Bushen Huoxue recipe attenuates early pregnancy loss via activating endometrial COX2-PGE2 angiogenic signaling in mice

Song, Yufan; Zhou, Fanru; Tan, Xiujuan; Liu, Xia; Ding, Jiahui; Zhang, Chu; Li, Fan; Zhu, Wenxin; Ma, Wenwen; Hu, Runan; Zhang, Mingmin

doi:10.1186/s12906-021-03201-9

Cited by 10 publications

(4 citation statements)

References 49 publications

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“…Previous studies have described downstream targets of STAT3, including cyclin D1, Bcl-2, Bcl-xL, MMP2 and the EMT promoter Twist (Hu et al 2015). Of these, abnormal MMP2 expression in the endometrium may lead to impaired embryo implantation (Song et al 2021). Here, we observed a reduction in MMP2 mRNA levels in uterine horns treated with knockdown si-Gankyrin-AAV.…”

Section: Discussionmentioning

confidence: 53%

Gankyrin has a potential role in embryo implantation via activation of STAT3

Peng

et al. 2022

Reproduction

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Embryo implantation, a critical step during the mammalian reproductive process, requires normal developing blastocysts and a receptive endometrium. Endometriosis, a common pathologically benign gynecological condition, is associated with decreased fertility and reduced endometrial receptivity. The oncoprotein, Gankyrin, has been associated with endometriosis and endometrial cancer. Here, we examined the role of Gankyrin during the process of embryo implantation. We found that Gankyrin expression levels were significantly increased during the mid-secretory phase, but unaffected during the proliferative phase in the human endometrium. Using an in vitro cell adhesion assay to examine the cell adhesion rate of BeWo trophoblast spheroids to Gankyrin-knockdown or overexpressing human endometrial carcinoma RL95-2 cells, we demonstrated that the adhesion rate was significantly reduced in Gankyrin-knockdown RL95-2 cells, while overexpression of Gankyrin promoted cell adhesion. Furthermore, we found that downregulation of Gankyrin inhibited STAT3 activation and subsequent matrix metalloproteinase 2 (MMP2) expression, while overexpression led to STAT3 activation and MMP2 expression. In vivo, we found that Gankyrin expression was increased in the endometrium after conception, but decreased with the prolongation of gestation time in female mice. siRNA-mediated knockdown of Gankyrin in the uterine horn led to a significant reduction in the number of implanted embryos nine days post-gestation, which was associated with a decrease in p-STAT3 expression and MMP2 transcription. Taken together, our findings indicate that Gankryin has a potential role in embryo implantation via STAT3 activation.

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Section: Discussionmentioning

confidence: 53%

Gankyrin has a potential role in embryo implantation via activation of STAT3

Peng

et al. 2022

Reproduction

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“…Progesterone is primarily secreted by the ovarian corpus luteum and plays an important role in fertilized egg implantation and early pregnancy maintenance. It has various effects such as inhibiting maternal immune rejection, regulating membrane permeability of uterine smooth muscle cells, regulating invasion and migration ability of trophoblast cells, reducing the sensitivity of the uterus to contractile hormones, and inhibiting the contraction of uterine smooth muscle and anti-phospholipid to promote the implantation of fertilized eggs and normal development in the uterus [ 27 – 29 ].…”

Section: Discussionmentioning

confidence: 99%

BushenHuoxue Recipe for the Treatment of Prethrombotic State of ACA-Positive Recurrent Miscarriage via the Regulation of the PI3K-AKT Signaling Pathway

Xuan

Ren

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Background. Although the Bushen Huoxue (BSHX) recipe is commonly used for the effective treatment of the prethrombotic state of recurrent abortions, its mechanism of action is unclear. In this article, we investigated the therapeutic effects of BSHX on anti-cardiolipin antibody (ACA) positive recurrent miscarriage mice and the molecular mechanism involved in the treatment of the prethrombotic state of ACA-positive recurrent miscarriages based on the PI3K-Akt signaling pathway, to provide a scientific basis for clinical practice. Methods. An ACA-positive recurrent miscarriage mouse model and normal pregnancy mouse model were adopted in this experiment. Seventy CBA/J female mice were induced to establish the ACA-positive recurrent model; the mice were mated with DBA/2 male mice. Of these mice, 50 became pregnant, which were randomly divided into a BSHX high-dose group (BH, 2.52 g/kg), BSHX medium-dose group (BM, 1.26 g/kg), BSHX low-dose group (BL, 0.63 g/kg), model group (M, distilled water), and an aspirin enteric-coated tablet group; each group had 10 mice. In addition, 16 CBA/J female mice were induced to establish the normal pregnant mouse model; the mice were mated with BALB/C male mice. Of these mice, 10 became pregnant, which were used as the blank control group (C) and received distilled water by gavage. Stillbirth and abortion rates were recorded for each group, and the uterine tissue, urine, and serum were collected. The serum expression levels of ACA, interleukin-6 (IL-6), progesterone ,estradiol, and endometrial histological changes were compared between the groups. Metabolomics was performed on the urine and uterine tissues of both groups using UHPLC-QTOF/MS, and the expression levels of PI3K, p-PI3K, AKT, and p-AKT proteins in the uterine tissues were detected using Western blot. Results. Compared with the model pregnancy group, the BSHX high-dose group, BSHX medium-dose group, and BSHX low-dose group all had a lower absorption rate of mouse embryos, improved uterine histopathological morphology, significantly reduced serum levels of ACA and IL-6, increased serum levels of progesterone and estradiol, and significantly upregulated uterine levels of p-AKT, PI3K, and p-PI3K proteins. The metabolomic results showed that the metabolic levels in the urine and uterine tissues were significantly altered in the mouse model of ACA-positive recurrent abortion. The results also suggested that the pathogenesis of ACA-positive recurrent abortion may be associated with metabolic pathways, such as pentose, glucuronide, lysine degradation, and steroid hormone biosynthesis. Conclusion. The BSHX recipe improved the uterine histopathological morphology of pregnant mice and promoted vascular formation in uterine tissues. The mechanisms involved the reduction in serum ACA and IL-6 levels, the increment in serumprogesterone and estradiol levels, the upregulation of the levels of p-AKT, PI3K, and p-PI3K proteins, and the activation of the PI3K-Akt signaling pathway. These data will be useful for effective drug research and development.

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“…It also increased the thickness and area of the endometrium, and improved the number, density, and secretory activity of endometrial glands. Several investigators found that CHM such as Bushen Huoxue recipe (kidney-nourishing and blood-promoting recipe) and Xiaoyao powder (Free Wanderer Powder) could increase the expression of endometrial pro-angiogenic factors such as HIF1 α and P38, the signaling pathways of COX-PGE2, JNK MAPK, and PI3K/Akt/eNOS, and the expression of its downstream factors such as MMP2, MMP9, PCNA, and FGF2, and then promote its receptor-mediated endometrial angiogenesis, improve endometrial receptivity, and promote embryo implantation, thereby treating infertility [ 67 , 68 ]. In addition, some formulas such as Tiaojing Cuyun recipe (regulating menstruation and helping pregnancy recipe) and Wenshen Yangxue decoction (kidney-warming and blood-nourishing decoction) have been shown in animal experiments that they can not only promote the formation of endometrial blood vessels, but also increase the number of well-developed mature pinopodes in the endometrium [ 69 , 70 ].…”

Section: Methodsmentioning

confidence: 99%

The Treatment of Complementary and Alternative Medicine on Female Infertility Caused by Endometrial Factors

Lin

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Recently, with the development of the social economy, the incidence of infertility has increased year by year. With its complex etiology and diversified syndromes, infertility has become one of the most important diseases that plague the physical and mental health of women of childbearing age worldwide. Endometrial factors as an important part affecting female reproductive capacity, due to which induced repeated abortion and multiple uterine cavity operations occur, can destruct endometrium, failing to provide a normal implantation environment for zygote, thus resulting in infertility. Many patients failed to achieve expected results after receiving conventional treatments such as hormone therapy, assisted reproductive technology (ART), granulocyte colony-stimulating factor (G-CSF) therapy, and cell therapy, then turn to complementary and alternative medicine (CAM) therapies for help. Aiming at clarifying the effectiveness and mechanisms of CAM therapy in the treatment of infertility caused by endometrial factors, our paper systematically searched and studied present related literature on the PubMed, CNKI, and other databases, focusing on the aspects of clinical application and mechanism explorations and highlighting the therapeutic effects of Chinese herbal medicine (CHM), acupuncture, and moxibustion on such diseases. Moreover, this paper also introduces the CAM treatments of traditional Chinese medicine (TCM) retention enema, neuromuscular electrical stimulation (NMES), photobiomodulation therapy, dietary intervention, and other measures for infertility caused by endometrial factors, in order to provide a reference for subsequent basic research and clinical work.

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Bushen Huoxue recipe attenuates early pregnancy loss via activating endometrial COX2-PGE2 angiogenic signaling in mice

Cited by 10 publications

References 49 publications

Gankyrin has a potential role in embryo implantation via activation of STAT3

Gankyrin has a potential role in embryo implantation via activation of STAT3

BushenHuoxue Recipe for the Treatment of Prethrombotic State of ACA-Positive Recurrent Miscarriage via the Regulation of the PI3K-AKT Signaling Pathway

The Treatment of Complementary and Alternative Medicine on Female Infertility Caused by Endometrial Factors

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