As a rare Chinese medicinal material， Paridis Rhizoma is mainly distributed in Yunnan， Guangxi， and Guizhou in southwestern China， with the effect of clearing heat and detoxifying， alleviating edema and relieving pain， cooling liver and tranquilizing mind. It is particularly effective for injuries from falls， fractures， contusions and strains， snake bites， cold wind-induced convulsion， and other diseases， which has been used for more than 2 000 years. According to modern research， polyphyllin Ⅱ， one of the main active components of Paridis Rhizoma， belongs to diosgenin in structure. It has the anti-tumor， anti-inflammatory， antiviral， antibacterial， immune-regulating， antioxidant， and multidrug resistance-reversing activities， showing good application prospect. Especially， the anti-tumor effect of polyphyllin Ⅱ has attracted wide attention， and the mechanism is inhibiting proliferation， migration， and invasion of tumor cells， inducing cell cycle arrest， apoptosis， and autophagy， suppressing angiogenesis， and modulating tumor microenvironment. However， the pharmacokinetic results show that polyphyllin Ⅱ has low bioavailability in vivo due to the low solubility， poor absorption， unsatisfactory distribution， and slow metabolism， which limit the clinical application. In recent years， there has been an explosion of research on the adverse reactions of polyphyllin Ⅱ， such as the strong hemolytic activity and obvious cytotoxicity to liver， kidney， myocardium and cardiovascular cells. Thus， papers were retrieved from "CNKI"， "VIP"， "Wanfang Data"， "PubMed"， "Web of Science"， and "Elsevier SD" with "Paris saponin Ⅱ"， "Polyphyllin Ⅱ" as the main keywords， and the pharmacological activities and mechanisms， pharmacokinetics， and adverse reactions were summarized. The findings are expected to serve as a reference for the in-depth research， development， and utilization of polyphyllin Ⅱ.
ABSTRACT
OBJECTIVE: To study the fingerprints of rhizomes of Paris polyphylla Smith var. polyphylla and Paris polyphylla Smith var. yunnanensis (Franch.) Hand. -Mazz from different origins in Dali and the differences of seven main steroidal saponins. METHODS: The fingerprints of rhizomes of Paris polyphylla var. polyphylla and Paris polyphylla var. yunnanensis from different origins in Dali were established by HPLC. The similarity of fingerprints and seven main steroidal saponins were compared and analyzed. RESULTS: There were 14 common peaks in the fingerprints of rhizomes of Paris polyphylla var. polyphylla from different origins in Dali, and the similarity of the fingerprints of the samples from different habitats except Jinhua Weishan and Longjie Weishan was greater than 0.9. There were 13 common peaks in the fingerprints of rhizomes of Paris polyphylla var. yunnanensis from different origins in Dali, and the similarity of the samples from different origins was greater than 0.92. There were 11 common peaks in the fingerprints of rhizomes of Paris polyphylla var. polyphylla and Paris polyphylla var. yunnanensis from different origins in Dali, and the similarity of the fingerprints was very low, between 0.057 and 0.225. Polyphyllin Ⅰ, polyphyllin Ⅱ, polyphyllin Ⅵ and polyphyllin Ⅶ are detected in the rhizomes of Paris polyphylla var. polyphylla and Paris polyphylla var. yunnanensis from different origins in Dali. The average peak areas of polyphyllin Ⅰ, polyphyllin Ⅱ, polyphyllin Ⅵ and polyphyllin Ⅶ in Paris polyphylla var. yunnanensis from different origins in Dali were higher than those of Paris polyphylla var. polyphylla. Polyphyllin H was detected in the rhizomes of Paris polyphylla var. yunnanensis from Leqiu Nanjian, Jinhua Weishan, Fengyu Eryuan, Dengchuan Eryuan, Hongyan Midu, Xiyi Heqing and the rhizomes of Paris polyphylla var. polyphylla from Wanqiao Dali, Fengyi Dali, Xiyi Heqing, Hongyan Midu and Leqiu Nanjian. Polyphyllin Ⅲ was detected in the rhizomes of Paris polyphylla var. polyphylla from the origins except Longjie Weishan. Polyphyllin Ⅴ was also detected in the rhizomes of Paris polyphylla var. polyphylla in Fengyu Eryuan and Xiyi Heqing. CONCLUSION: Polyphyllin Ⅰ, polyphyllin Ⅱ, polyphyllin Ⅵ and polyphyllin Ⅶ are detected in the rhizomes of Paris polyphylla var. polyphylla and Paris polyphylla var. yunnanensis from different origins in Dali. The similarity of the HPLC fingerprints of the rhizomes of Paris polyphylla var. polyphylla and Paris polyphylla var. yunnanensis is very low, and there are great differences in seven main steroidal saponins. The contents of polyphyllin Ⅰ, polyphyllin Ⅱ, polyphyllin Ⅵ and polyphyllin Ⅴ in Paris polyphylla var. yunnanensis are higher than those in Paris var. polyphylla.
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OBJECTIVE：To establish the method for content dete rmination of polyphyllin Ⅱ，Ⅵ，Ⅶ in Ypsilandra thibetica ， and to compare the differences of 3 saponins in different parts of Y. thibetica from different producing areas. METHODS ：HPLC method was adopted to determine the contents of polyphyllin Ⅱ，Ⅵ，Ⅶ in whole grass part and underground part of Y. thibetica from 10 producing areas. The determination was performed on Kromasil C 18column with mobile phase consisted of acetonirile-water （gradient elution ）at the flow rate of 1.0 mL/min. The column temperature was 35 ℃，and detection wavelength was set at 203 nm；sample size was 10 μL. With the contents of 3 saponins as the index ，20 batches of Y. thibetica were analyzed by cluster analysis and PLS-DA analysis ；the aggregation of samples was analyzed and determined the primary difference components. RESULTS：The linear range of polyphyllin Ⅱ，polyphyllin Ⅵ and polyphyllin Ⅶ were 0.051-2.04，0.007-0.28，0.168-6.72 μg， respectively（r≥0.999 5）；the detection limits were 1.92，1.75，1.87 ng，respectively；and the quantitative limits were 6.40，5.87， 6.23 ng，respectively；RSD of precision ，reproducibility and stability tests （24 h）were all lower than 2％（n＝6）；the average recovery rates were 99.29％，101.38％ and 99.64％，with RSDs of 1.17％，2.64％，0.75％（n＝6），respectively. The content of polyphyllin Ⅱ was 0.615-1.875 mg/g，that of polyphyllin Ⅵ was 0-0.095 mg/g，and that of polyphyllin Ⅶ was 3.158-12.354 mg/g. Cluster analysis showed that 20 batches of samples were clustered into two groups ，batch S 9-S12 were clustered in to one group，and the other 16 batches of samples were clustered into another group. PLS-DA analysis showed that 20 batches of samples were divided into 3 areas，batch S 1，S2，S8，S14，S16，S20 were included in area Ⅰ；batch S 9-S12 included in area Ⅱ；and the rest of the samples included in area Ⅲ. The quality of Y. thibetica from different habitats was different ，and there was no difference in the saponin composition between the whole grass and the underground part. Weight ranking found that mail：cscdtcm@126.com polyphyllin Ⅶ was the main difference component in Y. thibetica，and the content of polyphyllin Ⅶ in Y. thibetica from Pengzhou city and Dayi county was the highest. CONCLUSIONS ：The established method is simple ，convenient and sensitive. It can be used for the content determination of 3 saponins in Y. thibetica . The content of active components is higher and the quality is better in Y. thibetica from Pengzhou city and Dayi county.
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Objective To establish a method for determining the contents of polyphyllin Ⅰ and polyphyllin Ⅱ in Kangkeling Mixture. Methods The contents of polyphyllin Ⅰ and Ⅱ were determined by HPLC gradient elution. Poroshell 120 Ec-C18 column (4.6 mm × 150 mm, 4 μm) was used; Acetonitrile-water (A:B) was set as the mobile phase; the flow rate was 1.0 mL/min; the detection wavelength was 210 nm; column temperature was 30 ℃. Results Polyphyllin Ⅰ showed good linear relationship in the range of 1.009–10.09 μg (r=0.999 6), and the average recovery was 97.31% (RSD=2.05%, n=6). Polyphyllin Ⅱ showed good linear relationship in the range of 0.640 5–6.405 μg (r=0.999 8), and the average recovery was 96.41% (RSD=1.67%, n=6). Conclusion The method is simple, with good repeatability and accurate results, which can be used to determine the contents of polyphyllin Ⅰ and Ⅱ in Kangkeling Mixture.
ABSTRACT
Objective To establish a method for determining the contents of polyphyllin Ⅰ and polyphyllin Ⅱ in Kangkeling Mixture. Methods The contents of polyphyllin Ⅰ and Ⅱ were determined by HPLC gradient elution. Poroshell 120 Ec-C18 column (4.6 mm × 150 mm, 4 μm) was used; Acetonitrile-water (A:B) was set as the mobile phase; the flow rate was 1.0 mL/min; the detection wavelength was 210 nm; column temperature was 30 ℃. Results Polyphyllin Ⅰ showed good linear relationship in the range of 1.009–10.09 μg (r=0.999 6), and the average recovery was 97.31% (RSD=2.05%, n=6). Polyphyllin Ⅱ showed good linear relationship in the range of 0.640 5–6.405 μg (r=0.999 8), and the average recovery was 96.41% (RSD=1.67%, n=6). Conclusion The method is simple, with good repeatability and accurate results, which can be used to determine the contents of polyphyllin Ⅰ and Ⅱ in Kangkeling Mixture.