Pharmacokinetic–pharmacodynamic modeling to study the anti-dysmenorrhea effect of Guizhi Fuling capsule on primary dysmenorrhea rats

Cheng, Yezhe; Chu, Yanjie; Su, Xitong; Zhang, Kexia; Wang, Zhenzhong; Xiao, Wei; Zhao, Longshan; Chen, Xiaohui

doi:10.1016/j.phymed.2018.04.041

Cited by 41 publications

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“…It originated from a classical traditional Chinese herbal formula Guizhi-Fuling Wan which was first described in a classics named the Essential Prescriptions from the Golden Cabinet (Jin Kui Yao Lue) documented in 150–219 A.D. Guizhi-Fuling capsule is the modern dosage form of Guizhi-Fuling Wan, and the dosage and ratio of each Chinese herbal medicine in Guizhi-Fuling capsule is the same as Guizhi-Fuling Wan, consisting of five herbs: Cinnamomum cassia (L.) J. Presl (Guizhi), Poria cocos (Fuling), Paeonia lactiflora Pall (Baishao), Paeonia × suffruticosa Andrews (Mudanpi) and Prunus persica (L.) Batsch (Taoren). Pharmacokinetic-pharmacodynamic modeling study has demonstrated that GZFLC exhibited significant therapeutic effect on primary dysmenorrhea in rat model ( Cheng et al, 2018 ). Moreover, a randomized controlled trial showed that GZFLC significantly relieved pain and reduced the duration of pain compared with placebo during the 3-months treatment period, as well as in the 3-months follow up period, demonstrating a sustained benefit for patients with primary dysmenorrhea ( Liu et al, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Deciphering the Pharmacological Mechanisms of Guizhi-Fuling Capsule on Primary Dysmenorrhea Through Network Pharmacology

et al. 2021

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Guizhi-Fuling capsule (GZFLC), originated from a classical traditional Chinese herbal formula Guizhi-Fuling Wan, has been clinically used for primary dysmenorrhea in China. Nonetheless, the underlying pharmacological mechanisms of GZFLC remain unclear. The integration of computational and experimental methods of network pharmacology might be a promising way to decipher the mechanisms. In this study, the target profiles of 51 representative compounds of GZFLC were first predicted by a high-accuracy algorithm, drugCIPHER-CS, and the network target of GZFLC was identified. Then, potential functional modules of GZFLC on primary dysmenorrhea were investigated using functional enrichment analysis. Potential bioactive compounds were recognized by hierarchical clustering analysis of GZFLC compounds and first-line anti-dysmenorrhea drugs. Furthermore, the potential anti-dysmenorrhea mechanisms of GZFLC were verified through enzyme activity assays and immunofluorescence tests. Moreover, effects of GZFLC on primary dysmenorrhea were evaluated in oxytocin-induced dysmenorrhea murine model. In the network target analysis, GZFLC may act on five functional modules of pain, inflammation, endocrine, blood circulation and energy metabolism. Integrating computational and experimental approaches, we found that GZFLC significantly inhibited the writhing response and reduced the degree of uterine lesions in oxytocin-induced dysmenorrhea murine model. Furthermore, GZFLC may partially alleviate primary dysmenorrhea by inhibiting cyclooxygenase 2 (COX2) and downregulating MAPK signaling pathway. Consequently, GZFLC presented pain relief and sustained benefits for primary dysmenorrhea. This study could provide a scientific approach for deciphering pharmacological mechanisms of herbal formulae through network pharmacology.

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Section: Introductionmentioning

confidence: 99%

Deciphering the Pharmacological Mechanisms of Guizhi-Fuling Capsule on Primary Dysmenorrhea Through Network Pharmacology

et al. 2021

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“…The levels of PGF 2α and PGE 2 in the uterine tissues and peripheral blood of PD patients are higher than normal [2]. Additionally, numerous studies have illustrated that high levels of PGF 2α lead to pathological pain responsible for uterine contraction, hematological alterations, and the accumulation of acidic metabolites [32]. In this study, we found that PGF 2α and PGE 2 in uterine tissues of PD mice markedly decreased by inhibiting NLRP3 inflammasomes.…”

Section: Discussionmentioning

confidence: 46%

NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-κB/COX-2/PG pathway

et al. 2020

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Background: Primary dysmenorrhea (PD) constitutes a common gynecological disease among young women. The NLRP3 inflammasome may be activated and expressed in PD, but the mechanistic link between NLRP3 inflammasome activation and PD is still unclear. Methods: To investigate the potential role of NLRP3 inflammasome activation in the pathogenesis of PD, 30 female Kunming mice without pregnancy were used for experiments. The PD mouse model was constructed by 11 days of successive co-treatment with estradiol and oxytocin. MCC950, a potent and specific small-molecule inhibitor of the NLRP3 inflammasome, was used to treat PD mice. The disease level was assessed by the writhing response and hot water tail-flick test. The levels of prostaglandin E 2 (PGE 2) and prostaglandin F 2 alpha (PGF 2α) in the uterine tissues of mice were detected by ELISA. The expression levels of protein and cytokines, including NLRP3, cysteine aspartic acid-specific protease 1 (caspase-1), interleukin (IL)-1β, IL-18, nuclear factor kappa B (NF-κB) p65, phospho-NF-κB p65, and cyclooxygenase-2 (COX-2) were revealed by western blot analysis. Results: MCC950 greatly ameliorated the writhing response induced by the combination of oxytocin and estradiol, with an increasing length of tail-flick latency. MCC950 also significantly decreased the levels of PGF 2α and PGE 2 , and the expressions of NLRP3, caspase-1, IL-1β, IL-18, phospho-NF-κB p65, NF-κB p65, and COX-2 in the uterus. Conclusions: MCC950 markedly alleviated the pain and pathological damage in PD mice by inhibiting NLRP3 activation. The underlying mechanism may be related to hypoactive uterine inflammation via suppression of NLRP3 activation and the NF-κB/COX-2/PG pathway in uteruses of PD mice.

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“…The levels of PGF 2α and PGE 2 in the uterine tissues and peripheral blood of PD patients are higher than normal [24]. Additionally, numerous studies have illustrated that high levels of PGF 2α lead to pathological pain responsible for uterine contraction, hematological alterations, and the accumulation of acidic metabolites [25]. In this study, we found that PGF 2α and PGE 2 in uterine tissues of PD mice markedly decreased by inhibiting NLRP3 inflammasomes.…”

Section: Discussionmentioning

confidence: 46%

NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-κB/COX-2/PG pathway

Tang

Liu

Chen

et al. 2020

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Background: Primary dysmenorrhea (PD) constitutes a common gynecological disease among young women. The NLRP3 inflammasome may be activated and expressed in PD, but the mechanistic link between NLRP3 inflammasome activation and PD is still unclear.Methods: To investigate the potential role of NLRP3 inflammasome activation in the pathogenesis of PD, thirty female Kunming mice without pregnancy were used for experiments. The PD mouse model was constructed by 11 days of successive co-treatment with estradiol and oxytocin. MCC950, a potent and specific small-molecule inhibitor of the NLRP3 inflammasome, was used to treat PD mice. The disease level was assessed by the writhing response and hot water tail-flick test. The levels of prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2α) in the uterine tissues of mice were detected by ELISA. The expression levels of protein and cytokines, including NLRP3, cysteine aspartic acid-specific protease 1 (caspase-1), interleukin (IL)-1β, IL-18, nuclear factor kappa B (NF-κB) p65, phospho-NF-κB p65, and cyclooxygenase-2 (COX-2) were revealed by western blot analysis.Results: MCC950 greatly ameliorated the writhing response induced by the combination of oxytocin and estradiol, with an increasing length of tail-flick latency. MCC950 also significantly decreased the levels of PGF2α and PGE2, and the expressions of NLRP3, caspase-1, IL-1β, IL-18, phospho-NF-κB p65, NF-κB p65, and COX-2 in the uterus.Conclusions: MCC950 markedly alleviated the pain and pathological damage in PD mice by inhibiting NLRP3 activation. The underlying mechanism may be related to hypoactive uterine inflammation via suppression of NLRP3 activation and the NF-κB/COX-2/PG pathway in uteruses of PD mice.

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Pharmacokinetic–pharmacodynamic modeling to study the anti-dysmenorrhea effect of Guizhi Fuling capsule on primary dysmenorrhea rats

Cited by 41 publications

References 41 publications

Deciphering the Pharmacological Mechanisms of Guizhi-Fuling Capsule on Primary Dysmenorrhea Through Network Pharmacology

Deciphering the Pharmacological Mechanisms of Guizhi-Fuling Capsule on Primary Dysmenorrhea Through Network Pharmacology

NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-κB/COX-2/PG pathway

NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-κB/COX-2/PG pathway

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