Two new species of the macropsine leafhoppers (Hemiptera: Cicadellidae: Eurymelinae) from Japan, with description of a new subgenus.

Two new macropsine species, Celopsis yaeyamana sp. nov. and Pediopsoides (Glaphyropsis) aurantescens subgen. & sp. nov. are described and illustrated from the Ryukyu Islands of Japan. Four Celopsis species, C. membrana (Zhang), C. montaninversa (Yang & Zhang), C. trifurcata (Li, Dai & Li) and C. rhombica (Li, Dai & Li) are transferred to the new subgenus Glaphyropsis.

Transcriptome Analysis by RNA Sequencing of Mouse Embryonic Stem Cells Stocked on International Space Station for 1584 Days in Frozen State after Culture on the Ground.

As a space project, in "Stem Cells" by the Japan Aerospace Exploration Agency (JAXA), frozen mouse ES cells were stored on the International Space Station (ISS) in the Minus Eighty Degree Laboratory Freezer for ISS (MELFI) for 1584 days. After taking these cells back to the ground, the cells were thawed and cultured, and their gene expressions were comprehensively analyzed using RNA sequencing in order to elucidate the early response of the cells to long-time exposure to space radiation consisting of various ionized particles. The comparisons of gene expression involved in double-stranded break (DSB) repair were examined. The expressions of most of the genes that were involved in homologous recombination (HR) and non-homologous end joining (NHEJ) were not significantly changed between the ISS-stocked cells and ground-stocked control cells. However, the transcription of Trp53inp1 (tumor protein 53 induced nuclear protein-1), Cdkn1a (p21), and Mdm2 genes increased in ISS-stocked cells as well as Fe ion-irradiated cells compared to control cells. This suggests that accumulated DNA damage caused by space radiation exposure would activate these genes, which are involved in cell cycle arrest for repair and apoptosis in a p53-dependent or -independent manner, in order to prevent cells with damaged genomes from proliferating and forming tumors.

Medroxyprogesterone acetate-resistant endometrial cancer cells are susceptible to ferroptosis inducers.

AIMS: Medroxyprogesterone acetate (MPA) is the most common fertility-sparing treatment in patients with early-stage endometrial cancer. If MPA treatment fails, hysterectomy is recommended. Thus, there is an urgent need for novel treatment approaches for MPA-resistant endometrial cancer patients who wish to preserve their fertility. Ferroptosis is a recently discovered type of regulated cell death caused by the excessive accumulation of reactive oxygen species (ROS), followed by aberrant lipid peroxidation. Recent studies have shown that inducing ferroptosis is a potential therapeutic strategy for cancer. However, the role of ferroptosis in endometrial cancer treatment remains to be discussed. We therefore investigated the effects of ferroptosis inducers on MPA-resistant endometrial cancer cells. MAIN METHODS: The levels of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), the main mediators of ferroptosis, were examined. Cell viability was evaluated after treatment with the ferroptosis inducers sulfasalazine, erastin, or RSL3. The degree of intracellular oxidative stress after treatment with these drugs was evaluated by the glutathione level, ROS level, ferrous iron level, lipid peroxidation and changes in mitochondrial morphology. The effect of ferroptosis inducers in vivo was also examined. KEY FINDINGS: The expression of SLC7A11 and GPX4 in MPA-resistant ECC-1 cells decreased in comparison to parental ECC-1 cells. Sulfasalazine, erastin, and RSL3 significantly reduced cell viability and increased intracellular oxidative stress in MPA-resistant ECC-1 cells. Ferroptosis inducers also suppressed in vivo tumor growth more effectively in MPA-resistant ECC-1. SIGNIFICANCE: Treatment with ferroptosis inducers could be a novel therapeutic approach for MPA-resistant endometrial cancer.

Phylogenetic Analysis of the Genus Planaphrodes Hamilton (Hemiptera, Cicadellidae, Aphrodinae) Based on Morphological Characteristics, with Revision of Species from China, Korea and Japan.

A morphology-based phylogeny of the Holarctic leafhopper genus Planaphrodes Hamilton is reconstructed for the first time based on 39 discrete male adult morphological characters. The results support the monophyly of Planaphrodes, with the included species forming two monophyletic lineages defined mainly by the number and location of aedeagus processes. The position of Planaphrodes in the Aphrodini was resolved as follows: (Stroggylocephalus + (Anoscopus + (Planaphrodes + Aphrodes))). The fauna of Planaphrodes from China, Japan and Korea are reviewed and six species are recognized, including two new species: P. bifasciatus (Linnaeus), P. sahlbergii (Signoret), P. nigricans (Matsumura), P. laevus (Rey), P. baoxingensis sp. nov. (China: Sichuan) and P. faciems sp. nov. (China: Hubei). Acocephalus alboguttatus Kato, 1933 syn. nov. and Aphrodes daiwenicus Kuoh, 1981 syn. nov. are considered junior synonyms of Planaphrodes sahlbergii (Signoret, 1879). Planaphrodes bella Choe, 1981 is a junior synonym of Planaphrodes nigricans (Matsumura, 1912). A checklist and key to species of Planaphrodes are provided.

miR-515-5p suppresses trophoblast cell invasion and proliferation through XIAP regulation in preeclampsia.

MicroRNAs (miRNAs) are non-coding small RNA molecules that can be secreted into the circulation and which exist in remarkably stable forms. Circulating miRNAs regulate numerous biological process and are aberrantly expressed in pathological conditions. Differentially expressed circulating miRNAs have received attention as potential biomarkers for many diseases. In this study, we revealed that miR-515-5p was significantly upregulated in maternal serum from preeclampsia patients in comparison to normal pregnant women. Bioinformatics prediction and a dual-luciferase reporter gene assay revealed that miR-515-5p directly targets the X-linked inhibitor of apoptosis protein (XIAP) 3'-untranslated region. In addition, the overexpression of miR-515-5p inhibited the proliferation and invasion of HTR-8/SVneo trophoblast cells. The decreased XIAP expression and reduced epithelial-mesenchymal transition (EMT) were observed in the preeclamptic placenta. Collectively, miR-515-5p may play critical roles in the pathogenesis of preeclampsia through suppression of XIAP, and serum miR-515-5p may act as a potential biomarker for preeclampsia.

Exploring the impact of ovariectomy on hair growth: can ovariectomized mouse serve as a model for investigating female pattern hair loss in humans?

Female pattern hair loss (FPHL), a type of hair disease common in pre- and postmenopausal women, is characterized by thinning of hair to O-type, mainly at the crown. Although a mouse model of this disease has recently been established, its details are still unknown, and thus, warrants further analysis. In this study, 3 week-old and 7- to 8 week-old C57BL/6 female mice were divided into two groups: one group underwent ovariectomy (OVX), while the other underwent sham surgery. In the 3 week-old mice, the dorsal skin was collected at seven weeks of age, while in the 7- to 8 week-old mice, it was collected at 12 and 24 weeks of age. In the former group, both the pore size of the hair follicles (HFs) and diameter of the hair shaft of telogen HFs decreased upon OVX; while in the latter group, these factors increased significantly. Notably, the thickness of the dermis and subcutis increased significantly in the OVX group. It needs to be further elucidated whether OVX mouse could serve as an ideal mouse model for FPHL, but our results upon evaluation of skin thickness indicate that it could be used to establish a novel treatment for non-hair-related diseases, such as post-menopause-related skin condition.

miR-486-5p inhibits invasion and migration of HTR8/SVneo trophoblast cells by down-regulating ARHGAP5.

INTRODUCTION: Appropriate implantation of trophoblast cells is necessary for successful pregnancy outcome. This process requires proper migration and invasion of trophoblast cells into the maternal endometrium and the myometrium. Dysregulation of circulating microRNAs in preeclampsia has been reported in several studies. Furthermore, miR-486-5p was reportedly increased within exosomes derived from maternal circulation in preeclamptic pregnancy. However, the roles of elevated miR-486-5p in preeclampsia has not yet been clarified. METHODS: HTR8/SVneo trophoblast cells were transfected with miR-486-5p, and the ARHGAP5 expression was examined by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blotting. A reporter assay using a luciferase construct containing the ARHGAP5 3'-untranslated region (3'UTR) was performed to determine whether or not ARHGAP5 is a direct target of miR-486-5p. Changes in migration and invasion abilities were examined by a wound healing assay and invasion assay, respectively. RESULTS: The ARHGAP5 expression was significantly decreased in miR-486-5p-transfected cells according to RT-qPCR and Western blotting. A dual luciferase reporter gene assay showed that miR-486-5p acts directly on the 3'UTR of ARHGAP5 mRNA. The migration and invasion abilities were suppressed in miR-486-5p-transfected cells. Downregulation of ARHGAP5 by small interfering RNA transfection inhibited trophoblast cell migration and invasion, resembling that of miR-486-5p transfection. DISCUSSION: The migration and invasion abilities of HTR8/SVneo cells were suppressed by miR-486-5p at least partly through inhibiting the ARHGAP5 expression. These data suggest that miR-486-5p is involved in the pathogenesis of preeclampsia and that miR-486-5p is a viable potential biomarker for predicting the onset risk of preeclampsia.

Recognition of the genera Igutettix Matsumura and Vilbasteana Anufriev (Hemiptera: Cicadellidae: Typhlocybinae), with discovery of a new related genus from Japan.

The dikraneurine genus Igutettix Matsumura and its allies are revised. The definition of Igutettix is corrected and newly proposed on the basis of the true I. pulverosus Matsumura, resurrected from the synonymy with Dikraneura oculata Lindberg. Accordingly, the genus Vilbasteana Anufriev established for the latter species is resurrected as an independent valid genus. The genera Vikabara Dworakowska and Paraafrakra Chiang, Hsu et Knight, are newly synonymized under Igutettix and Vilbasteana, respectively. Igutettix is composed of three species, I. pulverosus Matsumura sp. rev., I. ater (Dworakowska) comb. nov. and I. glossatus (Dworakowska) comb. nov. Vilbasteana comprises two species, V. oculata (Lindberg) comb. rev. and V. fulva (Chiang, Hsu et Knight) comb. nov. Furthermore, a new genus, Cornicola gen. nov. related to Igutettix is described for a new species C. mizuki sp. nov. from Japan.

The therapeutic potential of exosomal miR-22 for cervical cancer radiotherapy.

Cervical cancer is the fourth-most prevalent malignancy in women. For advanced cervical cancer, radiotherapy is a major treatment. Micro RNAs (miRNAs) are small, noncoding RNAs that negatively regulate the target gene expression posttranscriptionally. miR-22 is frequently downregulated in various cancers including cervical cancer, and is associated with a poor prognosis in cervical cancer. Exosomes are small endosomally secreted vesicles that carry components such as proteins, messenger RNA (mRNA), DNA and miRNA. We investigated whether or not exosomes can efficiently deliver miR-22 to recipient cervical cancer cells and affect the gene expression in the cells, as well as assessed the role of exosomal miR-22 in radiosensitivity. Exosomes containing high levels of miR-22 were extracted by ultracentrifugation and then characterized by Western blotting, a nanoparticle tracking analysis and electron microscopy. The high presence of miR-22 in the exosome was confirmed by real-time polymerase chain reaction. After the administration of the collected exosomal miR-22 to SKG-II and C4-I cervical cancer cells, the level of miR-22 in the cells was significantly increased, indicating the absorption of the exosomal miR-22. When miR-22 encapsulated in exosomes was administered to the SKG-II cells, the level of c-Myc binding protein (MYCBP) and human telomerase reverse transcriptase (hTERT) was significantly decreased in correlation with increased radiosensitivity determined by a clonogenic assay. Taken together, these results suggest that the administration of exosomal miR-22 may be a novel drug delivery system for cervical cancer radiotherapy.

First East Asian record of the genus Alpagut (Hemiptera: Heteroptera: Dipsocoridae), with description of a new species and a note on the metacoxal adhesive pad of Dipsocoridae.

The genus Alpagut Kiyak, 1995, is recorded from East Asia for the first time based on the description of A. masakazui sp. nov. from Japan. Habitus images and illustrations of diagnostic features, including genitalia structures, are provided. The loculus capsulae of A. masakazui sp. nov. is discussed. The presence of a metacoxal adhesive pad is reconfirmed in Dipsocoridae along with a discussion of its morphology.

New genus and species of Leptopsaltriini (Hemiptera: Cicadidae: Cicadinae) from China and Vietnam, with colour-changing behaviour reported for the first time in Cicadoidea.

One new cicada genus Versicolora gen. nov. and two new species, V. ziyongi sp. nov. from China and V. bellula sp. nov. from China and Vietnam, are described. The new genus is placed in the tribe Leptopsaltriini of the subfamily Cicadinae. The relationship of this new genus to other related taxa is discussed. Versicolora ziyongi sp. nov. camouflages itself on the bark of the host-plants and gradually changes its body colour when captured. This colour-changing behaviour is recorded for the first time in Cicadoidea, which provides innovative information for ecomorphological study of this remarkable species and other cicadas that potentially exhibit this behaviour.

The differential expression of miRNAs between ovarian endometrioma and endometriosis-associated ovarian cancer.

BACKGROUND: MicroRNAs (miRNAs) have been implicated to play a vital role in development, differentiation, cell proliferation and apoptosis. However, which miRNAs are actually associated with endometriosis-associated ovarian cancer remains controversial. METHODS: Serum and ascites samples were obtained from all patients. Serum samples from 5 cases of ovarian endometrioma and endometriosis-associated ovarian cancer each were submitted for comprehensive miRNA microarray profiling. We investigated the differential expression of miRNAs between the two groups to confirm the pivotal role of miRNAs. Quantitative reverse transcription-polymerase chain reaction validation of five selected miRNAs [miR-92a-3p, miR-486-5p, miR-4484, miR-6821-5p, and miR-7108-5p] was performed, and miR-486-5p expression analysis was followed by proliferation and wound healing assays, depending on the expression of miR-486-5p. RESULT: miR-486-5p expression in serum and ascites samples from endometriosis-associated ovarian cancer patients was significantly higher than that from ovarian endometrioma patients. Moreover, the miR-486-5p level in serum and ascites samples was significantly correlated with the severity of the endometriosis. The upregulation of miR-486-5p in immortalized ovarian endometrioma cells significantly increased proliferation and migration. In contrast, the downregulation of miR-486-5p in these cells significantly decreased proliferation and migration. CONCLUSION: miR-486-5p might function as an oncogenic miRNA in endometriosis-associated ovarian cancer and could be a noninvasive biomarker to prospect the severity of ovarian endometrioma.

Effects of synchronised engine sound and vibration presentation on visually induced motion sickness.

Driving simulator usage is often accompanied by motion sickness, and techniques for its prevention are not yet established. To reduce visually induced motion sickness (VIMS), we investigated the effects of synchronised presentation of engine sounds and motorcycle vibration on VIMS. A total of 80 participants experienced a driving scene with a head-mounted display for 5 minutes with or without synchronised presentation of engine sound and vibration. The results showed that VIMS scores, as measured by the Fast Motion Sickness scale, were significantly lower in participants who experienced the driving scene with sounds and vibration than in those who experienced the scene with sounds only, vibration only, or neither. Multiple regression analyses revealed that susceptibility to VIMS consistently explained the severity of VIMS to some extent but not with perceived realism of the virtual reality (VR) scene, sex, and experiences about VR devices and vehicles. This study demonstrated that simultaneous presentation of engine sounds and vibration, which were synchronous to each other and tightly coupled with the visual flow speed, effectively reduces VIMS while experiencing motorcycling simulators. The findings not only improve practical knowledge for reducing VIMS in driving simulators but also provide evidence for understanding the mechanisms of VIMS.

Serum exosomal microRNA-34a as a potential biomarker in epithelial ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is a leading cause of cancer-related death in women, and thus an accurate diagnosis of the predisposition and its early detection is necessary. The aims of this study were to determine whether serum exosomal microRNA-34a (miR-34a) in ovarian cancer could be used as a potential biomarker. METHODS: Exosomes from OC patients' serum were collected, and exosomal miRNAs were extracted. The relative expression of miR-34a was calculated from 58 OC samples by quantitative real-time polymerase chain reaction. RESULTS: Serum exosomal miR-34a levels were significantly increased in early-stage OC patients compared with advanced-stage patients. Its levels were significantly lower in patients with lymph node metastasis than in those with no lymph node metastasis. Furthermore, its levels in the recurrence group were significantly lower than those in the recurrence-free group. CONCLUSIONS: Serum exosomal miR-34a could be a potential biomarker for improving the diagnostic efficiency of OC.

The Protective Effect of Testosterone on the Ovarian Reserve During Cyclophosphamide Treatment.

INTRODUCTION: Cyclophosphamide, which is widely used to treat malignant disease, causes ovarian follicular atresia, which leads to premature ovarian insufficiency. The present study evaluated the protective effect of testosterone in preventing the decline in the ovarian reserve during cyclophosphamide treatment. METHODS: Using the COV434 human granulosa cell line, the protective effect of testosterone against cyclophosphamide was evaluated by immunocytochemistry, Western blotting and an MTS assay. The follicles in mouse ovaries and serum anti-Mullerian hormone were also assessed to evaluate the effects of testosterone. RESULTS: Testosterone suppressed the decrease in cell viability and apoptosis caused by cyclophosphamide treatment in vitro. In vivo, the number of atretic follicles in the mouse ovary was significantly lower in the testosterone plus cyclophosphamide group than in the cyclophosphamide alone group (p=0.03). The serum anti-Mullerian hormone was significantly higher in the testosterone plus cyclophosphamide group than in the cyclophosphamide alone group (16.2 [9.7-22.6]) vs 11.2 [8.9-12.1], p<0.01). The rate of cleaved Caspase-3 expression in the testosterone plus cyclophosphamide group was lower than that in the cyclophosphamide alone group (28.4% vs 48.6%, p=0.03). CONCLUSION: These findings indicated that testosterone has the potential to prevent ovarian damage induced by cyclophosphamide by protecting granulosa cells from cyclophosphamide-induced apoptosis.

Pharmacokinetic evaluation and antitumor potency of liposomal nanoparticle encapsulated cisplatin targeted to CD24-positive cells in ovarian cancer.

CD24, which is upregulated in several human malignancies, is related to Epithelial-mesenchymal-transition (EMT) and has characteristics of cancer stem-like cells, especially in cisplatin-resistant ovarian carcinoma cells. Drug delivery systems represent a promising therapeutic approach for diseases with treatment resistance, and the present study investigated a novel CD24-targeted drug delivery system for advanced ovarian carcinoma. We produced liposomal cisplatin with a red fluorescent substance - cyanine 5.5 (GL-CDDP-Cy5.5). In order to target CD24-positive cells, an anti-CD24 monoclonal antibody was modified to the above drug (CD24-GL-CDDP-Cy5.5). Specific uptake of CD24-GL-CDDP-Cy5.5 was confirmed using a therapeutically resistant ovarian cancer cell line, Caov-3 cells. Antitumor effects of CD24-GL-CDDP-Cy5.5 were then evaluated in Caov-3 ×enograft mice. CD24-GL-CDDP-Cy5.5 showed more specific uptake by flow cytometry than GL-CDDP-Cy5.5. In xenograft mice, GL-CDDP-Cy5.5 and CD24-GL-CDDP-Cy5.5 treatment had significantly higher platinum concentration in disseminated tumor cells than cisplatin (P<0.05). Moreover, CD24-GL-CDDP-Cy5.5 suppressed tumor growth and prolonged survival time compared with other treatments. Median survival times of the control, cisplatin, GL-CDDP-Cy5.5 and CD24-GL-CDDP-Cy5.5 groups were 37, 36, 46 and 54 days after inoculation, respectively. Immunohistochemical analysis showed that CD24-GL-CDDP-Cy5.5 treatment, compared with GL-CDDP-Cy5.5, decreased the number of CD24-positive cells and suppressed the EMT phenomenon significantly (P<0.05). The present study demonstrated that CD24-GL-CDDP-Cy5.5, compared with other treatments, improved therapeutic efficacy. The present results suggested the potential for targeting anticancer therapeutics for CD24-positive cells to prevent disease progression.

MicroRNA-22 enhances radiosensitivity in cervical cancer cell lines via direct inhibition of c-Myc binding protein, and the subsequent reduction in hTERT expression.

MicroRNAs (miRs) influence the expression of their target genes post-transcriptionally and serve an important role in multiple cellular processes. The downregulation of miR-22 is associated with a poor prognosis in cervical cancer. However, the mechanisms underlying miR-22-mediated gene regulation and its function are yet to be elucidated. In the present study, the effect of miR-22 expression on the radiosensitivity of cervical cancer was investigated. First, miR-22 was either up- or downregulated to evaluate the regulation of the MYC-binding protein (MYCBP) in four cervical cancer cell lines (C-4I, SKG-II and SiHa). Notably, MYCBP expression was inversely associated with miR-22 induction. A dual-luciferase reporter gene assay revealed that miR-22 directly targets the MYCBP 3'-untranslated region. Subsequently, the level of human telomerase reverse transcriptase component (hTERT; an E-box-containing c-Myc target gene) was analyzed after the up- or downregulation of miR-22. Notably, miR-22-mediated repression of MYCBP reduced hTERT expression. In addition, the influence of miR-22 on radiosensitivity in C-4I, SKG-II and SiHa cells was examined using a clonogenic assay and in mouse xenograft models. Upregulation of miR-22 was associated with increased radiosensitivity. Furthermore, lentiviral transduction of miR-22 reduced the Ki-67 index while increasing the TUNEL index in xenograft tissue. The current findings indicate the potential utility of miR-22 in radiotherapy for cervical cancer.

New genus of dikraneurine leafhopper (Hemiptera: Cicadellidae: Typhlocybinae) from Japan, with description of two new species.

A new genus, Stictotettix gen. nov. and two new species of Dikraneurini, S. cleyerae sp. nov. and S. morishimai sp. nov., are described and illustrated, based on the specimens from Japan. This new genus is unique in the male genital features of the aedeagal atrium. The two new species live on pentaphylacacean trees, Cleyera japonica and Eurya japonica, respectively.

Foretinib (GSK1363089) induces p53-dependent apoptosis in endometrial cancer.

OBJECTIVE: Foretinib (GSK1363089 or XL880), which is an oral multikinase inhibitor developed to primarily target the hepatocyte growth factor (HGF)/Met signaling pathway, has shown anti-tumor effects against some cancers in preclinical and clinical studies. RESULTS: HGF/Met signaling in endometrial cancer cell lines was stimulated in an autocrine manner, and was essential for cell survival. Inhibiting the HGF/Met signaling with foretinib induced p53-dependent apoptosis in endometrial cancer cell lines in vitro. Foretinib also showed significant anti-cancer effects in vivo in experiments using cell tumor xenografts. p53 mutations were observed in 37 (10.8%) of 344 endometrial cancer specimens. CONCLUSION: The HGF/Met-MAPK/PI3K pathway in endometrial cancer is activated by HGF in an autocrine manner. Foretinib induces an anti-cancer effect through the anti-phosphorylation of Met, which results in the induction of p53-dependent apoptosis; foretinib was found to exert greater anti-cancer activity in endometrial cancer specimens with wild-type p53 than in specimens with p53 mutations. Our immunochemical analysis revealed that foretinib-induced p53-dependent apoptosis can be expected to have therapeutic potential in approximately 90% of endometrial cancer patients. METHODS: We evaluated the HGF/Met signaling pathway in endometrial cancer cell lines and assessed the anti-cancer effects of foretinib using in vitro and in vivo experimental models. Furthermore, endometrial cancer specimens were subjected to an immunohistochemical analysis.

Recombinant human soluble thrombomodulin as an anticoagulation therapy improves recurrent miscarriage and fetal growth restriction due to placental insufficiency - The leading cause of preeclampsia.

INTRODUCTION: Placental insufficiency is one of the major risk factors for growth restriction and preeclampsia. The aim of this study is to investigate whether recombinant human Thrombomodulin(r-TM) improves fetal conditions and physiological outcomes. METHODS: We used CBA/J × BALB/C mice as a control and CBA/J × DBA/2 mice - a well-studied model of recurrent spontaneous miscarriage. Pregnant mice received daily subcutaneous injections of r-TM or saline from day 0-15. The fetal resorption rate, fetal weight, and litter size were calculated at day 15. Additionally, we analyzed the mRNA expression of angiogenic factors and the concentration of soluble Flt-1 (sFlt-1) using the ELISA kit. RESULTS: The rate of fetal resorption in CBA/J × DBA/2 mice treated with r-TM was significantly lower compared with mice without r-TM treatment. Additionally, fetal weight and litter size were also significantly higher in the r-TM treated mice. Fibrinogen deposition in the labyrinth area of the CBA/J × DBA/2 mice treated with r-TM was significantly lower compared with deposits in the mice untreated with r-TM. As well, r-TM significantly increased the gene expression level of VEGF and Flt-1 mRNA in the placentas of the CBA/J × DBA/2 mice. r-TM treatment also significantly decreased the production of sFlt-1 protein in the placentas of preeclampsia-like diseased mice. CONCLUSION: r-TM as an anticoagulation therapy has the potential for the medical treatment of recurrent miscarriage and fetal growth restriction due to improved angiogenic factors. Additionally, r-TM treatment has the potential for the recovery of preeclampsia.