scholarly journals Paeoniflorin Enhances Endometrial Receptivity through Leukemia Inhibitory Factor

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 439
Author(s):  
Hye-Rin Park ◽  
Hee-Jung Choi ◽  
Bo-Sung Kim ◽  
Tae-Wook Chung ◽  
Keuk-Jun Kim ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Unmet Need ◽  
Water Extract ◽  
Implantation Rate ◽  
Endometrial Receptivity ◽  
Inhibitory Factor ◽  
Drug Candidate ◽  
Implantation Failure

Despite advances in assisted reproductive technology, treatment for deficient endometrial receptivity is a major clinical unmet need. In our previous study, the water extract of Paeonia lactiflora Pall. enhanced endometrial receptivity in vitro and in vivo via induction of leukemia inhibitory factor (LIF), an interleukin (IL)-6 family cytokine. In the present study, we found that paeoniflorin, a monoterpene glycoside, is the major active compound of P. lactiflora. Paeoniflorin significantly improved the embryo implantation rate in a murine model of mifepristone (RU486)-induced implantation failure. In addition, paeoniflorin increased the adhesion of human trophectoderm-derived JAr cells to endometrial Ishikawa cells through the expression of LIF in vitro. Moreover, using the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) database of the human endometrium, we confirmed that LIF signaling is a key regulator for improving human endometrial receptivity. Therefore, these results suggest that paeoniflorin might be a potent drug candidate for the treatment of endometrial implantation failure by enhancing endometrial receptivity.

scholarly journals Administration of a herbal formulation enhanced blastocyst implantation via IκB activation in mouse endometrium

2020 ◽  
Author(s):  
Songhee Jeon ◽  
Quan Feng Liu ◽  
Hua Cai ◽  
Ha Jin Jeong ◽  
Su-Hyun Kim ◽  
...  
Keyword(s):  
Embryo Implantation ◽  
Water Extract ◽  
Treated Group ◽  
Endometrial Receptivity ◽  
Implantation Failure ◽  
Herbal Formulation ◽  
Blastocyst Implantation ◽  
Implantation Sites

Abstract Background: BaelanChagsangBang (BCB), a herbal formulation consisting of eleven herbs, may be prescribed as a reproductive functional supplement to improve ovulation and implantation during the treatment of infertility and recurrent abortion in Korean Medicine. This study aimed to investigate the effects and action mechanisms of water-extracted BCB on endometrial receptivity and blastocyst implantation under normal conditions and in a mifepristone (RU486)-induced implantation failure murine model.Methods: In vitro, the antioxidant potentials of BCB were evaluated using DPPH and superoxide anion radical scavenging assays and a DCFH-DA assay, and the cytotoxic and cytoprotective effects of BCB were confirmed using an MTT assay. In vivo, C57BL/6 female mice (n = 6 per group) orally received BCB (300 mg/kg/day), a dose similar to that used clinically, from 7 days before pregnancy until the end of the experiment. On day 4 of pregnancy, RU486 (4 mg/kg) was injected subcutaneously to induce implantation failure. The effect of BCB on embryo implantation was evaluated by implantation rate analysis, histological examination, and western blotting of uterus tissues.Results: BCB water extract showed strong anti-oxidative and cytoprotective effects in vitro. In vivo administration of BCB water extract increased the number of newborn pups in BCB-treated mice versus sham-treated mice under normal conditions and improved the number of implantation sites in pregnant mice despite RU486 injection. BCB increased the protein levels of cyclooxygenase-2 and inducible nitric oxide synthase through IκB activation. Moreover, the expression levels of matrix metalloproteinases (MMPs) at uterus implantation sites were up-regulated in the BCB-treated group as compared with those in the RU486-treated group. Conclusion: These results show BCB improved embryo implantation through IκB activation in our mouse model and suggest that BCB has therapeutic potential in the context of poor endometrial receptivity.

scholarly journals Administration of a herbal formulation enhanced blastocyst implantation via IκB activation in mouse endometrium

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Songhee Jeon ◽  
Quan Feng Liu ◽  
Hua Cai ◽  
Ha Jin Jeong ◽  
Su-Hyun Kim ◽  
...  
Keyword(s):  
Embryo Implantation ◽  
Water Extract ◽  
Treated Group ◽  
Endometrial Receptivity ◽  
Implantation Failure ◽  
Herbal Formulation ◽  
Blastocyst Implantation ◽  
Implantation Sites

Abstract Background BaelanChagsangBang (BCB), a herbal formulation consisting of eleven herbs, may be prescribed as a reproductive functional supplement to improve ovulation and implantation during the treatment of infertility and recurrent abortion in Korean Medicine. This study aimed to investigate the effects and action mechanisms of water-extracted BCB on endometrial receptivity and blastocyst implantation under normal conditions and in a mifepristone (RU486)-induced implantation failure murine model. Methods In vitro, the antioxidant potentials of BCB were evaluated using DPPH and superoxide anion radical scavenging assays and a DCFH-DA assay, and the cytotoxic and cytoprotective effects of BCB were confirmed using an MTT assay. In vivo, C57BL/6 female mice (n = 6 per group) orally received BCB (300 mg/kg/day), a dose similar to that used clinically, from 7 days before pregnancy until the end of the experiment. On day 4 of pregnancy, RU486 (4 mg/kg) was injected subcutaneously to induce implantation failure. The effect of BCB on embryo implantation was evaluated by implantation rate analysis, histological examination, and western blotting of uterus tissues. Results BCB water extract showed strong anti-oxidative and cytoprotective effects in vitro. In vivo administration of BCB water extract increased the number of newborn pups in BCB-treated mice versus sham-treated mice under normal conditions and improved the number of implantation sites in pregnant mice despite RU486 injection. BCB increased the protein levels of cyclooxygenase-2 and inducible nitric oxide synthase through IκB activation. Moreover, the expression levels of matrix metalloproteinases at uterus implantation sites were up-regulated in the BCB-treated group as compared with those in the RU486-treated group. Conclusion These results show BCB improved embryo implantation through IκB activation in our mouse model and suggest that BCB has therapeutic potential in the context of poor endometrial receptivity.

An In Vitro and In Vivo Evidence That Downregulation of Leukemia Inhibitory Factor (LIF) Receptor (LIF-R) Decreases the Metastatic Potential of Human Rhabdomyosarcoma (RMS) Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2561-2561
Author(s):  
Marcin Wysoczynski ◽  
Katarzyna Miekus ◽  
Anna Marcinkowska ◽  
Anna Janowska-Wieczorek ◽  
Mariusz Z. Ratajczak
Keyword(s):  
Skeletal Muscle ◽  
Bone Marrow ◽  
Cell Line ◽  
Cell Lines ◽  
Leukemia Inhibitory Factor ◽  
Biological Significance ◽  
Human Cells ◽  
Inhibitory Factor

Abstract Rhabdomyosarcoma (RMS) and skeletal muscle-derived tumors frequently infiltrate bone marrow (BM). We have demonstrated that the stromal-derived factor (SDF)-1-CXCR4 receptor (Blood2002;100:2597) and hepatocyte growth factor (HGF)-c-Met receptor (Cancer Res. 2003;63:7926) play an important role in RMS metastasis to BM. Leukemia inhibitory factor (LIF) is a well known factor that plays an important role in skeletal muscle development/regeneration and similarly as SDF-1 and HGF is secreted by BM stroma. This prompted us to examine whether the LIF-LIF receptor (LIF-R) axis affects the biology/metastasis of RMS cells. We employed in our studies, human established RMS cell lines, as well as RMS samples isolated from patients and noticed that LIF-R was expressed not only on established human RMS cell lines (7/7) but more importantly, it was also detectable in patient samples (23/23). We also found that in RMS cells LIF stimulatesphosphorylation of MAPKp42/44, AKT and STAT3,chemotaxis and adhesion andincreases resistance to cytostatics (e.g., etoposide). These LIF-mediated effects were inhibited after downregulating the LIF-R by siRNA. To learn more on the biological significance of the LIF-LIF-R axis in vivo we employed two models. First, human RMS cells (RH-30) were exposed or not exposed to LIF-R siRNA and subsequently injected into SCID™-Beige immunodeficient mice. To estimate the number of RMS cells that seed to BM and liver in these animals, we isolated DNA and using real- time RT-PCR, amplified human a-satellite sequences and murine b-actin. The number of human cells present in murine organs was subsequently calculated from a standard curve derived from mixing varying numbers of human cells with a constant number of murine cells. We noticed that downregulation of LIF-R by siRNA significantly decreased the number of human RMS cells in murine BM and liver (x4 and x2 respectively). In a second model, the RH30 cell line was selected by repetitive chemotaxis for cells that are highly responsive to LIF (RH-30 L) and subsequently the cells from parental RH-30 cell line and RH-30 L cells were injected intramuscularly. Six weeks after tumour inoculation, we detected more metastasis in bone marrow and lungs in mice injected with RH-30L cells as compared to parental RH-30 clone (x6 and x3 respectively). In conclusion, we present evidence for the first time that the inhibition of LIF-LIF-R axis may decrease the invasive potential of human RMS both in vitro and in vivo. Hence, molecular targeting of LIF-LIF-R axis could possibly become a more effective new strategy to control the progression and metastasis of RMS.

scholarly journals Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro

Blood ◽  
1991 ◽  
Vol 77 (10) ◽  
pp. 2150-2153
Author(s):  
D Metcalf ◽  
D Hilton ◽  
NA Nicola
Keyword(s):  
Colony Formation ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Stimulating Factor ◽  
Murine Leukemia

Receptors for murine leukemia inhibitory factor (LIF) were demonstrated on immature and mature murine megakaryocytes. LIF alone had no effects in culture on the survival or proliferation of normal murine megakaryocytes or their precursors. However, combination of LIF with multipotential-colony-stimulating factor (Multi-CSF) (interleukin-3) enhanced the megakaryocyte colony formation able to be stimulated by Multi-CSF; the enhancement involved all types of megakaryocyte colony and resulted in the formation of increased numbers of megakaryocytes. These observations provide a possible basis for the observation that, when LIF is injected in vivo, elevations are observed in megakaryocyte numbers and platelet levels.

scholarly journals Enhancement of Endometrial Receptivity by Cnidium officinale through Expressing LIF and Integrins

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Tae-Wook Chung ◽  
Mi-Ju Park ◽  
Hoyoung Lee ◽  
Keuk-Jun Kim ◽  
Cheorl-Ho Kim ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Embryo Implantation ◽  
Implantation Rate ◽  
Endometrial Receptivity ◽  
Female Infertility ◽  
In Vivo Model ◽  
Cnidium Officinale ◽  
Ishikawa Cells

Improvement of endometrial receptivity is necessary for successful embryo implantation, and its impairment is associated with female infertility. In this study, we investigated the effect of the roots of Cnidium officinale Makino (CoM) on endometrial receptivity in both in vitro and in vivo model of embryo implantation. We found that CoM enhanced the adhesion of JAr cells to Ishikawa cells by stimulating expression of leukemia inhibitory factor (LIF) and integrins. In addition, blocking of LIFR using hLA or neutralization of integrins αV, β3, and β5 using antibodies significantly reduced the enhanced adhesion between JAr cell and CoM-treated Ishikawa cells, indicating that LIF and integrin play an important role in trophoblast-endometrium adhesion for embryo implantation. Furthermore, we identified that CoM significantly improved the implantation rate of blastocysts in the mouse model of RU-induced implantation failure. By collecting these results, here, we suggest that CoM has a therapeutic potential against female infertility associated with decreased endometrial receptivity.

scholarly journals Leukemia Inhibitory Factor Induces Proopiomelanocortin via CRH/CRHR Pathway in Mouse Trophoblast

2021 ◽  
Vol 9 ◽  
Author(s):  
He Wang ◽  
Hiromi Sakata-Haga ◽  
Hiroko Masuta ◽  
Mitsuhiro Tomosugi ◽  
Tsuyoshi Tsukada ◽  
...  
Keyword(s):  
Stem Cells ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Stat3 Pathway ◽  
Trophoblast Stem Cells ◽  
Protein Levels ◽  
Trophoblast Stem ◽  
Mouse Placenta

We previously showed that maternal leukemia inhibitory factor (LIF) induces placental production of adrenocorticotropic hormone (ACTH), which stimulates fetal nucleated red blood cells to further secrete LIF and promote neurogenesis in rodent brains. However, the underlying mechanism of LIF-dependent ACTH induction remains unclear. Recently, we found that LIF induces corticotropin-releasing hormone (CRH) in mouse trophoblast stem cells. This finding supports the results of a previous study that CRH, which is produced by the placenta, induces placental ACTH production. In this study, we examined whether the effects of LIF are mediated by the induction of Pomc via CRH upregulation in mouse trophoblast. In vivo, protein levels of LIF and CRH peak in mouse placenta at 13.5 days post coitum. In mouse placenta, Crh mRNA and protein levels significantly increased 3 h after intraperitoneal injection of LIF (5 μg/kg body weight) into dams at 13.5 days post coitum. We also examined the effect of LIF-induced CRH on the expression of Pomc induced by LIF in mouse trophoblast stem cells in vitro. After LIF supplementation for 3 days, we found that the increased expression of Crh-induced by new supplementation of LIF was earlier than that of Pomc. Furthermore, LIF-induced upregulation of Pomc in mouse trophoblast stem cells was attenuated by inhibition of the CRH/CRHR1 pathway, whereas LIF-induced secretion of ACTH was attenuated by inhibition of the JAK/STAT3 pathway. Therefore, LIF indirectly increases placental Pomc expression through the CRH/CRHR1 pathway, and placental ACTH secretion is induced directly by LIF via the JAK/STAT3 pathway.

scholarly journals Leukemia inhibitory factor can potentiate murine megakaryocyte production in vitro

Blood ◽  
1991 ◽  
Vol 77 (10) ◽  
pp. 2150-2153 ◽  
Author(s):  
D Metcalf ◽  
D Hilton ◽  
NA Nicola
Keyword(s):  
Colony Formation ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Colony Stimulating Factor ◽  
Interleukin 3 ◽  
Stimulating Factor ◽  
Murine Leukemia

Abstract Receptors for murine leukemia inhibitory factor (LIF) were demonstrated on immature and mature murine megakaryocytes. LIF alone had no effects in culture on the survival or proliferation of normal murine megakaryocytes or their precursors. However, combination of LIF with multipotential-colony-stimulating factor (Multi-CSF) (interleukin-3) enhanced the megakaryocyte colony formation able to be stimulated by Multi-CSF; the enhancement involved all types of megakaryocyte colony and resulted in the formation of increased numbers of megakaryocytes. These observations provide a possible basis for the observation that, when LIF is injected in vivo, elevations are observed in megakaryocyte numbers and platelet levels.

scholarly journals Downregulation of miR-29c promotes muscle wasting by modulating the activity of leukemia inhibitory factor in lung cancer cachexia

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Kairu Xie ◽  
Hairong Xiong ◽  
Wen Xiao ◽  
Zhiyong Xiong ◽  
Wenjun Hu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Leukemia Inhibitory Factor ◽  
Cancer Cachexia ◽  
Muscle Development ◽  
Muscle Wasting ◽  
The Cancer Genome Atlas ◽  
Inhibitory Factor ◽  
C2c12 Myotubes

Abstract Background Cancer cachexia is a wasting disorder characterized by significant weight loss, and is attributed to skeletal muscle weakness. In the process of cancer development, microRNAs act as oncogenes or tumor suppressors. Moreover, they are implicated in muscle development and wasting. This study sought to explore the mechanisms and correlation between miR-29c and muscle wasting in lung cancer cachexia. Methods Data for expression analysis were retrieved from the Cancer Genome Atlas (TCGA) database. qRT-PCR analyses were performed to explore the expression levels of miR-29c and Leukemia Inhibitory Factor (LIF). Lewis lung carcinoma (LLC) cell line was used to establish a cachexia model to explore the functions of miR-29c and LIF in lung cancer cachexia. Furthermore, in vitro (in C2C12 myotubes) and in vivo (in LLC tumor-bearing mice) experiments were performed to explore the mechanisms of miR-29c and LIF in lung cachexia. Results Analysis of the lung cancer cachexia model showed that miR-29c was down-regulated, and its expression was negatively correlated with muscle catabolic activity. Overexpression of miR-29c mitigated the cachectic phenotype. Mechanistic studies showed that LIF was a direct target gene of miR-29c, and LIF was upregulated in vitro and in vivo. Analysis showed that LIF promoted muscle wasting through the JAK/STAT and MAP-kinase pathways. Conclusions The findings indicated that miR-29c was negatively correlated with the cachectic phenotype, and the miR-29c-LIF axis is a potential therapeutic target for cancer cachexia.

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