Efficacy of granulocyte colony-stimulating factor for infertility undergoing IVF: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the effectiveness of granulocyte colony-stimulating factor (G-CSF) for infertility and recurrent spontaneous abortion. METHODS: Existing research was searched in PubMed, Embase and Cochrane Library till Dec 2021. Randomized control trials (RCTs) that compared G-CSF administration with the control group in infertility women undergoing IVF were included. The primary outcomes included clinical pregnancy rate; the secondary outcomes included live birth rate, abortion ratebiochemical pregnancy rate, embryo implantation rate, as well as endometrial thickness. RESULT(S): 20 RCTs were included in this study. G-CSF increased the clinical pregnancy rate (RR = 1.85; 95% CI: 1.07, 3.18) and the endometrial thickness (MD = 2.25; 95% CI: 1.58,2.92;) in patients with thin endometrium undergoing IVF. G-CSF increased the biochemical pregnancy rate (RR = 2.12; 95% CI: 1.54, 2.93), the embryo implantation rate (RR = 2.51; 95% CI: 1.82, 3.47) and the clinical pregnancy rate (RR = 1.93; 95% CI: 1.63, 2.29) in patients with a history of repeated implantation failure undergoing IVF. No differences were found in pregnancy outcomes of general IVF patients. CONCLUSIONS: Granulocyte colony-stimulating factor is likely to be a potential option for infertility women undergoing IVF with thin endometrium or recurrent implantation failure . TRIAL REGISTRATION: Retrospectively registered (The PROSPERO registration number: CRD42022360161).

Heterotopic pregnancy after assisted reproductive techniques with favorable outcome of the intrauterine pregnancy: A case report.

BACKGROUND: Heterotopic pregnancy (HP) is a rare condition in which both ectopic and intrauterine pregnancies occur. HP is uncommon after natural conception but has recently received more attention due to the widespread use of assisted reproductive techniques (ART) such as ovulation promotion therapy. CASE SUMMARY: Here, we describe a case of HP that occurred after ART with concurrent tubal and intrauterine singleton pregnancies. This was treated successfully with surgery to preserve the intrauterine pregnancy, resulting in the birth of a low-weight premature infant. This case report aims to increase awareness of the possibility of HP during routine first-trimester ultrasound examinations, especially in pregnancies resulting from ART and even if multiple intrauterine pregnancies are present. CONCLUSION: This case alerts us to the importance of comprehensive data collection during regular consultations. It is important for us to remind ourselves of the possibility of HP in all patients presenting after ART, especially in women with an established and stable intrauterine pregnancy that complain of constant abdominal discomfort and also in women with an unusually raised human chorionic gonadotropin level compared with simplex intrauterine pregnancy. This will allow symptomatic and timeous treatment of patients with better results.

Egr3 as an important regulator of uterine decidualization through targeting Hand2.

Early growth response 3 (Egr3) is required for embryogenesis, but little understanding is usable about its function in embryo implantation and decidualization. The present study exhibited an obvious localization of Egr3 in luminal epithelium and subluminal stroma at implantation sites. Administration of estrogen brought about a distinct gather of Egr3 mRNA in uterine luminal and glandular epithelia. Meanwhile, Egr3 was visualized in the decidua where it might facilitate the proliferation of stromal cells via Ccnd3 and accelerate stromal differentiation, testifying the significance of Egr3 in decidualization. In ovariectomized mice uteri or stromal cells, progesterone advanced the expression of Egr3 whose obstruction counteracted the inducement of stromal differentiation by progesterone. Consistently, Egr3 mediated the influence of cAMP and heparin-binding EGF-like growth factor (HB-EGF) on the differentiation program. Additionally, cAMP-protein kinase A (PKA) signaling mediated the adjustment of progesterone on Egr3. Impediment of HB-EGF antagonized the ascendance of Egr3 conferred by cAMP. In stromal cells, Egr3 activated the transcription of Hand2 whose promoter region exhibited the binding enrichment of Egr3. Activation of Hand2 relieved the weakness of stromal differentiation by Egr3 hinderance, whereas knockdown of Hand2 neutralized the guidance of Egr3 overexpression on the differentiation program. Collectively, Egr3 was identified as an important regulator of uterine decidualization through targeting Hand2 in response to progesterone/cAMP/HB-EGF pathway.

[Therapeutic effect of Heirong Kidney-Tonifying Granule on busulfan-induced dyszoospermia in model mice].

OBJECTIVE: To explore the therapeutic effect of Heirong Kidney-Tonifying Granule (HKTG) on busulfan-induced dyszoospermia in mice, and its mechanism in regulating testicular spermatogenesis. METHODS: Forty-eight male mice were randomly divided into six groups of an equal number: blank control (BC), negative control (NC), HKTG-1, HKTG-2, HKTG-3 and HKTG-4. The model of dyszoospermia was established in the latter five groups by intraperitoneal injection of busulfan at 40 mg/kg and, 30 days after modeling, the mice in the BC and NC groups were given gavage of normal saline, and those in the latter four groups treated with HKTG + pilose antler at 400 mg/kg/d, HKTG + pilose antler at 800 mg/kg/d, HKTG + black ants at 400 mg/kg/d and HKTG + black ants at 800 mg/kg/d, respectively, all for 5 consecutive weeks. The mean body weight of the mice was recorded daily, and their testes weighed after treatment. The microstructure of the testis tissue was detected by HE staining, and the localization and expression of spermatogenesis markers in the testis were determined by immunofluorescence staining. RESULTS: The mice in the BC and NC groups showed no statistically significant difference from those in the HKTG groups in the body weight and daily body weight gain (P > 0.05). Compared with the NC mice, the animals in the HKTG-1 group exhibited significantly increased testis weight (P < 0.05), and those in the HKTG-1 and HKTG-1 groups presented a large number of germ cells in the seminiferous tubules, including deformed sperm cells in the lumen, and some seminomatogonia in the seminogenic tubules, but almost no deformed sperm cells. The expressions of the total germ cell marker gene Ddx4, spermatogonial cell marker gene Dazl, spermatic cell marker gene Sycp3 and sperm cell marker gene Tnp1 were significantly upregulated (P < 0.05) while that of the Sertoli cell marker gene Sox9 downregulated (P < 0.05) in the HKTG-1 group. The number of Sertoli cells in the HKTG-1 group was remarkably reduced (P<0.05), corresponding to the increased number of germ cells in the HKTG-1 group. There were no significant changes in the relative expressions of the DDX4, Dazl, Sycp3 and Tnp1 genes, nor in the number of Sertoli cells in the HKTG-3 and HKTG-4 groups. The expressions of meiosis-related genes Meioc, Stra8 and Spo11were markedly upreguated in the HKTG-1 group, indicating significantly improved spermatogenesis in the testis tissue of the mice. CONCLUSION: HKTG improves the function of spermatogenic cells and increases sperm production in the testis tissue of mice by promoting meiosis.

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. Under oxidative stress, TAZ protected stromal differentiation against oxidative damage by reducing intracellular ROS and enhancing cellular antioxidant capacity dependent on the Nrf2/ARE/Foxo1 pathway. TAZ strengthened the transcriptional activity of Nrf2 which directly bound to the antioxidant response element (ARE) of Foxo1 promoter region. Additionally, silencing TAZ caused accumulation of intracellular ROS through heightening NOX activity whose blockade by APO reversed the disruption in stromal differentiation. Further analysis revealed that TAZ might restore mitochondrial function, as indicated by the increase in ATP level, mtDNA copy number and mitochondrial membrane potential with the reduction in mitochondrial superoxide. Additionally, TAZ modulated the activities of mitochondrial respiratory chain complexes I and III whose suppression by ROT and AA resulted in the inability of TAZ to defend against oxidative damage to stromal differentiation. Moreover, TAZ prevented stromal cell apoptosis by upregulating Bcl2 expression and inhibiting Casp3 activity and Bax expression. In summary, TAZ might mediate HB-EGF function in uterine decidualization through Ccnd3 and ameliorate oxidative damage to stromal cell differentiation via Nrf2/ARE/Foxo1 pathway.

Genistein exhibits therapeutic potential for PCOS mice via 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. Meanwhile, GEN improved the ovarian secretion function of PCOS mice and attenuated oxidative damage of the ovary through enhancing its antioxidant capability dependent on ER. Supplementation of GEN improved the defect of the ATP level and mitochondrial membrane potential, indicating the significance of GEN in preventing mitochondrial dysfunction. Further analysis demonstrated that GEN via ER heightened the expression of Nrf2 and Foxo1 whose blockage antagonized the defence of GEN on the secretory and mitochondrial functions of ovarian granulosa cells followed by the limited antioxidant capability and increased intracellular ROS level. Moreover, nuclear translocation and transcriptional activity of Nrf2 presented a notable enhancement after exposure to GEN. Addition of the Nrf2 inhibitor ML385 hampered the GEN induction of Foxo1. Nrf2 might directly bind to the antioxidant response element of the Foxo1 promoter region. Collectively, GEN might exhibit therapeutic potential for PCOS mice via the ER-Nrf2-Foxo1-ROS pathway.

Adenylate kinase 7 is a prognostic indicator of overall survival in ovarian cancer.

ABSTRACT: Ovarian cancer (OC), a common malignant heterogeneous gynecological tumor, is the primary cause of cancer-related death in women worldwide. Adenylate kinase (AK) 7 belongs to the adenylate kinase (AK) family and is a cytosolic isoform of AK. Recent studies have demonstrated that AK7 is expressed in several human diseases, including cancer. However, there is a scarcity of reports on the relationship between AK7 and OC. Here, we compared the expression of AK7 in normal and cancerous ovarian tissues from The Cancer Genome Atlas database and used the c2 test to assess the correlation between AK7 levels and the clinical symptoms of OC. Finally, the prognostic significance of AK7 in OC was determined using the Kaplan-Meier analyses and Cox regression and performed gene set enrichment analysis to detect any relevant signaling pathways. We found that AK7 levels were substantially downregulated in OC than that in normal ovarian tissues (P < .001). Low AK7 levels were related to the patients' age (P = .0093) in OC. The median overall survival (OS) of patients with low AK7-expressing OC was shorter than patients with high AK7-expressing OC (P = .019). The Cox regression analysis (multivariate) identified low AK7 levels were independently related to the prognosis of OC (HR 1.34; P = .048). Our study demonstrated that the downregulated levels of AK7 could serve as an independent prognostic indicator for the OS in OC. Additionally, gene set enrichment analysis revealed that EMT, apical junction, TGF-b signaling, UV response, and myogenesis were associated in the low AK7 expression phenotype (NOM P < .05).

[on oligozoospermia and asthenospermia].

OBJECTIVE: To observe the clinical effect of Yihechun Capsules (YHC) on oligozoospermia and asthenospermia. METHODS: A total of 181 male patients with infertility were randomly divided into a YHC+Levocarnitine (LC) group (n = 93, including 42 cases of oligozoospermia, 20 cases of asthenospermia and 31 cases of oligoasthenospermia) and an LC control group (n = 88, including 39 cases of oligozoospermia, 22 cases of asthenospermia and 27 cases of oligoasthenospermia), the former treated with YHC (ï¼»0.3 g per capsuleï¼½, once 4 capsules, bid, 30 minutes after meal) combined with LC oral liquid (2－3 g/d, tid, at mealtime) and the latter with LC oral liquid only (2－3 g/d, tid, at mealtime). After 3 months of treatment, comparisons were made between the two groups of patients in sperm concentration, the percentages of grade a and grade a+b sperm, and the rate of pregnancy. RESULTS: Of the 181 patients, 5 in the YHC+LC group and 2 in the LC control group failed to complete the course of treatment. There were no statistically significant differences between the two groups of patients in the baseline sperm concentration and the percentages of grade a and grade a+b sperm (P > 0.05), wich were all markedly increased in both the YHC+LC and the LC control groups (P < 0.05) after 3 months of treatment. And the patients of the YHC+LC group, compared with the controls, showed even more significant increases, as the oligozoospermia patients in sperm concentration (ï¼»21.07 ± 6.98ï¼½ vs ï¼»16.56 ± 1.82ï¼½ ×106/ml, P < 0.05) and the percentages of grade a sperm (ï¼»27.53 ± 3.34ï¼½% vs ï¼»26.88 ± 1.35ï¼½%, P < 0.05) and grade a+b sperm (ï¼»53.32 ± 3.16ï¼½% vs ï¼»52.63 ± 2.48ï¼½%, P < 0.05), the asthenospermia patients in sperm concentration (ï¼»26.36 ± 3.37ï¼½ vs ï¼»24.42 ± 2.21ï¼½ ×106/ml, P < 0.05) and the percentages of grade a sperm (ï¼»25.28 ± 4.64ï¼½% vs ï¼»21.32 ± 3.28ï¼½%, P < 0.05) and grade a+b sperm (ï¼»49.19 ± 2.87ï¼½% vs ï¼»45.64 ± 1.78ï¼½%, P < 0.05), and the oligoasthenospermia patients in sperm concentration (ï¼»19.38 ± 3.39ï¼½ vs ï¼»18.75 ± 1.35ï¼½ ×106/ml, P < 0.05) and the percentages of grade a sperm (ï¼»22.65 ± 4.81ï¼½% vs ï¼»21.31 ± 2.42ï¼½%, P < 0.05) and grade a+b sperm (ï¼»48.74 ± 5.61ï¼½% vs ï¼»44.36 ± 1.32ï¼½%, P < 0.05). The pregnancy rate was dramatically higher in the YHC+LC than in the LC control group (36.4% ï¼»32/88ï¼½ vs 15.1% ï¼»13/86ï¼½, P < 0.01). CONCLUSIONS: Yihechun Capsules combined with Levocarnitine oral liquid is evidently effective for the treatment of oligozoospermia and asthenospermia.

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. Meanwhile, Serpinb6b was identified as a target of Bmp2 regulation in stromal differentiation. Treatment with rBmp2 resulted in an accumulation of intracellular cAMP level whose function in this differentiation program was mediated by Serpinb6b. Addition of PKA inhibitor H89 impeded the Bmp2 induction of Serpinb6b, whereas 8-Br-cAMP rescued the defect of Serpinb6b expression elicited by Bmp2 knock-down. Attenuation of Serpinb6b greatly reduced the induction of constitutive Wnt4 activation on stromal cell differentiation. By contrast, overexpression of Serpinb6b prevented this inhibition of differentiation process by Wnt4 siRNA. Moreover, blockage of Wnt4 abrogated the up-regulation of cAMP on Serpinb6b. Collectively, Serpinb6b mediates uterine decidualization via Mmp2/9 in response to Bmp2/cAMP/PKA/Wnt4 pathway.

Dysregulated Expression of Long Noncoding RNAs in Endometriosis.

Endometriosis is a common debilitating gynecologic disease. Almost 10% of reproductive-age women are affected by this disease; they commonly suffer pelvic pain and/or infertility. Early diagnosis of this multifactorial disease remains difficult because its etiology is not clear and the early symptoms are nonspecific. In addition, many reproductive-age women are unwilling to undergo invasive laparoscopic surgery because of the possibility of decreasing fertility. Thus, identifying biomarkers for the early diagnosis of endometriosis a key focus of current research. Long noncoding RNAs (lncRNAs) are a class of noncoding transcripts that have length of > 200 nucleotides and lack protein-coding ability but still influence gene expression in various ways. With advances in genome-wide analysis, researchers have determined that lncRNAs play an important role in many human diseases, particularly tumors. Moreover, the role of lncRNAs in the pathogenesis of endometriosis has been continually recognized. In this review, we discuss the status of current research on dysregulated lncRNAs and their roles in the pathogenesis of endometriosis. We aim to stimulate new investigations toward the identification of lncRNAs as biomarkers for the early diagnosis and therapy of this long-term gynecological disease.

[Compound Amino Acid Capsules combined with clomiphene for severe oligospermia].

OBJECTIVE: To study the effect of Compound Amino Acid Capsules (CAAC) combined with clomiphene in the treatment of severe oligospermia. METHODS: A total of 104 patients with severe oligospermia admitted to our Center of Reproductive Medicine from January to September 2018 were randomly assigned to a trial (n = 60) and a control group (n = 44), the former treated by oral administration of CAAC combined with clomiphene and the latter with clomiphene only, both for 12 weeks. Comparisons were made between the two groups of patients in the sperm concentration, and the percentages of progressively motile sperm (PMS) and total motile sperm (TMS) before and after 4, 8 and 12 weeks of medication as well as the pregnancy rate during the treatment. RESULTS: Compared with the baseline, the trial group showed significant elevation at 4, 8 and 12 weeks in sperm concentration (ï¼»3.13 ± 1.29ï¼½ vs ï¼»12.06 ± 2.24ï¼½, ï¼»22.10 ± 2.65ï¼½ and ï¼»28.13 ± 3.59ï¼½ ×106/ml, P < 0.01), PMS (ï¼»14.03 ± 2.49ï¼½% vs ï¼»21.05 ± 3.14ï¼½%, ï¼»29.08 ± 4.70ï¼½% and ï¼»35.08 ± 3.70ï¼½%, P < 0.01) and TMS (ï¼»20.10 ± 4.05ï¼½% vs ï¼»27.10 + 4.87ï¼½%, ï¼»36.09 ± 5.64ï¼½% and ï¼»45.04 ± 6.69ï¼½%, P < 0.01), and so did the control group in sperm concentration (ï¼»3.27 ± 1.46ï¼½ vs ï¼»10.21 ± 2.35ï¼½, ï¼»19.89 ± 2.74ï¼½ and ï¼»25.23 ± 3.69ï¼½ ×106/ml, P < 0.01), PMS (ï¼»13.32 ± 3.12ï¼½% vs ï¼»17.02 ± 3.26ï¼½%, ï¼»22.13 ± 3.70ï¼½% and ï¼»27.18 ± 2.54ï¼½%, P < 0.01) and TMS (ï¼»21.30 ± 4.87ï¼½% vs ï¼»24.22 ± 5.07ï¼½%, ï¼»30.03 ± 5.33ï¼½% and ï¼»35.05 ± 5.69ï¼½%, P < 0.01), even more significant in the trial than in the control group at the three time points after medication (P < 0.01). The pregnancy rate was markedly higher in the former than in the latter group at 4 (1.72% vs 0.53%, P < 0.01), 8 (4.21% vs 2.87%, P < 0.01) and 12 weeks (8.32% vs 6.32%, P < 0.01). No adverse reactions were observed in neither of the two groups during the treatment. CONCLUSIONS: CAAC combined with clomiphene can significantly improve the semen parameters of the patients with severe oligospermia, with no obvious adverse events.

Egr2 mediates the differentiation of mouse uterine stromal cells responsiveness to HB-EGF during decidualization.

Although Egr2 is involved in regulating the folliculogenesis and ovulation, there is almost no data describing its physiological function in embryo implantation and decidualization. Here, we showed that Egr2 mRNA was distinctly accumulated in subluminal stromal cells around implanting blastocyst on day 5 of pregnancy as well as in estrogen-activated implantation uterus. Estrogen induced the expression of Egr2 in uterine epithelia. Elevated expression of Egr2 mRNA was also observed in the decidual cells. Silencing of Egr2 by specific siRNA weakened the proliferation of uterine stromal cells and reduced the expression of Ccnd1, Ccnd3, Cdk4, and Cdk6. Furthermore, Egr2 advanced the expression of Prl8a2, Prl3c1, and Pgr, the well-established differentiation markers for decidualization. Administration of exogenous recombinant heparin-binding EGF-like growth factor (rHB-EGF) to uterine stromal cells resulted in an increase in the level of Egr2 mRNA. Moreover, siRNA-mediated attenuation of Egr2 impeded the stimulation of HB-EGF on stromal cell differentiation. Knockdown of Egr2 led to a reduction in the expression of Cox-2, mPGES-1, Vegf, Trp53, and Mmp2. Further analysis found that Egr2 may serve as an intermediate to mediate the regulation of HB-EGF on Cox-2, mPGES-1, Vegf, Trp53, Mmp2, and Ccnd3. Collectively, Egr2 may play an important role during embryo implantation and decidualization.

Antidepressant-like Effect of a Chalcone Compound, DHIPC and Its Possible Mechanism.

DHIPC (2,4-dichloro-2´-hydroxyl-4´,6´-diisoprenyloxychalcone) is a new chalcone compound. In this study, its antidepressant-like activity of compound DHIPC was evaluated by the forced swimming test and the tail suspension test in mice. The results showed that DHIPC significantly reduced the immobility time for 2 h after treatment through the oral administration at dose of 10, 20, and 30 mg/kg in the forced swimming test and the tail suspension test, indicating a significant antidepressant-like effect. The maximal effect was obtained at 30 mg/kg, which is similar to the positive control fluoxetine. The main monoamine neurotransmitters and their metabolites in rat brain were also simultaneously determined. It was found that DHIPC significantly increased the concentrations of the main neurotransmitters serotonin and noradrenalin, and also significantly increased 5-hydroxyindoleacetic acid contents in hippocampus, hypothalamus, and cortex in brain part. So, the probable mechanism of action of DHIPC is thought to be related to increase in serotonin and noradrenalin in the brain.

Expression profiles of mRNA and long noncoding RNA in the ovaries of letrozole-induced polycystic ovary syndrome rat model through deep sequencing.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in reproductive-aged women. However, the exact pathophysiology of PCOS remains largely unclear. We performed deep sequencing to investigate the mRNA and long noncoding RNA (lncRNA) expression profiles in the ovarian tissues of letrozole-induced PCOS rat model and control rats. A total of 2147 mRNAs and 158 lncRNAs were differentially expressed between the PCOS models and control. Gene ontology analysis indicated that differentially expressed mRNAs were associated with biological adhesion, reproduction, and metabolic process. Pathway analysis results indicated that these aberrantly expressed mRNAs were related to several specific signaling pathways, including insulin resistance, steroid hormone biosynthesis, PPAR signaling pathway, cell adhesion molecules, autoimmune thyroid disease, and AMPK signaling pathway. The relative expression levels of mRNAs and lncRNAs were validated through qRT-PCR. LncRNA-miRNA-mRNA network was constructed to explore ceRNAs involved in the PCOS model and were also verified by qRTPCR experiment. These findings may provide insight into the pathogenesis of PCOS and clues to find key diagnostic and therapeutic roles of lncRNA in PCOS.

[Advances in the studies of teratospermia-related genes].

Sperm morphology is one of the important indicators for the evaluation of male fertility. In recent years, there has been a gradual increase in the incidence of male infertility and that of infertility-associated teratospermia. Scholars at home and abroad are trying to explore the pathogenesis of teratospermia at the molecular level. With a review of recent studies on teratospermia, we present an overview of abnormal sperm morphology in the aspects of sperm head, neck and tail deformities, focusing on teratospermia-related genes, such as SPATA16, DPY19L2, PICK1, ZPBP1, SIRT1, AURKC, SPATA6, SUN5, ODF1, and DNAH1, aiming to provide a theoretical basis and some reference for the diagnosis and treatment of teratospermia.

Evidence For Hmgn2 Involvement in Mouse Embryo Implantation and Decidualization.

BACKGROUND/AIMS: Hmgn2 is involved in regulating embryonic development, but its physiological function during embryo implantation and decidualization remains unknown. METHODS: In situ hybridization, real-time PCR, RNA interference, gene overexpression and MTS assay were used to examine the expression of Hmgn2 in mouse uterus during the pre-implantation period and explore its function and regulatory mechanisms in epithelial adhesion junction and stromal cell proliferation and differentiation. RESULTS: Hmgn2 was primarily accumulated in uterine luminal epithelia on day 4 of pregnancy and subluminal stromal cells around the implanting blastocyst at implantation sites on day 5. Similar results were observed during delayed implantation and activation. Meanwhile, Hmgn2 expression was visualized in the decidua. In uterine epithelial cells, silencing of Hmgn2 by specific siRNA reduced the expression of adhesion molecules Cdh1, Cdh2 and Ctnnb1 and enhanced the expression of Muc1, whereas constitutive activation of Hmgn2 exhibited the opposite effects, suggesting a role for Hmgn2 in attachment reaction during embryo implantation. Estrogen stimulated the expression of Hmgn2 in uterine epithelia, but the stimulation was abrogated by ER antagonist ICI 182,780. Further analysis evidenced that attenuation of Hmgn2 might eliminate the regulation of estrogen on the expression of Cdh1, Cdh2 and Ctnnb1. In uterine stromal cells, progesterone induced the accumulation of Hmgn2 which advanced the expression of Prl8a2 and Prl3c1, two well-known differentiation markers for decidualization, but did not affect the proliferation of stromal cells. Knockdown of Hmgn2 blocked the progesterone-induced differentiation of uterine stromal cells. Moreover, Hmgn2 might serve as an intermediate to mediate the regulation of progesterone on Hand2. CONCLUSION: Hmgn2 may play an important role during embryo implantation and decidualization.

Protective effects of Cervus nippon Temminck velvet antler polypeptides against MPP+­induced cytotoxicity in SH­SY5Y neuroblastoma cells.

The aim of the present study was to examine the protective effects and mechanism of sika deer (Cervus nippon Temminck) velvet antler polypeptides (VAPs) against MPP+ exposure in the SH­SY5Y human neuroblastoma cell line. MPP+ cytotoxicity and the protective effects of VAPs on the SH­SY5Y cells were determined using an MTT assay. Cell apoptosis and mitochondrial membrane potential were detected using Hoechst 33342 and Rhodamine123 staining, respectively. Endoplasmic reticulum (ER) stress­related reactive oxygen species (ROS) production in the SH­SY5Y cells was detected using 2',7'­dichlorodihydrofluorescein diacetate fluorescent probes. The expression levels of proteins, including caspase­12, glucose regulated protein 78 (GRP78), CCAAT/enhancer binding protein homologous protein (CHOP) and phosphorylated c­Jun N­terminal kinase (p­JNK) were detected using western blot analysis. The results showed that the half inhibitory concentration of MPP+ at 72 h was 120.9 µmol/l, and that 62.5, 125, and 250 µg/ml concentrations of VAPs protected the SH­SY5Y cells under MPP+ exposure. When exposed to 120.9 µmol/l MPP+, changes in cell nucleus morphology, mitochondrial membrane potential and intracellular ROS were observed. VAPs at concentrations of 62.5, 125, 250 µg/ml reduced this damage. Western blot analysis showed that protein expression levels of caspase­12, GRP78 and p­JNK were upregulated in the SH­SY5Y cells exposed to 120.9 µmol/l MPP+ for 72 h. In addition, 62.5, 125, and 250 µg/ml VAPs downregulated the expression levels of caspase­12 and p­JNK in a concentration­ dependent manner, particularly the p­JNK pathway. The effects of VAPs on GRP78 and CHOP were weak. In conclusion, MPP+­induced SH­SY5Y cell death may be linked to ER stress. VAPs prevented MPP+­induced SH­SY5Y cell death by affecting the p­JNK pathway and caspase­12­mediated apoptosis. These findings assist in understanding the mechanism underlying the protective effect of VAPs on neurons.

Role of lncRNAs as Novel Biomarkers and Therapeutic Targets in Ovarian Cancer.

Ovarian cancer (OC) is the leading cause of death among all gynecological malignancies in the world and its underlying mechanism is still unclear. Compared with research on microRNAs, research on long non-coding RNAs (lncRNAs) is still in its infancy. Studies in recent years have demonstrated that lncRNAs exhibit multiple biological functions in various stages of OC development. In this review, we conclude that lncRNAs are closely involved in the pathogenesis of OC. The expression of lncRNAs indicates the early diagnosis, prognosis, and response to chemotherapy of OC. An attractive approach to treatment of OC is lncRNA small interfering RNA or acting as a plasmid targeting the expression of toxic genes, which is a novel step toward a major breakthrough in the treatment of human OC. E2-regulated lncRNA and its polymorphism, methylation, are also involved in OC. Further research efforts are needed before fully identifying, characterizing, and elucidating the actual functions of lncRNAs in OC at the molecular level and putting them into clinical practice.

Polymorphisms in inhibin α gene promoter associated with male infertility.

Inhibins play important roles in normal gonadal function, including regulation of proliferation, differentiation, and steroidogenesis of Leydig and Sertoli cells via paracrine and autocrine processes. In adult males, circulating inhibin levels are correlated with fertility by regulating the number of Sertoli cells, total sperm count, and testicular volume. Given this important role, inhibin-α subunit (INHA) is a strong candidate gene in male fertility. However, limited data regarding the association of polymorphisms of INHA with male fertility are available. This study was based on the hypothesis that polymorphisms in the promoter of INHA are associated with male fertility. Han Chinese patients with non-normozoospermia (n=153) and normozoospermia (n=72) from Northern China were screened, and genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism after INHA promoter was amplified. Statistical analysis results revealed a significant difference in the allele frequency of INHA promoter between males with non-normozoospermia and normozoospermia. For c.-124G>A, males carrying c.-124GG genotype and c.-124GA genotype showed an increased risk of non-normozoospermic syndrome. For c.-16C>T polymorphism, no significant difference in allele frequency was observed between the two groups. Therefore, the haplotype AC possibly displayed a considerable reduced risk of non-normozoospermic syndrome.

[Updated molecular genetic mechanisms of globozoospermia].

Globozoospermia is a rare and serious teratozoospermia, which is one of the important causes contributing to human male infertility. The assisted reproductive technique remains the only means for such patients to produce offspring. However, the pathogenesis of globozoospermia is not yet clear. In recent years, related studies have shown that some genes are connected with the onset of globozoospermia. This paper outlines the progress in the studies of pathogenicity genes, aiming to contribute to the molecular diagnosis and mechanism investigation of the disease.