Leveraging Machine Learning To Predict the Atmospheric Lifetime and the Global Warming Potential of SF6 Replacement Gases.

The global warming potential (GWP) is a relative measure of the capability of a molecule to trap the Earth's infrared radiation as heat. The measurement or prediction of the GWP of a molecule is based on two factors: the radiative efficiency and atmospheric lifetime of a molecule. While the calculation of the radiative efficiency of a molecule using the computational chemistry approach, such as density functional theory (DFT), is well-established and robust, the development of a computational approach to estimate the atmospheric lifetime remains challenging and limited to date. In this contribution, we developed a machine learning (ML) approach to estimate a molecule's atmospheric lifetime and GWP100 based on electronic and geometrical features. We benchmarked the state-of-the-art computational workflow with the developed ML model in estimating the atmospheric lifetime and GWP100. The developed ML model outperforms the existing approach with the mean absolute error values of 0.234 (ML-predicted atmospheric lifetime) and 0.249 (direct ML model for GWP100) compared with 0.535 (Atkinson's method) and 0.773 (Kazakov et al.) from previous works. The developed models were used to screen >7000 molecules in PubChem and bigQM7 data sets in a search for SF6 replacement gas for the electric industry and identified 84 potential candidates.

Sodium Butyrate Inhibits the Expression of Thymidylate Synthase and Induces Cell Death in Colorectal Cancer Cells.

The most commonly used chemotherapy for colorectal cancer (CRC) is the application of 5-fluorouracil (5-FU). Inhibition of thymidylate synthase (TYMS) expression appears to be a promising strategy to overcome the decreased sensitivity to 5-FU caused by high expression of TYMS, which can be induced by 5-FU treatment. Several compounds have been shown to potentially inhibit the expression of TYMS, but it is unclear whether short-chain fatty acids (SCFAs), which are naturally produced by bacteria in the human intestine, can regulate the expression of TYMS. Sodium butyrate (NaB) is the most widely known SCFA for its beneficial effects. Therefore, we investigated the enhancing effects on inhibition of cell viability and induction of apoptosis after co-treatment of NaB with 5-FU in two CRC cell lines, HCT116 and LoVo. This study suggests that the effect of NaB in improving therapeutic sensitivity to 5-FU in CRC cells may result from a mechanism that strongly inhibits the expression of TYMS. This study also shows that NaB inhibits the migration of CRC cells and can cause cell cycle arrest in the G2/M phase. These results suggest that NaB could be developed as a potential therapeutic adjuvant to improve the therapeutic effect of 5-FU in CRC.

Melatonin inhibits endometriosis development by disrupting mitochondrial function and regulating tiRNAs.

Endometriosis is a benign gynecological disease characterized by abnormal growth of endometrial-like cells outside the uterus. Melatonin, a hormone secreted by the pineal gland, has been shown to have therapeutic effects in various diseases, including endometriosis. However, the underlying molecular mechanisms are yet to be elucidated. The results of this study demonstrated that melatonin and dienogest administration effectively reduced surgically induced endometriotic lesions in a mouse model. Melatonin suppressed proliferation, induced apoptosis, and dysregulated calcium homeostasis in endometriotic cells and primary endometriotic stromal cells. Melatonin also caused mitochondrial dysfunction by permeating through the mitochondrial membrane to disrupt redox homeostasis in the endometriotic epithelial and stromal cells. Furthermore, melatonin affected oxidative phosphorylation systems to decrease ATP production in End1/E6E7 and VK2/E6E7 cells. This was achieved through messenger RNA-mediated downregulation of respiratory complex subunits. Melatonin inhibited the PI3K/AKT and ERK1/2 pathways and the mitochondria-associated membrane axis and further suppressed the migration of endometriotic epithelial and stromal cells. Furthermore, we demonstrated that tiRNAGluCTC and tiRNAAspGTC were associated with the proliferation of endometriosis and that melatonin suppressed the expression of these tiRNAs in primary endometriotic stromal cells and lesions in a mouse model. Thus, melatonin can be used as a novel therapeutic agent to manage endometriosis.

Fraxetin induces cell death in colon cancer cells via mitochondria dysfunction and enhances therapeutic effects in 5-fluorouracil resistant cells.

Fraxetin is a natural compound extracted from Fraxinus spp. and has various functions such as antibacterial, antioxidant, neuroprotective, and antifibrotic effects. Although studies have reported its anticancer properties in lung and breast cancer, little is known about colon cancer, the most frequent type of cancer. Thus, we used two colon cancer cell lines, HT29 and HCT116 cells, to investigate whether fraxetin could inhibit the capabilities acquired during tumor development. In this study, fraxetin suppressed cell viability and induced apoptotic cell death in HT29 and HCT116 cells. Furthermore, fraxetin regulated the expression of proteins involved in apoptosis in HT29 and HCT116 cells. Additionally, fraxetin induced reactive oxygen species levels and calcium influx with loss of mitochondrial membrane potential (ΔΨm) and endoplasmic reticulum stress. Moreover, fraxetin induced G2/M arrest and modulated the intracellular signaling pathway, including AKT, ERK1/2, JNK, and P38. Nevertheless, we found no cause-effect correlation between the antiproliferative action of fraxetin and modulation of the phosphorylation state of signaling proteins. Fraxetin-induced inhibitory effect on colon cancer cell viability was synergistic with 5-fluorouracil (5-FU) or irinotecan even in 5-FU resistant-HCT116 cells. Collectively, our results suggest that fraxetin can be effectively used as a therapeutic agent for targeting colon cancer, although it is necessary to further elucidate the relationship between the hallmark capabilities that fraxetin inhibits and the intracellular regulatory mechanism.

Identification of tissue-specific expression of CXCL14 in black rockfish (Sebastes schlegelii).

CXCL14 is a chemokine which is orthologous in mammals and fish. CXCL14 has a functional role in different organs, with immunomodulatory functions in mammals, but its expression and function in fish is not well known. Moreover, it shows no effects related to immunity in the central nervous system or the reproductive tract in diverse species. Black rockfish (Sebastes schlegelii) is an economically important fish in Asian countries, whose CXCL14 expression pattern is yet to be understood. In this study, the homology of the CXCL14 amino acid sequence in S. schlegelii was compared with that in other species, including fish. Moreover, in situ hybridization analysis revealed that it was highly expressed in the brain and ovary of S. schlegelii. Taken together, we identified for the first time, the cell-specific expression of CXCL14 in S. schlegelii.

Mechanisms of deleterious effects of some pesticide exposure on pigs.

The increase in the size of the global population increases the food and energy demand, making the use of pesticides in agricultural and livestock industries unavoidable. Exposure to pesticides can be toxic to the non-target species, such as humans, wildlife, and livestock, in addition to the target organisms. Various chemicals are used in the livestock industry to control harmful organisms, such as insects, weeds, and parasites. Pigs are one of the most important food sources for humans. In addition, pigs can be used as promising models for assessing the risk of absorption of environmental pollutants through the skin and oral exposure since they are physiologically similar to humans. Exposure to numerous environmental pollutants, such as mycotoxins, persistent organic pollutants, and heavy metals, has been reported to adversely affect growth, fertility, and endocrine homeostasis in pigs. Various pesticides have been observed in porcine tissues, blood, urine, and processed foods; however, there is a lack of comprehensive understanding of their effects on porcine health. This review provides a comprehensive description of the characteristics of pesticides that pigs can be exposed to and how their exposure affects porcine reproductive function, intestinal health, and endocrine homeostasis in vivo and in vitro.

Alterations in egg white-related genes expression in response to hormonal stimulation.

The reproductive tract in avian females is sensitive to hormonal regulation. Exogenous estrogen induces immature oviduct development to improve egg production after molting. In this process, regressed female reproductive tract is regenerated in response to the secretion of estrogen. However, there is limited knowledge on the physiological mechanisms underlying the regulation of the avian female reproductive system. In our previous study, results from microarray analysis revealed that the expression of genes encoding egg white proteins is affected during molting. Herein, we artificially induced the molting period in chickens through a zinc-containing diet. Subsequently, changes in the expression of genes encoding egg white proteins were confirmed in the oviduct tissue. The levels of MUC5B, ORM1, RTBDN, and TENP mRNA were significantly high in the oviduct, and the genes were repressed in the regression phase, whereas these were expressed in the recrudescence phase, particularly in the luminal epithelium and glandular epithelium of the oviduct, during molting. Moreover, we observed that gene expression was induced in the magnum, the site for the secretion of egg white components. Next, differences in expression levels of the four genes in normal and cancerous ovaries were compared. Collectively, results suggest that the four selected genes are expressed in the female chicken reproductive tract in response to hormonal regulation, and egg white protein-encoding genes may serve as modulators of the reproductive system in hens.

Melatonin improves uterine-conceptus interaction via regulation of SIRT1 during early pregnancy.

Melatonin has been shown to improve in vitro fertilization and offspring survival after bacterial infection, but its role in regulating maternal-fetal communication during early pregnancy has not been investigated. Results of this study demonstrated expression of abundant melatonin receptors in conceptus and endometrium during early pregnancy. In gilts, expression of melatonin receptor 1A (MTNR1A or MT1) and melatonin receptor 1B (MTNR1B or MT2) increased in trophectoderm (Tr) and uterine luminal epithelium (LE) with advancing days during early pregnancy in a different manner. Melatonin increased proliferation and migration of porcine trophectoderm (pTr) cell, the percent pTr cells in the G2 phase of the cell cycle, and the expression of implantation-related genes by pTr cells and endometrial luminal epithelium (pLE). Melatonin also attenuated the production of LPS-induced pro-inflammatory cytokines and tunicamycin-induced endoplasmic reticulum (ER) stress-sensing proteins. The expression of sirtuin 1 (SIRT1) as a potential target of melatonin increased between Days 9 and 14 of gestation. Co-treatment with SIRT1 inhibitor EX527 and melatonin restored cell-cell interactions through PI3K and MAPK signaling. Knockdown of SIRT1 decreased the expression of implantation-related genes, as well as migration of pTr and pLE cells. The expression of microRNAs regulated by SIRT1 was suppressed in response to melatonin. Furthermore, melatonin significantly increased lipopolysaccharide (LPS)-reduced fertilization and embryogenesis in zebrafish model. These results suggest that melatonin may improve the uterine-conceptus interactions via the regulation of SIRT1 during early pregnancy.

Fucoidan Derived from Fucus vesiculosus Inhibits the Development of Human Ovarian Cancer via the Disturbance of Calcium Homeostasis, Endoplasmic Reticulum Stress, and Angiogenesis.

Marine organisms are sources of several natural compounds with potential clinical use. However, only a few marine-based pharmaceuticals have been approved for use due to limited knowledge on their biological activities. Here, we identified the functional role of fucoidan extracted from Fucus vesiculosus on ovarian cancer. Fucoidan increased the death of ES-2 and OV-90 cells, through a reduction in proliferation, cell cycle arrest, releases of cytochrome c, reactive oxygen species (ROS) generation, and endoplasmic reticulum (ER) stress. Additionally, fucoidan increased the concentration of cytosolic and mitochondrial calcium in both cells. The decrease of cell proliferation was controlled by the inactivation of PI3K and MAPK signaling cascades in ES-2 and OV-90 cells. In a toxicity assay with normal zebrafish larvae, fucoidan did not induce toxicity, cardiotoxicity, development, kinesis, and apoptosis at different concentrations. However, it disrupted tumor formation and vascular development in a zebrafish xenograft model and angiogenesis transgenic (Tg, fli1-eGFP) model, respectively. Collectively, the results indicate that fucoidan may be a novel pharmaceutical for the management of human ovarian cancer.

The potential role of exosomes derived from ovarian cancer cells for diagnostic and therapeutic approaches.

Most patients with ovarian cancer (OC) are diagnosed at the advanced stages due to the absence of appropriate early diagnostic markers. Thus, OC is a gynecological disease with a low-survival rate. Exosomes are extracellular vesicles that are widely being considered as mediators for the noninvasive diagnosis of OC. Exosomes are expected to aid in the effective diagnosis of OC because they carry components, such as RNAs, proteins, and lipids, the compositions of which vary depending on the pathological characteristics of the patient. In this review, we document the methods that have been developed to detect exosomes and their components in OC. We also assess the potential biomarkers contained in exosomes that could be clinically useful, such as proteins, microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and phospholipids. Moreover, we described the role played by exosomes in the tumor microenvironment and in OC angiogenesis, migration, and tumor growth. Various types of cells in the tumor microenvironment, including macrophages, fibroblasts, and mesenchymal stem cells (MSCs), interact directly with exosomes and promote or inhibit the progression of OC. Therefore, we summarize the studies that have suggested a therapeutic approach to OC using exosomes. Collectively, understanding the mechanism of exosome-based OC progression would broaden our knowledge regarding the diagnosis and therapy of OC.

Anti-inflammatory effects of mesenchymal stem cell-derived exosomal microRNA-146a-5p and microRNA-548e-5p on human trophoblast cells.

Human umbilical cord mesenchymal stem cells (MSCs) have been reported to improve the migration and invasion of trophoblast cells; however, little is known about whether MSC-derived exosomes and exosomal miRNAs can regulate trophoblast cell properties. In this study, we investigated whether exosomal miRNAs from amniotic fluid-derived MSC (AF-MSC) could regulate the inflammatory response of the human trophoblast cell line HTR8/SVneo. We verified the anti-inflammatory effects of AF-MSCs on lipopolysaccharide (LPS)-induced inflammatory trophoblast cells and found that miR-146a-5p and miR-548e-5p in the AF-MSC-derived exosomes regulate nuclear factor κB, AKT and mitogen-activated protein kinase protein phosphorylation. Furthermore, we found that the transfection of human trophoblast cells with miR-146a-5p and miR-548e-5p inhibitors reduced trophoblast migration (P < 0.05 vs control) and the expression of proliferating cell nuclear antigen, a protein essential for cell proliferation (P < 0.01 vs control). In particular, the miR-548e-5p inhibitor induced apoptosis, while tumor necrosis factor receptor-associated factor 6, a predicted target of miR-146a-5p and miR-548e-5p, was involved in the regulation of oxidative stress in the human trophoblast cells. In a mouse model of LPS-induced preterm birth (PB), miR-146a-5p expression was found to be relatively low in the group in which the effect of AF-MSCs was insignificant. However, this study is limited in that the changes in the expression of some genes in response to AF-MSCs differ between the cell line and mouse model. Collectively, these data show that exosomal miR-146a-5p and miR-548e-5p from AF-MSCs have anti-inflammatory effects on human trophoblast cells and may be novel targets for treating inflammatory diseases and associated problems that occur during pregnancy, such as PB.

Effects of extracellular vesicles on placentation and pregnancy disorders.

In humans, pregnancy maintenance depends on normal placental formation following trophoblast invasion into the endometrium and vascular remodeling. In the early stages of pregnancy, immune tolerance, inflammatory response and adaptation to hypoxia need to be precisely regulated in the placental microenvironment. Various types of cells, such as trophoblasts, endothelial cells, immune cells, mesenchymal stem cells (MSCs) and adipocytes, induce normal placental development via intercellular interactions through soluble factors. Extracellular vesicles (EVs) are used to diagnose various diseases because their constituents vary depending on the type of cell of origin and pathological characteristics. EV-derived microRNAs (miRNAs) and proteins in the placenta regulate inflammatory responses and the invasion of trophoblasts through intercellular delivery in the placental microenvironment. If the placenta does not adapt to the changed environment during early pregnancy, pregnancy disorders such as pre-eclampsia, preterm birth and gestational diabetes mellitus can occur. Thus, the important roles of EVs during pregnancy and development is fast emerging. This review describes the physiological role of EVs during placentation and their composition in the human placenta. It also suggests the possibility of finding EV markers that can diagnose pregnancy disorders. Furthermore, it describes the properties of EVs that affect pregnancy in livestock.

Insilico direct folding of thrombin-binding aptamer G-quadruplex at all-atom level.

The reversible folding of the thrombin-binding DNA aptamer G-quadruplexes (GQs) (TBA-15) starting from fully unfolded states was demonstrated using a prolonged time scale (10-12 µs) parallel tempering metadynamics (PTMetaD) simulation method in conjunction with a modified version of the AMBER bsc1 force field. For unbiased descriptions of the folding free energy landscape of TBA-15, this force field was minimally modified. From this direct folding simulation using the modified bsc1 force field, reasonably converged free energy landscapes were obtained in K+-rich aqueous solution (150 mM), providing detailed atomistic pictures of GQ folding mechanisms for TBA-15. This study found that the TBA folding occurred via multiple folding pathways with two major free energy barriers of 13 and 15 kcal/mol in the presence of several intermediate states of G-triplex variants. The early formation of these intermediates was associated with a single K+ ion capturing. Interestingly, these intermediate states appear to undergo facile transitions among themselves through relatively small energy barriers.

Chrysophanol induces cell death and inhibits invasiveness via mitochondrial calcium overload in ovarian cancer cells.

Chrysophanol is a phytochemical typically extracted from rhubarb. Similar to other extracts from rhubarb, chrysophanol possesses anticancer activity against diverse cancerous cells. However, the apoptotic effects of chrysophanol in ovarian cancer remain unknown. In the current study, we examined the antitumorigenic activity of chrysophanol in human epithelial ovarian cancer cells, such as ES2 and OVCAR3. Chrysophanol decreased cell viability and increased cell death in a dose-dependent manner. In addition, chrysophanol markedly increased the intracellular reactive oxygen species production in ES2 cells, but only increased it slightly in OVCAR3 cells. Consistent with increased reactive oxygen species production, extensive lipid peroxidation was detected in chrysophanol-treated ES2 cells compared with that in untreated cells, whereas lipid peroxidation was unchanged in OVCAR3 cells in response to chrysophanol. Although there were no significant changes in calcium ions in the of ES2 and OVCAR3 cells, the concentration of calcium in the mitochondria increased dose dependent through disruption of the mitochondrial membrane potential in both ES2 and OVCAR3 cells compared with nontreated control cells. Moreover, chrysophanol activated the MAPK signaling pathways in the ovarian cancer cells. In addition, ovarian cancer cell invasiveness was suppressed, which implied that chrysophanol plays a role in preventing ovarian cancer metastasis. In conclusion, chrysophanol exhibits an anticancer effect via mitochondrial calcium overload and MAPK activation, suggesting its potential as a novel anticancer agent for human epithelial ovarian cancer.

Decanoic acid suppresses proliferation and invasiveness of human trophoblast cells by disrupting mitochondrial function.

Decanoic acid (DA) is a medium-chain fatty acid used in the manufacture of various products including plastics, cosmetics, and lubricants. In addition to antiviral and antibacterial effects, DA's, reported biological activities include regulation of signaling pathways and redox homeostasis in various human cell types. The influence of DA on functional properties of human trophoblasts, including proliferation, invasion and apoptosis is currently unknown. In the present study, we evaluated the anti-proliferative and anti-invasive effects of DA on the human trophoblast cell line HTR8/SVneo. In addition, DA induced oxidative stress, as evidenced by generation of reactive oxygen species (ROS) and induction of lipid peroxidation (LPO). This oxidative stress was accompanied by activation of the mitochondria-dependent apoptotic pathway in HTR8/SVneo cells. We also observed elevated mitochondrial Ca2+, and loss of mitochondrial membrane potential in response to DA treatment. Chelation of mitochondrial Ca2+ using BAPTA-AM rescued cellular proliferation suppressed by DA. We also verified that signaling proteins including AKT, P70S6K, S6, and ERK1/2 and their targets were significantly reduced in HTR8/SVneo cells by DA treatment. Pre-treatment of cells with selective inhibitors of AKT (LY294002) and ERK1/2 (U0126) revealed that the AKT and ERK1/2 signaling pathways regulated by DA displayed cross-talk in HTR8/SVneo cells. Collectively, these results suggest that personal products containing DA will have harmful effects on human trophoblasts, and could cause implantation and placentation failure during early pregnancy.

C-C motif chemokine ligand 2 induces proliferation and prevents lipopolysaccharide-induced inflammatory responses in bovine mammary epithelial cells.

C-C motif chemokine ligand 2 (CCL2) is a small chemokine which belongs to the CC-type chemokine family, and has chemoattractant activity for recruitment of monocytes to sites of inflammation. Overexpressed CCL2 binding to its receptor C-C chemokine receptor 2 increases the risk of breast cancer in humans, but its effects on proliferation of bovine mammary epithelial cells is not known. Maintaining a high level of proliferative activity in bovine mammary epithelial cells during lactation is important for improving milk yield and can benefit the dairy industry economically. In the present study, we demonstrated that CCL2 induces proliferation of MAC-T cells, a bovine mammary epithelial cell line, and stimulates progression of the cell cycle through stimulation of expression of cyclin D1. Moreover, CCL2 activates phosphoinositide 3-kinase (PI3K)/AKT [AKT, P70-S6 kinase 1 (P70S6K), ribosomal protein S6 (S6)] and mitogen activated protein kinase (MAPK) [extracellular signal-regulated kinase-1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and P38] pathways, which are involved in proliferation of MAC-T cells, as evidenced by co-treatment of MAC-T cells with pharmacological inhibitors of cell signaling transcription factors including Wortmannin, U0126, and SP600125. The CCL2 in MAC-T cells attenuates endoplasmic reticulum stress induced by tunicamycin, suggesting that CCL2 regulates intracellular synthesis of proteins and lipids and prevents activation of apoptotic pathways initiated in response to endoplasmic reticulum stress. Furthermore, CCL2 is involved in alleviating lipopolysaccharide (LPS)-induced inflammatory responses in MAC-T cells by reducing LPS-induced expression of IL8, IL6, and nuclear factor kappa B subunit 1 (NFKB1). Collectively, CCL2 is a novel target for improving the quantity and quality of milk from cows through stimulation of proliferation on mammary epithelial cells and attenuation of LPS-induced inflammatory responses.

Butyl paraben promotes apoptosis in human trophoblast cells through increased oxidative stress-induced endoplasmic reticulum stress.

Butyl paraben (BP) has antimicrobial effects and is widely used as a preservative in cosmetics, foods, and pharmaceuticals. It is also absorbed into various tissues of the human body. It is known that BP is measurable in maternal and fetal tissues during pregnancy, but the effects of BP on placental development, essential for maintaining normal pregnancy, are unclear. Therefore, we investigated the effect of BP on the proliferation, apoptosis, and invasiveness of human trophoblast cells, using an HTR8/SVneo cell line. BP inhibited cell proliferation and induced both apoptosis and endoplasmic reticulum stress. In addition, BP promoted the production of intracellular reactive oxygen species, increased Ca2+ concentration in HTR8/SVneo cells, and induced mitochondrial membrane depolarization. BP also inhibited the activation of PI3K/AKT pathways including AKT, ribosomal protein S6, P70 S6 kinase, and glycogen synthase kinase 3ß. Furthermore, pretreatment of cells with LY294002 (an AKT inhibitor) and U0126 (ERK1/2 inhibitor) revealed that ERK1/2 activity is also involved in BP-mediated signal transduction in HTR8/SVneo cells. We therefore suggest that exposing human trophoblast cells to BP diminishes normal physiological activity, leading to apoptosis and problems with early placental development.

Inhibitory Effects of Quercetin on Progression of Human Choriocarcinoma Cells Are Mediated Through PI3K/AKT and MAPK Signal Transduction Cascades.

As a major dietary flavonol, quercetin mitigates proliferation and progression of cancer due to its anti-angiogenic, anti-inflammatory, anti-oxidant, and apoptotic biological effects on cells. Although its apoptotic effects have been reported for various cancers, little is known of the functional role of quercetin in gestational choriocarcinoma. Results of the present study indicated that quercetin reduced proliferation and induced cell death in two choriocarcinoma cell lines, JAR and JEG3 cells, with an increase in the sub-G1 phase of the cell cycle. In addition, quercetin induced mitochondrial dysfunction significantly reduced mitochondrial membrane potential (MMP) and increased production of reactive oxygen species (ROS) in both JAR and JEG3 cells. Further, quercetin inhibited phosphorylation of AKT, P70S6K and S6 proteins whereas, it increased phosphorylation of ERK1/2, P38, JNK and P90RSK proteins in JAR and JEG3 cells. The decrease in viability of choriocarcinoma cells treated with quercetin was confirmed by using combinations of quercetin and pharmacological inhibitors of the PI3K and MAPK signaling pathways. Classical chemotherapeutic agents, cisplatin (a platinum-based drug) and paclitaxel (a taxene-based drug), inhibited proliferation of JAR and JEG3 cells, and when combined with quercetin, the antiproliferative effects of cisplatin and paclitaxel were enhanced for both choriocarcinoma cell lines. Collectively, these results suggest that quercetin prevents development of choriocarcinoma and may be a valuable therapeutic agent for treatment of choriocarcinoma through its regulation of PI3K and MAPK signal transduction pathways. J. Cell. Physiol. 232: 1428-1440, 2017. © 2016 Wiley Periodicals, Inc.

Chrysophanol Induces Apoptosis of Choriocarcinoma Through Regulation of ROS and the AKT and ERK1/2 Pathways.

Chrysophanol is an anthraquinone compound, mainly isolated from rhubarb, with anti-cancer effects on some types of cancer cells. However, effects of chrysophanol on human choriocarcinoma cells are not known. Therefore, the objective of this study was to determine effects of chrysophanol on choriocarcinoma cells (JAR and JEG-3) and identify signal transduction cascades activated by chrysophanol. Results of present study, showed that chrysophanol decreased cell viability and induced apoptosis of JEG-3, but not JAR cells, in a dose-dependent manner. Chrysophanol also increased oxidative stress in JEG-3 cells by inducing ROS generation followed by mitochondrial dysfunction including depolarization of mitochondrial inner membrane potential. Western blot analysis revealed that ERK1/2, P90RSK, AKT, and P70S6K were increased significantly in JEG-3 cells by chrysophanol. Next, we investigated chrysophanol-mediated effects on proliferation of JEG-3 cells using pharmacological inhibitors of PI3K/AKT (LY294002) and ERK1/2 (U0126). Inhibition of AKT and ERK1/2 prevented chrysophanol-induced stimulation of proliferation of JEG-3 cells. In addition, the phosphorylation of AKT and ERK1/2 was suppressed by LY294002 and U0126 in JEG-3 cells treated with chrysophanol, whereas, the AKT protein was activated by pre-treatment of JEG-3 cells with U0126. Furthermore, we compared therapeutic effects of chrysophanol with cisplatin and paclitaxel which are conventional salvage regimens for choriocarcinoma. Our results verified that chrysophanol has synergistic effects with traditional therapy to increase apoptosis of JEG-3 cells. Collectively, these results indicate that chrysophanol is a potential effective chometherapeutic agent for treatment of choriocarcinoma therapy, and minimizing side effects of conventional treatment regimens. J. Cell. Physiol. 232: 331-339, 2017. © 2016 Wiley Periodicals, Inc.

Oleic acid stimulation of motility of human extravillous trophoblast cells is mediated by stearoyl-CoA desaturase-1 activity.

STUDY QUESTION: Do fatty acids regulate development and motility of human extravillous trophoblast cells (EVTs)? SUMMARY ANSWER: Oleic acid is a promising lipid molecule that has beneficial effects on motility and development of human EVTs. WHAT IS KNOWN ALREADY: Fatty acid uptake into trophoblast cells is important for maintaining cellular events during pregnancy, but the molecular mechanisms of action of various fatty acids, including trans fatty acids, saturated fatty acids and monounsaturated fatty acids, in EVT cell lines are not clear. STUDY DESIGN, SIZE, DURATION: Effects of oleic acid, elaidic acid, palmitic acid and stearic acid on HTR8/SVneo cells were assessed in diverse assays in a dose- and time-dependent manner. PARTICIPANTS/MATERIALS, SETTING, METHODS: Effects of fatty acids on cell proliferation, migration, invasion and apoptosis (Annexin V expression, propidium iodide staining, TUNEL and invasion assays) of HTR8/SVneo cells were determined. Signal transduction pathways in HTR8/SVneo cells in response to fatty acids were determined by Western blot analyses. Regulation of fatty acids on oxidative conditions in EVTs were determined and validated by measurement of production of cellular reactive oxygen species, intracellular concentrations of free Ca2+and lipid peroxidation assays. MAIN RESULTS AND THE ROLE OF CHANCE: In present study, we confirmed different effects of oleic acid and elaidic acid on migration, invasion, proliferation and apoptosis of the EVT cell line, HTR8/SVneo. We also investigated stearoyl-CoA desaturase-1 (SCD1) to determine if its activity contributed to oleic acid-induced migration of HTR8/SVneo cells. Next, we analyzed cell signaling molecules mediated by oleic acid and elaidic acid treatment, including MAPK and PI3K/AKT pathways in HTR8/SVneo cells. We further established whether selective inhibition of signaling molecules altered the ability of fatty acids to cause changes in migration and proliferation of HTR8/SVneo cells. Last, we examined the regulatory effects of oleic acid and SCD1 on oxidative stress in HTR8/SVneo cells. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: The lack of in vivo animal studies is a major limitation of this research. Effectiveness of oleic acid to stimulate migration of human EVT cells requires further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that oleic acid can play an important role in promoting invasion of human EVT cell lines while both trans fatty acids and saturated fatty acids are not conducive to normal placentation. This may have implications for the prevention of pre-eclampsia and intrauterine growth restriction. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (No. HI15C0810) awarded to G.S. and (No. HI17C0929) awarded to W.L. There are no conflicts of interest.