Osthole exhibits the remedial potential for polycystic ovary syndrome mice through Nrf2-Foxo1-GSH-NF-κB pathway.

Polycystic ovary syndrome (PCOS) is the primary cause of female infertility with a lack of universal therapeutic regimen. Although osthole exhibits numerous pharmacological activities in treating various diseases, its therapeutic effect on PCOS is undiscovered. The present study found that application of osthole improved the symptoms of PCOS mice through preventing ovarian granulosa cells (GCs) production of more estrogen and alleviating the liberation of pro-inflammatory cytokine interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha.

Melatonin modulates endometrial decidualization via NOTCH1-NRF2-FOXO1-GSH pathway†.

Melatonin is important for oocyte maturation, fertilization, early embryonic development, and embryo implantation, but less knowledge is available regarding its role in decidualization. The present study found that melatonin did not alter the proliferation of human endometrial stromal cells (ESCs), as well as cell cycle progress, but suppressed stromal differentiation after binding to the melatonin receptor 1B (MTNR1B), which was visualized in decidualizing ESCs. Further analysis evidenced that application of melatonin resulted in the diminishment for NOTCH1 and RBPJ expression.

TAZ ameliorates the microglia-mediated inflammatory response via the Nrf2-ROS-NF-κB pathway.

Transcriptional co-activator with PDZ-binding motif (TAZ), one of core modules of the Hippo pathway, involves inflammatory cell infiltration in the liver, but little information is available regarding its physiological function in the microglia-mediated inflammatory response. Here we revealed that activation of TAZ prevented microglia production of proinflammatory cytokines, indicating TAZ's importance in anti-inflammation. After translocation into the nucleus, TAZ interacted with transcriptional enhanced associate domain (TEAD) and bound to the promoter of nuclear factor erythroid 2-related factor 2 (Nrf2), whose blockage caused inability of TAZ to improve inflammation, implying that Nrf2 is a direct target of TAZ.

Yap is essential for uterine decidualization through Rrm2/GSH/ROS pathway in response to Bmp2.

Yap is required for ovarian follicle and early embryo development, but little information is available regarding its physiological significance in decidualization. Here we determine the effects of YAP on decidualization, mitochondrial function, cell apoptosis and DNA damage, and explore its interplay with Bmp2, Rrm2, GSH and ROS. The results exhibited that Yap was abundant in decidual cells and its inactivation impaired the proliferation and differentiation of stromal cells along with the deferral of G1/S phase transition, indicating Yap importance in decidualization.

HB-EGF induces mitochondrial dysfunction via estrogen hypersecretion in granulosa cells dependent on cAMP-PKA-JNK/ERK-Ca-FOXO1 pathway.

Polycystic ovarian syndrome (PCOS) is one of the most prevalent endocrinopathies and the leading cause of anovulatory infertility, but its pathogenesis remains elusive. Although HB-EGF is involved in ovarian cancer progression, there is still no clarity about its relevance with PCOS. The present study exhibited that abundant HB-EGF was noted in follicular fluid from PCOS women, where it might induce the granulosa cells (GCs) production of more estrogen via the elevation of CYP19A1 expression after binding to EGFR.

TAZ as a novel regulator of oxidative damage in decidualization via Nrf2/ARE/Foxo1 pathway.

TAZ, as a crucial effector of Hippo pathway, is required for spermatogenesis and fertilization, but little is known regarding its physiological function in uterine decidualization. In this study, we showed that TAZ was localized in the decidua, where it promoted stromal cell proliferation followed by accelerated G1/S phase transition via Ccnd3 and Cdk4 and induced the expression or activity of stromal differentiation markers Prl8a2, Prl3c1 and ALP, indicating the importance of TAZ in decidualization. Knockdown of TAZ impeded HB-EGF induction of stromal cell proliferation and differentiation.

Genistein exhibits therapeutic potential for PCOS mice the ER-Nrf2-Foxo1-ROS pathway.

Polycystic ovarian syndrome (PCOS) is a complex endocrinopathy in women of reproductive age and the main cause of female infertility, but there is no universal drug for PCOS therapy. As a predominant dietary isoflavone present in soybeans, genistein (GEN) possesses estrogenic and antioxidative properties, but limited information is available regarding its therapeutic potential and underlying molecular mechanism in PCOS. In this study, we found that GEN might restore the estrous cycle of PCOS mice and ameliorate the elevation of circulating T, AMH and LH levels as well as LH/FSH ratios along with reduced cystic follicles, indicating the importance of GEN in PCOS therapy.

Bmp2 regulates Serpinb6b expression via cAMP/PKA/Wnt4 pathway during uterine decidualization.

Serpinb6b is a novel member of Serpinb family and found in germ and somatic cells of mouse gonads, but its physiological function in uterine decidualization remains unclear. The present study revealed that abundant Serpinb6b was noted in decidual cells, and advanced the proliferation and differentiation of stromal cells, indicating a creative role of Serpinb6b in uterine decidualization. Further analysis found that Serpinb6b modulated the expression of Mmp2 and Mmp9.

Novel insights into Dhh signaling in antler chondrocyte proliferation and differentiation: Involvement of Foxa.

The desert hedgehog (Dhh) is crucial for spermatogenesis and Leydig cell differentiation, but little is known regarding its physiological function in cartilage. In this study, Dhh mRNA was abundant in antler chondrocytes, where it advanced cell proliferation concomitant with accelerated transition from the G1 to the S phase and induced elevation of the hypertrophic chondrocyte markers, Col X and Runx2. Silencing of Ptch1 resulted in appreciable Smo accumulation and enhanced rDhh stimulation of Smo, whose impediment by cyclopamine obscured the proliferative function of Dhh and alleviated its guidance of chondrocyte differentiation.

Malic enzyme 1 is important for uterine decidualization in response to progesterone/cAMP/PKA/HB-EGF pathway.

Malic enzyme 1 (Me1), a member of the malic enzymes involving in glycolytic pathway and citric acid cycle, is essential for the energy metabolism and maintenance of intracellular redox balance state, but its physiological role and regulatory mechanism in the uterine decidualization are still unknown. Current study showed that Me1 was strongly expressed in decidual cells, and could promote the proliferation and differentiation of stromal cells followed by an accelerated cell cycle transition, indicating an importance of Me1 in the uterine decidualization. Silencing of Me1 attenuated NADPH generation and reduced GR activity, while addition of NADPH improved the defect of GR activity elicited by Me1 depletion.

HB-EGF Ameliorates Oxidative Stress-Mediated Uterine Decidualization Damage.

HB-EGF is essential for uterine decidualization, but its antioxidant function remains largely unclear. Here, we found that HB-EGF promoted the proliferation of stromal cells followed by the accelerated transition of the cell cycle from G1 to S phase and enhanced the expression or activity of Prl8a2, Prl3c1, and ALP which were well-established markers for uterine stromal cell differentiation during decidualization. Under oxidative stress, stromal cell differentiation was impaired, but this impairment was abrogated by rHB-EGF accompanied with the reduced levels of ROS and MDA which were regarded as the biomarkers for oxidative stress, indicating an antioxidant role of HB-EGF.

Hydroxysafflor yellow A exerts beneficial effects by restoring hormone secretion and alleviating oxidative stress in polycystic ovary syndrome mice.

New Findings: What is the central question of this study? What are the potential therapeutic roles of ginsenoside Rb1 and hydroxysafflor yellow A (HSYA) in polycystic ovary syndrome (PCOS). What is the main finding and its importance? HSYA restored the oestrous cycles of PCOS mice, reduced follicular cysts in ovaries and rescued abnormal hormone secretion; ginsenoside Rb1 did not ameliorate the main symptoms of PCOS mice. HSYA alleviated oxidative stress along with an enhancement of antioxidant enzyme activity.

Genistein protects ovarian granulosa cells from oxidative stress via cAMP-PKA signaling.

Genistein is an isoflavone that has estrogen (E )-like activity and is beneficial for follicular development, but little is known regarding its function in oxidative stress (OS)-mediated granulosa cell (GC) injury. Here, we found that after exposure to H O , Genistein weakened the elevated levels of intracellular reactive oxygen species (ROS) and malondialdehyde (MDA), which were regarded as the biomarkers for OS, and rescued glutathione (GSH) content and GSH/GSSG ratio accompanying with a simultaneous increase in cyclic adenosine monophosphate (cAMP) level, whereas addition of protein kinase A (PKA) inhibitor H89 impeded the effects of Genistein on the levels of ROS and MDA. Further analysis evidenced that Genistein enhanced the activities of antioxidant enzymes superoxide dismutase (SOD), GSH-peroxidase (GSH-Px), and catalase (CAT) in H O -treated GCs, but this enhancement was attenuated by H89.

Function and regulation of transforming growth factor β1 signalling in antler chondrocyte proliferation and differentiation.

Objectives: Chondrocyte proliferation and differentiation are crucial for endochondral ossification, but their regulatory mechanism remains unclear. The present study aimed to determine the physiological function of TGFβ1 signalling in the proliferation and differentiation of antler chondrocytes and explore its relationship with Notch, Shh signalling and Foxa.

Materials And Methods: Immunofluorescence, Western blot, MTS assay, flow cytometry, RNA interference and real-time PCR were used to analyse the function and regulatory mechanisms of TGFβ1 signalling in antler chondrocyte proliferation and differentiation.

Crosstalk between Activin A and Shh signaling contributes to the proliferation and differentiation of antler chondrocytes.

Chondrocyte proliferation and differentiation are crucial for endochondral ossification and strictly regulated by numerous signaling molecules and transcription factors, but the hierarchical regulatory network remains to be deciphered. The present study emphasized the interplay of Activin A, Foxa, Notch and Shh signaling in the proliferation and differentiation of antler chondrocytes. We found that Activin A promoted chondrocyte proliferation and differentiation, and accelerated the transition of cell cycle from G1 into S phase along with the activation of Notch and Shh signaling whose blockage attenuated above function of Activin A.

High Mobility Group Box 1 Regulates Uterine Decidualization through Bone Morphogenetic Protein 2 and Plays a Role in Kruppel-Like Factor 5-Induced Stromal Differentiation.

Background/aims: High mobility group box 1 (Hmgb1) is associated with a variety of physiological processes including embryonic development, cell proliferation and differentiation, but little information is available regarding its biological role in decidualization.

Methods: In situ hybridization, real-time PCR, RNA interference, gene overexpression and MTS assay were used to analyze the spatiotemporal expression of Hmgb1 in mouse uterus during the pre-implantation period, and explore its function and regulatory mechanisms during uterine decidualization.

Results: Hmgb1 mRNA was obviously observed in uterine epithelium on day 2 and 3 of pregnancy, but its expression was scarcely detected on day 4 of pregnancy.

Hmgb3 Induces the Differentiation of Uterine Stromal Cells Through Targeting Ptn.

Uterine decidualization is crucial for placenta formation and pregnancy maintenance. Although previous studies have reported that high mobility group box 3 (Hmgb3) is involved in the regulation of cellular proliferation and differentiation, little is known regarding its physiological role in uterine decidualization. Here, in situ hybridization result exhibited a dynamic expression pattern of Hmgb3 messenger RNA (mRNA) during early gestation, and it was mainly localized to the decidua on days 6 to 8 of gestation.

Ptn functions downstream of C/EBPβ to mediate the effects of cAMP on uterine stromal cell differentiation through targeting Hand2 in response to progesterone.

Ptn is a pleiotropic growth factor involving in the regulation of cellular proliferation and differentiation, but its biological function in uterine decidualization remains unknown. Here, we showed that Ptn was highly expressed in the decidual cells, and could induce the proliferation of uterine stromal cells and expression of Prl8a2 and Prl3c1 which were two well-established differentiation markers for decidualization, suggesting an important role of Ptn in decidualization. In the uterine stromal cells, progesterone stimulated the expression of Ptn accompanied with an accumulation of intracellular cAMP level.

ATRA Signaling Regulates the Expression of COL9A1 through BMP2-WNT4-RUNX1 Pathway in Antler Chondrocytes.

Although all-trans retinoic acid (ATRA) is involved in the regulation of cartilage growth and development, its regulatory mechanisms remain unknown. Here, we showed that ATRA could induce the expression of COL9A1 in antler chondrocytes. Silencing of cellular retinoic acid binding protein 2 (CRABP2) could impede the ATRA-induced upregulation of COL9A1, whereas overexpression of CRABP2 presented the opposite effect.

Expression and regulation of Angiopoietins and their receptor Tie-2 in sika deer antler.

The cartilage vascularization and chondrocyte survival are essential for endochondral ossification which occurs in the process of antler growth. Angiopoietins (Ang) is a family of major angiogenic growth factors and involved in regulating the vascularization. However, the expression and regulation of Angs in the antler are still unknown.

WNT4 acts downstream of BMP2 to mediate the regulation of ATRA signaling on RUNX1 expression: Implications for terminal differentiation of antler chondrocytes.

Although ATRA is involved in regulating the proliferation and differentiation of chondrocytes, its underlying mechanism remains unknown. Here we showed that ATRA could stimulate the proliferation of antler chondrocytes and expression of COL X and MMP13 which were two well-known markers for hypertrophic chondrocytes. Silencing of CRABP2 prevented the induction of ATRA on chondrocyte terminal differentiation, while overexpression of CRABP2 exhibited the opposite effects.

acts downstream of to regulate uterine decidualization via in mice.

Although has been proved to play an important role in uterine decidualization, its regulatory mechanism remains largely unknown. Here, we showed that was highly expressed in the decidual cells and promoted the proliferation of uterine stromal cells and expression of and , which were two well-known differentiation markers for decidualization. Further analysis revealed that might act downstream of and cAMP to regulate the differentiation of uterine stromal cells.

13cRA regulates the differentiation of antler chondrocytes through targeting Runx3.

Although 13cRA is involved in the regulation of cellular proliferation and differentiation, its physiological roles in chondrocyte proliferation and differentiation still remain unknown. Here, we showed that 13cRA could induce the proliferation of sika deer antler chondrocytes and expression of Ccnd3 and Cdk6. Administration of 13cRA to antler chondrocytes resulted in an obvious increase in the expression of chondrocyte marker Col II and hypertrophic chondrocyte marker Col X.

IGF1 regulates RUNX1 expression via IRS1/2: Implications for antler chondrocyte differentiation.

Although IGF1 is important for the proliferation and differentiation of chondrocytes, its underlying molecular mechanism is still unknown. Here we addressed the physiologic function of IGF1 in antler cartilage and explored the interplay of IGF1, IRS1/2 and RUNX1 in chondrocyte differentiation. The results showed that IGF1 was highly expressed in antler chondrocytes.

Runx2 acts downstream of C/EBPβ to regulate the differentiation of uterine stromal cells in mice.

Although Runx2 is involved in the regulation of cellular differentiation, its physiological roles in the differentiation of uterine stromal cells during decidualization still remain unknown. The aim of this study was to examine the expression, regulation and function of Runx2 in mouse uterus during decidualization. The results showed that Runx2 was highly expressed in the decidua and oil-induced decidualized cells.