White crystalline powder
Tripterygium wilfordii Hook. f./Alkaloid from Tripterygium wilfordii and Maytenus senegalensis (Celastraceae)
(1S,3R,15S,18S,19R,20R,21R,22S,23R,24R,25R,26S)-20,22,23,25-Tetraacetoxy-21-(acetoxymethyl)-26-hydroxy-3,15,26-trimethyl-6,16-dioxo-2,5,17-trioxa-11-azapentacyclo[188.8.131.52.0.0]hexaco sa-7,9,11-trien-19-yl benzoate/20,22,23,25-Tetraacetoxy-21-(acetoxymethyl)-26-hydroxy-3,15,26-trimethyl-6,16-dioxo-2,5,17-trioxa-11-azapentacyclo[184.108.40.206.0.0]hexacosa-7,9,11-trien-19-yl benzoate/26-Deoxywilfordine
871.5±65.0 °C at 760 mmHg
HS Code Reference
Personal Projective Equipment
For Reference Standard and R&D, Not for Human Use Directly.
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Background: The quality standard of Tripterygium glycosides tablet (TGT) by CFDA can not fully reflect the effectiveness and safety. While, Q-marker was proposed to solve the problem of traditional Chinese medicine. PK-marker is mainly used to reflect the material exposure and the influencing factors of Chinese medicine after administration.
Purpose: Based on the study of quantitative analysis, cytotoxicity and pharmacokinetics, this study screened out and confirmed whether wilforine could be served as a potential Q-marker and PK-marker of TGT.
Methods: A sensitive and selective UPLC-MS/MS method was developed and applied to quantitative research of TGT preparation and pharmacokinetics study of TGT. Then, HepG2 cells assay was used to evaluate the cytotoxicity induced by alkaloids in TGT. Then, a PK-PD research was carried out in adjuvant arthritis (AA) rats and control rats after oral administration of TGT, with different dosage and timing. The pharmacokinetic characteristics were determined and calculated by DAS1.0. The pharmacodynamics of TGT was evaluated by the change of paw swelling through one-way ANOVA analysis.
Results: The quality of four alkaloids showed significant difference among four manufacturers, and they were abundant component in TGT from three manufacturers of all. HepG2 cells test revealed that wilforine and wilforgine could induce the cytotoxicity obviously. Pharmacodynamics index suggested that TGT had therapeutic effect on adjuvant arthritis. Thus, the four cases of death occurred in the high dose AA rat group had proven the significant toxicity caused by continuous high dose TGT administration. Furthermore, the result of pharmacokinetic study proved that Cmax, and AUC(0-tn) of wilforine have dose-dependent and time-dependent characteristics. But for wilforgine, there was no indication that there was an accumulation phenomenon in vivo and its plasma concentration showed low exposure. Therefore, it could hardly become the PK-marker of TGT.
Conclusion: Wilforine is proposed as a biologically active and toxic component of TGT that can be served both as Q-marker and PK-marker. The quality, clinical safety, and efficacy of TGT should be evaluated by the quality of wilforine.
Alkaloid; PK-maker; Q-marker; Tripterygium glycosides; Wilforine.
Wilforine, the Q-marker and PK-maker of Tripterygium Glycosides Tablet: Based on Preparation Quantitative Analysis and PK-PD Study
Xue Gao 1 , Xi Du 2 , Lijun An 1 , Yangyang Wang 1 , Lili Wang 1 , Zengguang Wu 1 , Cong Huang 1 , Xin He 3
2019 Feb 15
Although the action site of wilforine is located in the muscle tissue of insects, the insecticidal mechanism of wilforine is not yet clear. This research explored the effects of wilforine on the calcium signaling pathway using the calcium imaging technique to reveal the insecticidal mechanism. It was confirmed that wilforine had strong cytotoxicity to Mythimna separata myocytes with the IC50 values of 25.14 and 19.65 mg/L using CCK-8 and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide methods, respectively. The morphological development of M. separata myocytes was also affected. The calcium imaging technique showed that the intracellular calcium ion concentration ([Ca2+]i) increased by 23.45% of the initial value after being treated with 100 nM wilforine. However, wilforine did not increase [Ca2+]i after the myocytes were preincubated with thapsigargin, and the [Ca2+]i could not be decreased by 50 μM ryanodine after being treated with 100 nM wilforine. These results indicated that the targets of wilforine are located in the sarcoplasmic reticulum, and ryanodine receptor (RyR) is an important action target of wilforine. Furthermore, wilforine can also activate the inositol triphosphate receptor (IP3R), which was confirmed through the use of 2-aminoethyl diphenylborinate, an inhibitor of IP3R. Connected with previous research studies, it can be concluded that wilforine affects the calcium signaling pathway by combining with RyR and IP3R, causing calcium dyshomeostasis, which results in insect paralysis and death.
Mythimna separata myocytes; calcium imaging; cytotoxicity; insecticidal mechanism; ryanodine receptor; wilforine.
Effect of Wilforine on the Calcium Signaling Pathway in Mythimna separata Walker Myocytes Using the Calcium Imaging Technique
Shujie Ma 1 2 , Jiahuan Liu 1 , Xiaopeng Lu 1 , Xing Zhang 1 , Zhiqing Ma 1 3
2019 Dec 11
This study investigated the mode of action of wilforine, an alkaloid with insecticidal properties, extracted from Tripterygium wilfordii Hook f., on the microstructure and ultrastructure of the muscle cells of larvae and adults of the oriental armyworm Mythimna separata Walker. The bioassay results showed that wilforine had oral toxicity against both M. separata larvae (LC50=63μg/mL) and adults (LC50=36μg/mL). The typical toxicity sign was paralysis leading to death. Both light and electron microscope observations revealed that damage to the muscle cells increased with poisoning time in larvae and adults treated with the LC80 dose of wilforine. Histopathological examinations in the muscle cells of M. separata adults showed that there were large cytoplasmic spaces, disrupted Z-lines and swollen mitochondria in the muscle cells. Further, the sarcoplasmic reticulum was excessively dilated and fragmented; the nuclear membrane was ruptured; nuclear material was overflowing; and the myolemma was damaged. The similar pathological changes in the muscle cells of oriental armyworm larvae were observed, as above. In addition, a medullary sheath structure appeared and crystalline inclusion was also observed in the muscle cells of M. separata larvae. In conclusion, wilforine could induce pathological changes in the muscle cells of oriental armyworm larvae and adults, leading to their death; thus, the active site of action of wilforine maybe located in the muscle tissue of insects.
Histopathological features; Insecticidal mechanism; Muscle cells; Mythimna separata; Wilforine.
Microstructural and Ultrastructural Changes in the Muscle Cells of the Oriental Armyworm Mythimna Separata Walker (Lepidoptera: Noctuidae) on Treatment With Wilforine
Shujie Ma 1 , Lin Liu 1 , Zhiqing Ma 2 , Xing Zhang 1