Comparison of Echocardiography and Myocardial Scintigraphy to Detect Cancer Therapy-Related Cardiovascular Toxicity in Breast Cancer Patients.

The mortality rate of cancer patients has been decreasing; however, patients often suffer from cardiac disorders due to chemotherapy or other cancer therapies (e.g., cancer-therapy-related cardiovascular toxicity (CVR-CVT)). Therefore, the field of cardio-oncology has drawn more attention in recent years. The first European Society of Cardiology (ESC) guidelines on cardio-oncology was established last year. Echocardiography is the gold standard for the diagnosis of CVR-CVT, but many breast cancer patients are unable to undergo echocardiography due to their surgery wounds or anatomical reasons. We performed a study to evaluate the usefulness of myocardial scintigraphy using Iodine-123 ß-methyl-P-iodophenyl-pentadecanoic acid (123I-BMIPP) in comparison with echocardiography and published the results in the Journal of Imaging last year. This is the secondary analysis following our previous study. A total of 114 breast cancer patients who received chemotherapy within 3 years underwent echocardiography, as well as Thallium (201Tl) and 123I-BMIPP myocardial perfusion and metabolism scintigraphy. The ratio of isotope uptake reduction was scored by Heart Risk View-S software (Nihon Medi-Physics). The scores were then compared with the echocardiography parameters. All the patients' charts and data from January 2022 to November 2023 were reviewed for the secondary analysis. Echocardiogram parameters were obtained from 99 patients (87% of total patients). No correlations were found between the echocardiography parameters and Heart Risk View-S scores of 201Tl myocardial perfusion scintigraphy, nor those of the BMIPP myocardial metabolism scintigraphy. In total, 8 patients out of 114 (7.0%) died within 22 months, while 3 patients out of 26 CVR-CVT patients (11.5%) died within 22 months. Evaluation by echocardiography was sometimes difficult to perform on breast cancer patients. However, other imaging modalities, including myocardial scintigraphy, cannot serve as alternatives to echocardiography. Cardiac scintigraphy detects circulation disorder or metabolism disorder in the myocardium; therefore, it should be able to reveal myocardial damage to some extent. The mortality rate of breast cancer patients was higher with CVR-CVT. A new modality to detect CVR-CVT besides echocardiography can possibly be anticipated for patients who cannot undergo echocardiography.

SMAD2/3 signaling regulates initiation of mouse Wolffian ducts and proximal differentiation in Müllerian ducts.

Male and female reproductive tracts develop from anterior intermediate mesoderm with similar differentiation processes. The anterior intermediate mesoderm develops into the mesonephros, and the Wolffian duct initiates by epithelialization in the mesonephros. The Müllerian duct invaginates from the coelomic epithelium of the cranial mesonephros for ductal formation and is then regionalized into proximal to caudal female reproductive tracts. In this study, we focused on the epithelialization of the Wolffian duct, initiation of the Müllerian duct, and the regionalization step of the Müllerian ducts as a continuous process. By using intermediate mesodermal cells from mouse pluripotent stem cells, we identified that inhibition of SMAD2/3 signaling might be involved in the differentiation into mesenchymal cells, after which mesonephric cells might be then epithelialized during differentiation of the Wolffian duct. Aggregation of coelomic epithelial cells might be related to initiation of the Müllerian duct. Transcriptomic analysis predicted that consensus sequences of SMAD3/4 were enriched among highly expressed genes in the proximal Müllerian duct. SMAD2/3 signaling to regulate differentiation of the Wolffian duct was continuously activated in the proximal Müllerian duct and was involved in proximal and oviductal regionalization. Therefore, SMAD2/3 signaling may be finely tuned to regulate differentiation from initiation to regionalization steps.

Diagnostic Performance of Preoperative Imaging in Endometrial Cancer.

BACKGROUND: Endometrial cancer is one of the most common gynecological malignancies. Because the findings mentioned in radiogram interpretation reports issued by diagnostic radiologists influence treatment strategies, we aimed to evaluate the diagnostic accuracy of preoperative computed tomography (CT) and magnetic resonance imaging (MRI) interpretation results in clinically relevant settings. METHODS: The clinical records of patients diagnosed with endometrial cancer treated at Tohoku University Hospital from January 2012 to December 2021 were reviewed. The preoperative and pathologically estimated cancer stages were compared based on the results mentioned in the radiogram interpretation report. RESULTS: The preoperative and postoperative cancer stages were concordant in 70.0% of the patients. By contrast, the cancer stage was underdiagnosed and overdiagnosed in 21.7% and 8.2% of the patients, respectively. The sensitivities of MRI for deep myometrial invasion, cervical stromal invasion, vaginal invasion, and adnexal metastasis were 65.1%, 58.2%, 33.3%, and 18.4%, respectively. The sensitivity and specificity for pelvic lymph node metastasis using a combination of CT and MRI were 40.9% and 98.4%, respectively. Those for para-aortic lymph node metastases using CT were 37.0% and 99.5%, respectively. CONCLUSIONS: The low sensitivity observed in this study clarified the limitations of preoperative diagnostic performance in current clinical practice.

Hepatic compartment syndrome treated with damage control surgery and transarterial embolization: A case report.

Background: Hepatic compartment syndrome (HCS) is a complication of nonoperative management in patients with blunt hepatic injury. Although decompression of elevated intrahepatic pressure through surgical exploration or drainage and hemorrhage control are required to manage this condition, evidence for such a management for this complication is insufficient. Herein, we report a pediatric patient treated with a planned combination strategy of surgical decompression with perihepatic packing to reduce intrahepatic pressure and subcapsular hemorrhage control as well as angioembolization to control intraparenchymal hemorrhage. Case presentation: A 12-year-old boy was referred to our emergency department 5 h after sustaining severe bruising in the upper abdomen in a traffic accident. Computed tomography (CT) showed an intraparenchymal hematoma in the right lobe of the liver; nonoperative management was selected based on stable hemodynamic status. Two days after the injury, he complained of severe abdominal pain and shock. CT showed an intraparenchymal and large subcapsular hematoma with right branch compression of the portal vein and extravasation of contrast material. Laboratory data showed progression of hepatocellular damage. We successfully managed this patient with a planned combination strategy of surgical decompression with perihepatic packing for reduction of intrahepatic pressure and subcapsular hemorrhage control, followed by angioembolization for control of intraparenchymal hemorrhage. Conclusion: Our study suggests that for the management of HCS, a planned combination strategy of damage control surgery and angioembolization is a therapeutic option.

Iodine-123 ß-methyl-P-iodophenyl-pentadecanoic Acid (123I-BMIPP) Myocardial Scintigraphy for Breast Cancer Patients and Possible Early Signs of Cancer-Therapeutics-Related Cardiac Dysfunction (CTRCD).

(1) Background: The mortality of breast cancer has decreased due to the advancement of cancer therapies. However, more patients are suffering from cancer-therapeutics-related cardiac dysfunction (CTRCD). Diagnostic and treatment guidelines for CTRCD have not been fully established yet. Ultrasound cardiogram (UCG) is the gold standard for diagnosis of CTRCD, but many breast cancer patients cannot undergo UCG due to the surgery wounds or anatomical reasons. The purpose of the study is to evaluate the usefulness of myocardial scintigraphy using Iodine-123 ß-methyl-P-iodophenyl-pentadecanoic acid (123I-BMIPP) in comparison with UCG. (2) Methods: 100 breast cancer patients who received chemotherapy within 3 years underwent Thallium (201Tl) and 23I-BMIPP myocardial perfusion and metabolism scintigraphy. The images were visually evaluated by doctors and radiological technologists, and the grade of uptake reduction was scored by Heart Risk View-S software (Nihon Medi-Physics). The scores were deployed in a 17-segment model of the heart. The distribution of the scores were analyzed. (3) Results: Nine patients (9%) could not undergo UCG. No correlation was found between left ventricular ejection fraction (LVEF) and Heart Risk View-S scores of 201Tl myocardial perfusion scintigraphy nor those of BMIPP myocardial metabolism scintigraphy. In a 17-segment model of the heart, the scores of the middle rings were higher than for the basal ring. (4) Conclusions: Evaluation by UCG is not possible for some patients. Myocardial scintigraphy cannot serve as a perfect alternative to UCG. However, it will become the preferable second-choice screening test, as it could point out the early stage of CTRCD.

Longitudinal increase in albumin-bilirubin score is associated with non-malignancy-related mortality and quality of life in patients with liver cirrhosis.

Due to the developments in the treatment for hepatitis, it is possible to prevent the progression of liver fibrosis and improve patients' prognosis even if it has already led to liver cirrhosis (LC). Consequently, a two-step study was conducted. To begin with, a retrospective study was conducted to identify the potential predictors of non-malignancy-related mortality from LC. Then, we prospectively analyzed the validity of these parameters as well as their association with patients' quality of life. In the retrospective study, 89 cases were included, and the multivariate Cox regression analysis indicated that age (P = 0.012), model for end-stage liver disease (MELD) score (P = 0.012), and annual rate of change of the albumin-bilirubin (ALBI) score (P < 0.001) were significantly associated with LC prognosis. In the prospective study, 70 patients were included, and the patients were divided into cirrhosis progression and non-progression groups. The univariate logistic regression analysis indicated the serum procollagen type III N-terminal peptide level (P = 0.040) and MELD score (P = 0.010) were significantly associated with the annual rate of change of the ALBI score. Furthermore, the mean Chronic Liver Disease Questionnaire score worsened from 5.3 to 4.9 in the cirrhosis progression group (P = 0.034). In conclusion, a longitudinal increase in the ALBI score is closely associated with non-malignancy-related mortality and quality of life.

Crystal structure of CmABCB1 multi-drug exporter in lipidic mesophase revealed by LCP-SFX.

CmABCB1 is a Cyanidioschyzon merolae homolog of human ABCB1, a well known ATP-binding cassette (ABC) transporter responsible for multi-drug resistance in various cancers. Three-dimensional structures of ABCB1 homologs have revealed the snapshots of inward- and outward-facing states of the transporters in action. However, sufficient information to establish the sequential movements of the open-close cycles of the alternating-access model is still lacking. Serial femtosecond crystallography (SFX) using X-ray free-electron lasers has proven its worth in determining novel structures and recording sequential conformational changes of proteins at room temperature, especially for medically important membrane proteins, but it has never been applied to ABC transporters. In this study, 7.7 mono-acyl-glycerol with cholesterol as the host lipid was used and obtained well diffracting microcrystals of the 130 kDa CmABCB1 dimer. Successful SFX experiments were performed by adjusting the viscosity of the crystal suspension of the sponge phase with hy-droxy-propyl methyl-cellulose and using the high-viscosity sample injector for data collection at the SACLA beamline. An outward-facing structure of CmABCB1 at a maximum resolution of 2.22 Šis reported, determined by SFX experiments with crystals formed in the lipidic cubic phase (LCP-SFX), which has never been applied to ABC transporters. In the type I crystal, CmABCB1 dimers interact with adjacent molecules via not only the nucleotide-binding domains but also the transmembrane domains (TMDs); such an interaction was not observed in the previous type II crystal. Although most parts of the structure are similar to those in the previous type II structure, the substrate-exit region of the TMD adopts a different configuration in the type I structure. This difference between the two types of structures reflects the flexibility of the substrate-exit region of CmABCB1, which might be essential for the smooth release of various substrates from the transporter.

Summary of 17 chemicals evaluated by OECD TG229 using Japanese Medaka, Oryzias latipes in EXTEND 2016.

In June 2016, the Ministry of the Environment of Japan announced a program "EXTEND2016" on the implementation of testing and assessment for endocrine active chemicals, consisting of a two-tiered strategy. The aim of the Tier 1 screening and the Tier 2 testing is to identify the impacts on the endocrine system and to characterize the adverse effects to aquatic animals by endocrine disrupting chemicals detected in the aquatic environment in Japan. For the consistent assessment of the effects on reproduction associated with estrogenic, anti-estrogenic, androgenic, and/or anti-androgenic activities of chemicals throughout Tier 1 screening to Tier 2 testing, a unified test species, Japanese medaka (Oryzias latipes), has been used. For Tier 1 screening, the in vivo Fish Short-Term Reproduction Assay (OECD test guideline No. 229) was conducted for 17 chemicals that were nominated based on the results of environmental monitoring, existing knowledge obtained from a literature survey, and positive results in reporter gene assays using the estrogen receptor of Japanese medaka. In the 17 assays using Japanese medaka, adverse effects on reproduction (i.e., reduction in fecundity and/or fertility) were suggested for 10 chemicals, and a significant increase of hepatic vitellogenin in males, indicating estrogenic (estrogen receptor agonistic) potency, was found for eight chemicals at the concentrations in which no overt toxicity was observed. Based on these results, and the frequency and the concentrations detected in the Japanese environment, estrone, 4-nonylphenol (branched isomers), 4-tert-octylphenol, triphenyl phosphate, and bisphenol A were considered as high priority candidate substances for the Tier 2 testing.

Cereblon-Based Small-Molecule Compounds to Control Neural Stem Cell Proliferation in Regenerative Medicine.

Thalidomide, a sedative drug that was once excluded from the market owing to its teratogenic properties, was later found to be effective in treating multiple myeloma. We had previously demonstrated that cereblon (CRBN) is the target of thalidomide embryopathy and acts as a substrate receptor for the E3 ubiquitin ligase complex, Cullin-Ring ligase 4 (CRL4CRBN) in zebrafish and chicks. CRBN was originally identified as a gene responsible for mild intellectual disability in humans. Fetuses exposed to thalidomide in early pregnancy were at risk of neurodevelopmental disorders such as autism, suggesting that CRBN is involved in prenatal brain development. Recently, we found that CRBN controls the proliferation of neural stem cells in the developing zebrafish brain, leading to changes in brain size. Our findings imply that CRBN is involved in neural stem cell growth in humans. Accumulating evidence shows that CRBN is essential not only for the teratogenic effects but also for the therapeutic effects of thalidomide. This review summarizes recent progress in thalidomide and CRBN research, focusing on the teratogenic and therapeutic effects. Investigation of the molecular mechanisms underlying the therapeutic effects of thalidomide and its derivatives, CRBN E3 ligase modulators (CELMoDs), reveals that these modulators provide CRBN the ability to recognize neosubstrates depending on their structure. Understanding the therapeutic effects leads to the development of a novel technology called CRBN-based proteolysis-targeting chimeras (PROTACs) for target protein knockdown. These studies raise the possibility that CRBN-based small-molecule compounds regulating the proliferation of neural stem cells may be developed for application in regenerative medicine.

Summary of reference chemicals evaluated by the fish short-term reproduction assay, OECD TG229, using Japanese Medaka, Oryzias latipes.

Under the Organisation for Economic Co-operation and Development (OECD), the Ministry of the Environment of Japan (MOE) added Japanese medaka (Oryzias latipes) to the test guideline fish short-term reproduction assay (FSTRA) developed by the United States Environmental Protection Agency (US EPA) using fathead minnow (Pimephales promelas). The FSTRA was designed to detect endocrine disrupting effects of chemicals interacting with the hypothalamic-pituitary-gonadal axis (HPG axis) such as agonists or antagonists on the estrogen receptor (Esr) and/or the androgen receptor (AR) and steroidogenesis inhibitors. We conducted the FSTRA with Japanese medaka, in accordance with OECD test guideline number 229 (TG229), for 16 chemicals including four Esr agonists, two Esr antagonists, three AR agonists, two AR antagonists, two steroidogenesis inhibitors, two progesterone receptor agonists, and a negative substance, and evaluated the usability and the validity of the FSTRA (TG229) protocol. In addition, in vitro reporter gene assays (RGAs) using Esr1 and ARß of Japanese medaka were performed for the 16 chemicals, to support the interpretation of the in vivo effects observed in the FSTRA. In the present study, all the test chemicals, except an antiandrogenic chemical and a weak Esr agonist, significantly reduced the reproductive status of the test fish, that is, fecundity or fertility, at concentrations where no overt toxicity was observed. Moreover, vitellogenin (VTG) induction in males and formation of secondary sex characteristics (SSC), papillary processes on the anal fin, in females was sensitive endpoints to Esr and AR agonistic effects, respectively, and might be indicators of the effect concentrations in long-term exposure. Overall, it is suggested that the in vivo FSTRA supported by in vitro RGA data can adequately detect effects on the test fish, O. latipes, and probably identify the mode of action (MOA) of the chemicals tested.

New frontiers of developmental endocrinology opened by researchers connecting irreversible effects of sex hormones on developing organs.

In the early 1960's, at Professor Bern's laboratory, University of California, Berkeley) in the US, Takasugi discovered ovary-independent, persistent vaginal changes in mice exposed neonatally to estrogen, which resulted in vaginal cancer later in life. Reproductive abnormalities in rodents were reported as a result of perinatal exposure to various estrogenic chemicals. Ten years later, vaginal cancers were reported in young women exposed in utero to the synthetic estrogen diethylstilbestrol (DES) and this has been called the "DES syndrome". The developing organism is particularly sensitive to developmental exposure to estrogens inducing long-term changes in various organs including the reproductive organs. The molecular mechanism underlying the persistent vaginal changes induced by perinatal estrogen exposure was partly demonstrated. Persistent phosphorylation and sustained expression of EGF-like growth factors, lead to estrogen receptor α (ESR1) activation, and then persistent vaginal epithelial cell proliferation. Agents which are weakly estrogenic by postnatal criteria may have major developmental effects, especially during a critical perinatal period. The present review outlines various studies conducted by four generations of investigators all under the influence of Prof. Bern. The studies include reports of persistent changes induced by neonatal androgen exposure, analyses of estrogen responsive genes, factors determining epithelial differentiation in the Müllerian duct, ESR and growth factor signaling, and polyovular follicles in mammals. This review is then expanded to the studies on the effects of environmental estrogens on wildlife and endocrine disruption in Daphnids.

Characterization of G protein-coupled estrogen receptors in Japanese medaka, Oryzias latipes.

The G protein-coupled estrogen receptor 1 (Gper1) is a membrane-bound estrogen receptor that mediates non-genomic action of estrogens. A Gper1-mediating pathway has been implicated in reproductive activities in fish, including oocyte growth, but Gper1 has been characterized in only a very limited number of fish species. In this study, we cloned and characterized two genes encoding medaka (Oryzias latipes) Gper1s, namely, Gper1a and Gper1b, and phylogenic and synteny analyses suggest that these genes originate through a teleost-specific whole genome duplication event. We found that Gper1a induced phosphorylation of mitogen-activated protein kinase (MAPK) in 293T cells transfected with medaka Gper1s on exposure to the natural estrogen, 17ß-estradiol (E2) and a synthetic Gper1 agonist (G-1), and treatment with both E2 and G-1 also decreased the rate of spontaneous maturation in medaka oocytes. These findings show that the processes for oocyte growth and maturation are sensitive to estrogens and are possibly mediated through Gper1a in medaka. We also show that 17α-ethinylestradiol (EE2), one of the most potent estrogenic endocrine-disrupting chemicals, and bisphenol A (BPA, a weak environmental estrogen) augmented phosphorylation of MAPK through medaka Gper1s in 293T cells. Interestingly, however, treatment with EE2 or BPA did not attenuate maturation of medaka oocytes. Our findings support that Gper1-mediated effects on oocytes are conserved among fish species, but effects of estrogenic endocrine-disrupting chemicals on oocytes acting through Gper1 may be divergent among fish species.

Hedgehog signaling regulates the basement membrane remodeling during folliculogenesis in the neonatal mouse ovary.

In the mouse ovary, interactions between oocytes and somatic cells are essential for folliculogenesis and subsequent follicle development. The polyovular follicle (PF), which contains more than two oocytes in a follicle, can be induced in the neonatal mouse ovary when interactions between oocytes and somatic cells are disrupted by agents such as the potent synthetic estrogen diethylstilbestrol (DES) acting through estrogen receptor (ER) ß. Hedgehog signaling is known to regulate granulosa cell proliferation, thecal cell differentiation, and follicle growth. To investigate the role of hedgehog signaling in the early folliculogenesis and in PF induction by DES, neonatal mouse ovaries were cultured with or without 10 µM cyclopamine (CPA), an inhibitor of hedgehog signaling, and grafted under the kidney capsule of adult ovariectomized host mice. The number and the incidence of PFs were significantly increased in organ-cultured ovaries post-grafting. Expression of procollagen type IV, alpha 1 (Col4a1) in organ-cultured ovaries was significantly reduced by CPA, but not by DES. The expression of two hedgehog ligands, Desert hedgehog (Dhh) and Indian hedgehog (Ihh), and a target gene, Hedgehog interacting protein (Hhip), was significantly increased by DES both in WT and ERß KO mice. Therefore, we infer that DES can affect expression of those genes through ERα but not via suppression of hedgehog signaling. Thus, PFs are induced by DES or CPA, but the induction mechanism is different. Our results revealed an important role of hedgehog signaling in basement membrane remodeling during folliculogenesis even before thecal cell differentiation.

Colorectal neuroendocrine carcinoma: A case report and review of the literature.

BACKGROUND: Colorectal neuroendocrine carcinoma (NEC) is a rare tumor that demonstrates aggressive growth pattern with ingrowth into the tract, metastasis to the other organs, and invasion to the surrounding organs; these clinical characteristics result in poor prognosis. Surgical resection appears as an effective approach; however, because it is difficult to accurately diagnose NEC during the early stage and owing to its aggressive growth pattern, development of a reliable standard chemotherapy regimen and management strategies are essential. CASE SUMMARY: Here, we report the case of patient with NEC showing an aggressive growth pattern that resulted in the rupture of the tumor to the outside the colon after stenting of the internal colonic stenosis. In addition, the tumor invaded into the duodenum, thereby causing duodenal stenosis that required an additional stent in the duodenum. This aggressive growth pattern is one of the main features of the NEC that is different from adenocarcinoma. To clarify the clinical characteristics, we reviewed 60 recently reported cases, including data on tumor location, size, treatment, and prognosis. CONCLUSION: We consider that the information presented here is of great significance for the diagnosis, treatment, and management of symptoms of the patients with NEC.

Diethylstilbestrol Alters the Expression of Activins in the Neonatal Mouse Ovary In Vitro.

BACKGROUND/AIM: Perinatal diethylstilbestrol (DES) treatment induces the polyovular follicle containing two or more oocytes in a follicle of mouse ovary through estrogen receptor (ER) ß. The aim of the study was to investigate the direct effects of DES on the neonatal mouse ovary and the gene expression of activins. MATERIALS AND METHODS: Ovaries from neonatal wild-type (WT) or ERß- knockout (ERßKO) mice were organ-cultured in a serum-free medium with or without DES, and polyovular follicle induction and expression of activin signaling related genes were examined. RESULTS: The polyovular follicle and cyst incidence in DES-treated organ-cultured ovaries from WT mice, but not from ERßKO mice, was significantly higher than that of control non-treated cultures. DES altered inhibin (Inh) a, Inhba and Inhbb expression in organ-cultured ovaries from C57BL/6J mice, while no change in Inha and an increase of Inhbb were observed by DES, in both WT and ERßKO mice. CONCLUSION: Alterations in activin signaling are involved in the polyovular follicle induction by DES.

Retinoic acid signaling determines the fate of the uterus from the mouse Müllerian duct.

In female mice, the Müllerian duct develops into the oviduct, uterus and vagina. The fate of epithelia is determined by factors secreted from the mesenchyme. Retinoic acid (RA) and its receptors are present in the mesenchyme of cranial Müllerian duct. RA induces Müllerian duct to uterine epithelial differentiation whereas inhibition of RA receptors induces vaginal epithelial differentiation. Thus, RA signaling in the Müllerian duct is required to promote differentiation of the mesenchyme into the future uterus. Perinatal estrogen exposure induces various abnormalities in Müllerian duct-derived organs. These include a cranial shift of the border among oviduct, uterus and vagina as well as precancerous lesions suppressed by co-treatment with RA and estrogen. Since RA synthesis enzymes and receptors are expressed both in the epithelium and stroma after birth, RA signaling may act in the epithelia to maintain adult epithelial homeostasis and to prevent irreversible lesions induced by perinatal estrogen exposure.

Heparin prevents oxidative stress-induced apoptosis in human decidualized endometrial stromal cells.

Clinical trials have shown that administering heparin during the luteal phase has beneficial effects on implantation and live birth rates. Heparin exerts direct effects on decidual human endometrial stromal cells (HESCs), which are independent of its anticoagulant effect. However, the accurate effects of heparin on the decidualization process remain unidentified. Here, we demonstrate that HESCs become dramatically resistant to oxidative stress upon decidualization, and we hypothesize a possible direct action of heparin on the decidualization of HESCs, which would lead to improved implantation. To test this hypothesis, we established primary HESC cultures and propagated them, and then we decidualized confluent cultures with 8-bromo-cAMP, with medroxyprogesterone acetate, and with or without heparin. We treated the cells with hydrogen peroxide (H2O2) as a source of reactive oxygen species (ROS). Adding heparin to decidualized HESCs induced prolactin secretion. Decidualized HESCs treated with heparin were prevented from undergoing apoptosis induced by oxidative stress. Heparin induced nuclear accumulation of the forkhead transcription factor FOXO1 and expression of its downstream target, the ROS scavenger superoxide dismutase 2. These results demonstrate that heparin-treated decidualized HESCs acquired further resistance to oxidative stress, suggesting that heparin may improve the implantation environment.

Loss of high-mobility group N5 contributes to the promotion of human endometrial stromal cell decidualization.

PURPOSE: High-mobility group N (HMGN) proteins are the only non-histone proteins that specifically bind within the nucleosome between core histones and DNA. Among them, HMGN5 is one of the candidates that could participate in mouse endometrial decidualization; however, the specific role of HMGN5 remains to be clarified in human endometrial stromal cells (HESCs). METHODS: Primary HESCs were isolated from hysterectomy specimens and incubated with or without 8-bromo-cyclic adenosine monophosphate (8-br-cAMP) and medroxyprogesterone acetate (MPA). RESULTS: We demonstrated that HMGN5 expression in decidualized HESCs stimulated by 8-br-cAMP and MPA decreased significantly. The inhibition of HMGN5 expression by small interfering RNA (siRNA) induced the major decidual marker genes expression, including IGFBP1 (insulin-like growth factor binding protein 1) and PRL (prolactin). In addition, microRNA-542-3p (miR-542-3p), which was identified as a regulatory miRNA of IGFBP1 during decidualization, was significantly suppressed by HMGN5 siRNA. However, the expression of HMGN5 was not alternated by miR-542-3p overexpression. CONCLUSIONS: These findings suggest that the down-regulation of HMGN5 plays a role in the promotion of human endometrial stromal decidualization and acts upstream of miR-542-3p.

The Involvement of Granulosa Cells in the Regulation by Gonadotropins of Cyp17a1 in Theca Cells.

BACKGROUND/AIM: Theca cells produce androgen by 17α-hydroxylase-17,20-lyase encoded by Cyp17a1, and conversion of androgen to estrogen in granulosa cells is regulated by gonadotropins. Women with polycystic ovarian syndrome (PCOS) exhibit elevated levels of androgens due to high Cyp17a1 expression and alterations in gene expression in granulosa cells. The aim of this study was to examine the interaction between theca and granulosa cells in PCOS-model mice. MATERIALS AND METHODS: To produce PCOS-model mice, neonatal mice were injected with 1 µg TP for 3 days from the day of birth. Gonadotropins were injected according to the superovulation protocol to 3-month-old control mice and PCOS-model mice. Histological changes and expression of genes involved in steroidogenesis, ovulation and luteinization were investigated by immunohistochemistry and real-time RT-PCR, respectively. RESULTS: Pregnant mare serum gonadotropin (PMSG) induced the expression of genes involved in steroidogenesis in control prepubertal mice, whereas human chorionic gonadotropin (hCG) reduced Cyp17a1 expression and induced phospho-ERK1/2 in granulosa cells. Cyp17a1 was reduced in PMSG-primed PCOS-model mice regardless of hCG injection, and PMSG induced phosphorylation of ERK1/2 in granulosa cells. CONCLUSION: Phospho-ERK1/2 in granulosa cells can be correlated with reduced Cyp17a1 expression in theca cells, and the interaction between granulosa and theca cells may be impaired in PCOS-model mice.

Functional distinctions associated with the diversity of sex steroid hormone receptors ESR and AR.

Sex steroid hormones including estrogens and androgens play fundamental roles in regulating reproductive activities and they act through estrogen and androgen receptors (ESR and AR). These steroid receptors have evolved from a common ancestor in association with several gene duplications. In most vertebrates, this has resulted in two ESR subtypes (ESR1 and ESR2) and one AR, whereas in teleost fish there are at least three ESRs (ESR1, ESR2a and ESR2b) and two ARs (ARα and ARß) due to a lineage-specific whole genome duplication. Functional distinctions have been suggested among these receptors, but to date their roles have only been characterized in a limited number of species. Sexual differentiation and the development of reproductive organs are indispensable for all animal species and in vertebrates these events depend on the action of sex steroid hormones. Here we review the recent progress in understanding of the functions of the ESRs and ARs in the development and expression of sexually dimorphic characteristics associated with steroid hormone signaling in vertebrates, with representative fish, amphibians, reptiles, birds and mammals.