Resveratrol Reduces Myometrial Infiltration, Uterine Hyperactivity, and Stress Levels and Alleviates Generalized Hyperalgesia in Mice With Induced Adenomyosis

Zhu, Bo; Chen, Yumei; Zhang, Hongping; Liu, Xishi; Guo, Sun‐Wei

doi:10.1177/1933719115572479

Cited by 29 publications

(25 citation statements)

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“…We note that the anti-platelet treatment achieved the therapeutic effects very similar to EGCG [ 20 , 26 , 45 ] and resveratrol [ 46 , 47 ] as we reported earlier. However, it is perhaps no coincidence that EGCG is anti-platelet [ 48 ] and so is resveratrol [ 46 ].…”

Section: Discussionsupporting

confidence: 74%

Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence

Zhu

Chen

Shen

et al. 2016

Reprod Biol Endocrinol

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BackgroundRecently emerging evidence indicates that endometriotic lesions are wounds undergoing repeated tissue injury and repair (ReTIAR), and platelets induce epithelial-mesenchymal transition (EMT), fibroblast-to-myofibroblast transdifferentiation (FMT), leading ultimately to fibrosis. Due to the commonality of cyclic bleeding as in endometriosis, adenomyotic lesions are also wounds that undergo ReTIAR, and we have recently provided evidence corroborating platelet-induced EMT, FMT and fibrogenesis in adenomyosis. This study sought to evaluate the effect of antiplatelet therapy in a mouse model of adenomyosis.MethodsAdenomyosis was induced in 57 female ICR mice with neonatal dosing of tamoxifen, while another 12 (group C) were dosed with solvent only, serving as a blank control. Starting from 4 weeks after birth, hotplate test was administrated to all mice every 4 weeks. At the 16th week, all mice with induced adenomyosis were randomly divided into 6 groups: untreated, low- and high-dose Ozagrel, low- and high-dose anti-mouse GPIbα polyclonal IgG antibody to deplete platelets, and isotype-matched inert IgG non-immune antibody. Group C received no treatment. After 3 weeks of treatment, they were hotplate tested again, their uterine horns and brains were harvested, and a blood sample was taken to measure the plasma corticosterone level by ELISA. The left uterine horn was used for immunohistochemistry analysis. The brainstem nucleus raphe magnus (NRM) sections were subjected to immunofluorescence staining for GAD65. The depth of myometrial infiltration and uterine contractility were evaluated.ResultsWe found that both Ozagrel treatment and platelet depletion dose-dependently suppressed myometrial infiltration, improved generalized hyperalgesia, reduced uterine contractility, and lowered plasma corticosterone levels, improved the expression of some proteins known to be involved in adenomyosis and slowed down the process of fibrogenesis. It also elevated the number of GAD65-expressing neurons in the brainstem NRM, possibly boosting the GABAergic inhibition of pain due to adenomyosis.ConclusionThis study further provides evidence that platelets play important roles in the development of adenomyosis. Anti-platelet treatment is efficacious in suppression of myometrial infiltration, improving generalized hyperalgesia, reducing uterine hyperactivity and systemic corticosterone levels. Collectively, these results demonstrate that anti-platelet therapy seems to be promising for treating adenomyosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12958-016-0198-1) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 74%

Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence

Zhu

Chen

Shen

et al. 2016

Reprod Biol Endocrinol

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“…To our knowledge, our study is the first to analyze the effect of adenomyosis on pregnancy outcome in a mouse model. Previous research has focused on the relationship between uterine muscle contraction and adenomyosis in mice 19,37. The mechanisms behind these effects may be related to the induction of inflammatory factors,38 the increased production of oxygen free radicals,39 and abnormal uterine contraction 40.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, a mouse adenomyosis model was generated using previously published methods 16–19. Five pregnant Institute of Cancer Research strain mice were purchased from Shanghai Laboratory Animal Corporation (Shanghai, People’s Republic of China), and each was housed in a single cage during the perinatal period.…”

Section: Methodsmentioning

confidence: 99%

Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

Guo

et al. 2017

DDDT

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PurposeAdenomyosis is a common, benign gynecological condition of the female reproductive tract characterized by heavy menstrual bleeding and dysmenorrhea. Gonadotropin-releasing hormone (GnRH) agonists are one of the medications used in adenomyosis treatment; however, their underlying mechanisms are poorly understood. Moreover, it is difficult to obtain endometrial samples from women undergoing such treatment. To overcome this, we generated an adenomyosis mouse model, which we treated with an GnRH agonist to determine its effect on pregnancy outcomes. We also analyzed endometrial gene expression following GnRH agonist treatment to determine the mechanisms that may affect pregnancy outcome in individuals with adenomyosis.MethodsNeonatal female mice were divided into a control group, an untreated adenomyosis group, and an adenomyosis group treated with a GnRH agonist (n=6 each). The pregnancy outcome was observed and compared among the groups. Then, three randomly chosen transcriptomes from endometrial tissues from day 4 of pregnancy were analyzed between the adenomyosis group and the GnRH agonist treatment group by RNA sequencing and quantitative reverse transcription polymerase chain reaction (PCR).ResultsThe litter size was significantly smaller in the adenomyosis group than in the control group (7±0.28 vs 11±0.26; P<0.05). However, the average live litter size was increased (10±0.28 vs 7±0.28; P<0.05) after GnRH agonist treatment. Three hundred and fifty-nine genes were differentially expressed in the GnRH agonist-treated group compared with the untreated group (218 were downregulated and 141 were upregulated). Differentially expressed genes were related to diverse biological processes, including estrogen metabolism, cell cycle, and metabolite biosynthesis.ConclusionGnRH agonist treatment appears to improve the pregnancy outcome of adenomyosis in a mouse model. Besides pituitary down-regulation, other possible mechanisms such as the regulation of cell proliferation may play a role in this. These new insights into GnRH agonist mechanisms will be useful for future adenomyosis treatment.

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“…Hotplate test procedure. The hotplate test was performed using a commercially available Hot Plate Analgesia Meter (BME-480; Chinese Academy of Medical Sciences) as described previously (24). The surface of the plate was heated to and maintained at a constant temperature of 50.0±0.1˚C as measured using a built-in digital thermometer.…”

Section: Preparation Of Animalsmentioning

confidence: 99%

Celecoxib, a selective COX‑2 inhibitor, markedly reduced the severity of tamoxifen‑induced adenomyosis in a murine model

Jin

Liu

et al. 2020

Exp Ther Med

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The aim of the present study was to evaluate the effects of the selective cyclooxygenase (COX)-2 inhibitor celecoxib on the development of uterine adenomyosis in mice. ICR neonatal mice were first exposed to tamoxifen to establish a mouse model of adenomyosis. Following 60 days of celecoxib treatment, pathological formation of adenomyosis lesions and the depth of myometrial infiltration were evaluated using hematoxylin and eosin staining. To examine thermal pain modulation in mice, a hotplate test was conducted every 15 days from postnatal day 30 onwards. Immunohistochemistry was performed to assess the expression of aromatase P450, N-cadherin, E-cadherin, COX-2 and cluster of differentiation 31, whereas the levels of estrogen were analyzed in uterine tissue homogenates using ELISA. Masson trichrome staining was performed to assess the extent of fibrosis in the uterus. Celecoxib treatment significantly inhibited the depth of infiltration into the myometrium, resulting in significantly reduced disease severity. Treatment with high doses of celecoxib significantly prolonged thermal response latency. Following celecoxib treatment, the expression of E-cadherin was significantly increased whereas the expression of N-cadherin was significantly decreased. Concomitantly, the extent of fibrosis was also reduced following celecoxib treatment. Uterine tissue homogenates isolated from mice treated with both high and low doses of celecoxib exhibited lower concentrations of estrogen and decreased expression of aromatase P450. These observations suggest that celecoxib reduces adenomyosis severity by suppressing estrogen production in the uterus, reversing epithelial-mesenchymal transition and relieving fibrosis. Taken together, the results of the present study support the potential use of celecoxib, a selective COX-2 inhibitor, for the treatment of adenomyosis.

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Resveratrol Reduces Myometrial Infiltration, Uterine Hyperactivity, and Stress Levels and Alleviates Generalized Hyperalgesia in Mice With Induced Adenomyosis

Cited by 29 publications

References 49 publications

Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence

Anti-platelet therapy holds promises in treating adenomyosis: experimental evidence

Transcriptome analysis of endometrial tissues following GnRH agonist treatment in a mouse adenomyosis model

Celecoxib, a selective COX‑2 inhibitor, markedly reduced the severity of tamoxifen‑induced adenomyosis in a murine model

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