Publications by authors named "Changwon Yang"

52 Publications

Inhibition of the cleaved half of tRNA enhances palmitic acid-induced apoptosis in human trophoblasts.

J Nutr Biochem 2021 Sep 23:108866. Epub 2021 Sep 23.

Department of Food and Nutrition, Kookmin University, Seoul, 02707, Republic of Korea. Electronic address:

Palmitic acid (PA) induces apoptosis in the human trophoblast cell line HTR8/SVneo. However, the molecular mechanism underlying this effect remains unclear. Although small non-coding RNAs are involved in trophoblast growth and invasion during early pregnancy, the functional roles of tRNA-derived species are currently unknown. Therefore, the purpose of this study was to examine the involvement of tRNA-derived species in PA-induced apoptosis in human trophoblasts. In this study, we investigate the expression and function of tRNA-derived stress-induced RNAs (tiRNAs) in HTR8/SVneo. We determined the expression of tiRNAs in HTR8/SVneo cells in response to PA. Then, we transfected inhibitor of target tiRNA in HTR8/SVneo with or without PA to examine the tRNA-derived species-regulated intracellular signal transduction by detecting calcium homeostasis, mitochondrial membrane potential, and signaling proteins. We found that the expression of tRNA-derived tiRNAs decreased in PA-treated human trophoblasts. Moreover, inhibition of tiRNA enhanced the PA-induced apoptosis along with the induction of DNA fragmentation and mitochondrial depolarization. Inhibition of tiRNA enhanced the expression of endoplasmic reticulum stress-related proteins and increased Ca levels in the cytoplasm and mitochondria. Moreover, the levels of cytochrome c released from the mitochondria were synergistically affected by tiRNA inhibitor and PA. Furthermore, artificial regulation of ANG inhibited the expression of tiRNA and similar effects were observed upon the inhibition of tiRNA in human trophoblasts. These results suggest that tiRNA might be the molecule via which PA induces its effects in human trophoblasts.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108866DOI Listing
September 2021

Apigenin enhances apoptosis induction by 5-fluorouracil through regulation of thymidylate synthase in colorectal cancer cells.

Redox Biol 2021 Sep 21;47:102144. Epub 2021 Sep 21.

Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul, 02707, Republic of Korea. Electronic address:

Although effective drugs have been developed, including 5-fluorouracil (5-FU), advanced colorectal cancer (CRC) shows low therapeutic sensitivity resulting from the development of 5-FU resistance. Thymidylate synthase (TS) is a target protein of 5-FU, and elevated TS lowers the 5-FU sensitivity of CRC cells. Here, we tested the efficacy of several candidate phytochemicals against human CRC-derived HCT116 cells expressing wild-type tumor suppressor protein P53 and HT29 cells expressing mutant P53. Among them, we found that apigenin enhanced the inhibitory effect of 5-FU on cell viability. In addition, apigenin inhibited the upregulation of TS induced by 5-FU. Apigenin also potentiated 5-FU-induced apoptosis of HCT116 cells and enhanced cell cycle disruption. Furthermore, apigenin increased reactive oxygen species production, intracellular and intramitochondrial Ca concentrations, and mitochondrial membrane potential upon cotreatment with 5-FU. Knockdown of forkhead box protein M, a transcription factor modulating 5-FU sensitivity, enhanced the potentiation of apoptosis by apigenin in HCT116 cells. Moreover, apigenin suppressed TS expression and inhibited the viability of 5-FU-resistant HCT116 cells. Therefore, apigenin may improve the therapeutic efficacy of 5-FU against CRC by suppressing TS, but apoptosis induction is mainly dependent on functional P53.
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http://dx.doi.org/10.1016/j.redox.2021.102144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476449PMC
September 2021

Eupatilin Impacts on the Progression of Colon Cancer by Mitochondria Dysfunction and Oxidative Stress.

Antioxidants (Basel) 2021 Jun 15;10(6). Epub 2021 Jun 15.

Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul 02707, Korea.

Colon cancer is one of the most frequently diagnosed cancer types. Some colon cancer cases resist standard anticancer drugs. Therefore, many studies have focused on developing therapeutic supplements using natural products with low side effects and broad physiological activity. Eupatilin is a flavonoid that is mainly extracted from artemisia and promotes apoptosis in numerous cancer types. However, since the current understanding of its physiological mechanisms on colon cancer cells is insufficient, we investigated how eupatilin affects the growth of two colon cancer cell lines, namely HCT116 and HT29. Our results showed that eupatilin inhibits cell viability and induces apoptosis accompanied by mitochondrial depolarization. It also induces oxidative stress in colon cancer cells and regulates the expression of proteins involved in the endoplasmic reticulum stress and autophagic process. Moreover, eupatilin may target the PI3K/AKT and mitogen-activated protein kinase (MAPK) signaling pathways in colon cancer cells. It also prevents colon cancer cell invasion. Furthermore, eupatilin has a synergistic effect with 5-fluorouracil (5-FU; a standard anticancer drug) on 5-FU-resistant HCT116 cells. These results suggest that eupatilin can be developed as an adjuvant to enhance traditional anticancer drugs in colon cancer.
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http://dx.doi.org/10.3390/antiox10060957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232173PMC
June 2021

Reproductive toxicity due to herbicide exposure in freshwater organisms.

Comp Biochem Physiol C Toxicol Pharmacol 2021 Oct 12;248:109103. Epub 2021 Jun 12.

Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address:

Excessively used pesticides in agricultural areas are spilled into aquatic environments, wherein they are suspended or sedimented. Owing to climate change, herbicides are the fastest growing sector of the pesticide industry and are detected in surface water, groundwater, and sediments near agricultural areas. In freshwater, organisms, including mussels, snails, frogs, and fish, are exposed to various types and concentrations of herbicides. Invertebrates are sensitive to herbicide exposure because their defense systems are incomplete. At the top of the food chain in freshwater ecosystems, fish show high bioaccumulation of herbicides. Herbicide exposure causes reproductive toxicity and population declines in freshwater organisms and further contamination of fish used for consumption poses a risk to human health. In addition, it is important to understand how environmental factors are physiologically processed and assess their impacts on reproductive parameters, such as gonadosomatic index and steroid hormone levels. Zebrafish is a good model for examining the effects of herbicides such as atrazine and glyphosate on embryonic development in freshwater fish. This review describes the occurrence and role of herbicides in freshwater environments and their potential implications for the reproduction and embryonic development of freshwater organisms.
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http://dx.doi.org/10.1016/j.cbpc.2021.109103DOI Listing
October 2021

Mechanisms of deleterious effects of some pesticide exposure on pigs.

Pestic Biochem Physiol 2021 Jun 7;175:104850. Epub 2021 Apr 7.

Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address:

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.
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http://dx.doi.org/10.1016/j.pestbp.2021.104850DOI Listing
June 2021

Immunotoxicological effects of insecticides in exposed fishes.

Comp Biochem Physiol C Toxicol Pharmacol 2021 Sep 24;247:109064. Epub 2021 Apr 24.

Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address:

Biologically active compounds used in agriculture that develop near aquatic environments easily spill into rivers or lakes. As a result, insecticides, herbicides and fungicides are observed worldwide in aquatic environments and accumulated in aquatic organism. Many insecticides, including organochlorine and organophosphate, have long been banned long ago because of their high persistence and non-target toxicity. However, previous studies have shown that persistent pesticides remain in aquatic organisms. The immune system is the first defense mechanism against exposure to persistent organic pollutants or pesticides that have been released into the aquatic environment. Many insecticides have been reported to cause immunotoxicity, which is represented by alteration of phagocytic and lysozyme activity. Recent studies show that immunotoxicity by insecticides exerts a more complex mechanism in fish. Insecticides induce immunotoxic effects, such as the release of inflammatory cytokines from head kidney macrophages and inhibition of immune cell proliferation in fish, which can lead to death in severe cases. Even currently used pesticides, such as pyrethroid, with low bioaccumulation have been shown to induce immunotoxicological effects in fish when exposed continuously. Therefore, this review describes the types and bioaccumulation of insecticides that cause immunotoxicity and detailed immunotoxicological mechanisms in fish tissues.
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http://dx.doi.org/10.1016/j.cbpc.2021.109064DOI Listing
September 2021

Disruption of Endoplasmic Reticulum and ROS Production in Human Ovarian Cancer by Campesterol.

Antioxidants (Basel) 2021 Mar 3;10(3). Epub 2021 Mar 3.

Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul 02707, Korea.

Phytosterols, which are present in a variety of foods, exhibit various physiological functions and do not have any side effects. Here, we attempted to identify functional role of campesterol in regulation of oxidative stress by leading to cell death of ovarian cancer. We investigated the effects of campesterol on cancer cell aggregation using a three-dimensional (3D) culture of human ovarian cancer cells. The effects of campesterol on apoptosis, protein expression, proliferation, the cell cycle, and the migration of these cells were determined to unravel the underlying mechanism. We also investigated whether campesterol regulates mitochondrial function, the generation of reactive oxygen species (ROS), and calcium concentrations. Our results show that campesterol activates cell death signals and cell death in human ovarian cancer cells. Excessive calcium levels and ROS production were induced by campesterol in the two selected ovarian cancer cell lines. Moreover, campesterol suppressed cell proliferation, cell cycle progression, and cell aggregation in ovarian cancer cells. Campesterol also enhanced the anticancer effects of conventional anticancer agents. The present study shows that campesterol can be used as a novel anticancer drug for human ovarian cancer.
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http://dx.doi.org/10.3390/antiox10030379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001332PMC
March 2021

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

Fish Shellfish Immunol 2021 May 19;112:135-142. Epub 2021 Mar 19.

Department of Food and Nutrition, Kookmin University, Seoul, 02707, Republic of Korea. Electronic address:

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.
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http://dx.doi.org/10.1016/j.fsi.2021.03.009DOI Listing
May 2021

Free-Energy Landscape of a pH-Modulated G·C Base Pair Transition from Watson-Crick to Hoogsteen State in Duplex DNA.

J Chem Theory Comput 2021 Apr 10;17(4):2556-2565. Epub 2021 Mar 10.

Department of Chemistry and Institute of Functional Materials, Pusan National University, Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, South Korea.

In double-helical DNAs, the most stable Watson-Crick (WC) base pair (bp) can be in thermal equilibrium with much less abundant Hoogsteen (HG) bp by the spontaneous rotation of the glycosidic angle in purine bases. Previous experimental studies showed that in the case of a G·C bp, the population of the transient HG is enhanced as a protonated form (HG) through the protonation of the cytosine base under weakly acidic conditions. Hence, pH is a key factor that can modulate this transition event from the WC to HG bp. In this study, to computationally probe the overall free-energy landscapes of this pH-modulated G·C HG breathing, a comprehensive classical molecular dynamics (MD) simulation protocol is proposed using an enhanced sampling MD in conjunction with the standard thermodynamic integration method. From this MD protocol proposed, the free-energy surfaces of the G·C bp transition from the WC to HG bp were constructed successfully at any pH range, producing pH-dependent free-energy quantities in close agreement with previously reported experimental results. The simulation protocol is expected to provide valuable atomistic insight into the DNA bp transition events coupled with protonation or tautomeric shift in a target bp.
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http://dx.doi.org/10.1021/acs.jctc.0c01330DOI Listing
April 2021

tRNA-Derived Fragment Alleviates Cisplatin-Induced Apoptosis in Prostate Cancer Cells.

Pharmaceutics 2021 Jan 4;13(1). Epub 2021 Jan 4.

Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul 02707, Korea.

Cisplatin is a standard treatment for prostate cancer, which is the third leading cause of cancer-related deaths among men globally. However, patients who have undergone cisplatin can rxperience relapse. tRNA-derived fragments (tRFs) are small non-coding RNAs generated via tRNA cleavage; their physiological activities are linked to the development of human diseases. Specific tRFs, including tRF-315 derived from tRNA, are highly expressed in prostate cancer patients. However, whether tRF-315 regulates prostate cancer cell proliferation or apoptosis is unclear. Herein, we confirmed that tRF-315 expression was higher in prostate cancer cells (LNCaP, DU145, and PC3) than in normal prostate cells. tRF-315 prevented cisplatin-induced apoptosis and alleviated cisplatin-induced mitochondrial dysfunction in LNCaP and DU145 cells. Moreover, transfection of tRF-315 inhibitor increased the expression of apoptotic pathway-related proteins in LNCaP and DU145 cells. Furthermore, tRF-315 targeted the tumor suppressor gene , thus regulating the cell cycle, which was altered by cisplatin in LNCaP and DU145 cells. Thus, tRF-315 protects prostate cancer cells from mitochondrion-dependent apoptosis induced by cisplatin treatment.
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http://dx.doi.org/10.3390/pharmaceutics13010055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824007PMC
January 2021

Computational Probing of Temperature-Dependent Unfolding of a Small Globular Protein: From Cold to Heat Denaturation.

J Chem Theory Comput 2021 Jan 8;17(1):515-524. Epub 2020 Dec 8.

Department of Chemistry and Institute of Functional Materials, Pusan National University, Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, South Korea.

Fully atomistic replica exchange molecular dynamics simulations are performed to compute the stability curve of a small globular protein as accurately as possible. To investigate the individual roles of the protein and water parts, we compute the conformational entropy change of this protein directly from the simulation ensembles. This entropy calculation enables complete separations of the unfolding changes of enthalpy and the entropy into their own protein and hydration components. From this decomposition, we are able to determine the main thermodynamic factors governing the cold and heat unfolding events: the cold and heat unfolding events are largely driven by the hydration enthalpy gain and the protein conformational entropy gain, respectively. This computational study discloses several temperature-dependent unfolding thermodynamic behaviors of the protein and water compartments and establishes their unique relationship. Upon unfolding, the changes of enthalpy and entropy in the protein part are all positive convex functions of temperature, whereas the equivalent changes in the water part are all negative concave functions of temperature. Hence, these two mutually opposing effects from the protein and water parts dictate the thermodynamics of unfolding. Furthermore, consistent with the temperature-dependent behaviors of the protein part, the changes of the solvent-accessible surface area and the radius of gyration of the protein upon unfolding are also convex functions of temperature. Hence, all these new temperature dependences, combined together, pave the way to unveiling the thermodynamic and structural features of protein denaturation events at various temperature conditions.
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http://dx.doi.org/10.1021/acs.jctc.0c01046DOI Listing
January 2021

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

Reproduction 2020 11;160(5):793-801

Department of Food and Nutrition, Kookmin University, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1530/REP-20-0342DOI Listing
November 2020

Methiothepin Suppresses Human Ovarian Cancer Cell Growth by Repressing Mitochondrion-Mediated Metabolism and Inhibiting Angiogenesis In Vivo.

Pharmaceutics 2020 Jul 20;12(7). Epub 2020 Jul 20.

Institute of Animal Molecular Biotechnology and Department of Biotechnology, Korea University, Seoul 02841, Korea.

Ovarian cancer is the fifth leading cause of cancer-related deaths in women. Despite treatment, most patients experience relapse and the 5-year survival rate of ovarian cancer is less than 50%. Serotonin has cell growth-promoting functions in a variety of carcinomas, but the effect of serotonin receptor antagonists on ovarian cancer cells is unknown. In this study, it was confirmed that methiothepin, a serotonin receptor antagonist, suppresses the viability of, and induces apoptosis in, ovarian cancer cells. Methiothepin also induces mitochondrial dysfunction, represented by depolarization of the mitochondrial membrane and increased mitochondrion-specific Ca levels, and causes metabolic disruption in cancer cells such as decreased ATP production and oxidative phosphorylation. Methiothepin also interferes with vascular development in transgenic zebrafish embryos. Combination treatment with methiothepin improves the anti-cancer effect of paclitaxel, a standard chemotherapeutic agent. In conclusion, this study revealed that methiothepin is a potential novel therapeutic agent for ovarian cancer treatment.
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http://dx.doi.org/10.3390/pharmaceutics12070686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407284PMC
July 2020

A review of the toxicity in fish exposed to antibiotics.

Comp Biochem Physiol C Toxicol Pharmacol 2020 Nov 5;237:108840. Epub 2020 Jul 5.

Department of Food and Nutrition, Kookmin University, Seoul 02707, Republic of Korea. Electronic address:

Antibiotics are widely used in the treatment of human and veterinary diseases and are being used worldwide in the agriculture industry to promote livestock growth. However, a variety of antibiotics that are found in aquatic environments are toxic to aquatic organisms. Antibiotics are not completely removed by wastewater treatment plants and are therefore released into aquatic environments, which raises concern about the destruction of the ecosystem owing to their non-target effects. Since antibiotics are designed to be persistent and work steadily in the body, their chronic toxicity effects have been studied in aquatic microorganisms. However, research on the toxicity of antibiotics in fish at the top of the aquatic food chain is relatively poor. This paper summarizes the current understanding of the reported toxicity studies with antibiotics in fish, including zebrafish, to date. Four antibiotic types; quinolones, sulfonamides, tetracyclines, and macrolides, which are thought to be genetically toxic to fish have been reported to bioaccumulate in fish tissues, as well as in aquatic environments such as rivers and surface water. The adverse effects of these antibiotics are known to cause damage to developmental, cardiovascular, and metabolic systems, as well as in altering anti-oxidant and immune responses, in fish. Therefore, there are serious concerns about the toxicity of antibiotics in fish and further research and strategies are needed to prevent them in different regions of the world.
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http://dx.doi.org/10.1016/j.cbpc.2020.108840DOI Listing
November 2020

Eupatilin Promotes Cell Death by Calcium Influx through ER-Mitochondria Axis with SERPINB11 Inhibition in Epithelial Ovarian Cancer.

Cancers (Basel) 2020 Jun 3;12(6). Epub 2020 Jun 3.

Department of Food and Nutrition, Kookmin University, Seoul 02707, Korea.

Ovarian cancer is the leading cause of gynecological cancer-related mortality. The anticancer effect of eupatilin, a family of flavonoids, is known in many cancer types, but it is unclear what mechanism it plays in ovarian cancer. In this study, eupatilin promoted cell death of ovarian cancer cells by activating caspases, cell cycle arrest, reactive oxygen species (ROS) generation, calcium influx, disruption of the endoplasmic reticulum (ER)-mitochondria axis with SERPINB11 inhibition, and downregulation of phosphoinositide 3-kinase (PI3K) and mitogen activated protein kinase (MAPK) pathways. Additionally, eupatilin-reduced SERPINB11 expression enhanced the effect of conventional chemotherapeutic agents against ovarian cancer cell progression. Cotreatment with siSERPINB11 and eupatilin increased calcium-ion-dependent apoptotic activity in ovarian cancer cells. Although there were no significant toxic effects of eupatilin on embryos, eupatilin completely inhibited tumorigenesis in a zebrafish xenograft model. In addition, eupatilin suppressed angiogenesis in zebrafish transgenic models. Collectively, downregulating SERPINB11 with eupatilin against cancer progression may improve therapeutic activity.
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http://dx.doi.org/10.3390/cancers12061459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353024PMC
June 2020

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

J Pineal Res 2020 Sep 30;69(2):e12670. Epub 2020 May 30.

Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul, Korea.

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.
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http://dx.doi.org/10.1111/jpi.12670DOI Listing
September 2020

Mediation of oxidative stress toxicity induced by pyrethroid pesticides in fish.

Comp Biochem Physiol C Toxicol Pharmacol 2020 Aug 11;234:108758. Epub 2020 Apr 11.

Institute of Animal Molecular Biotechnology, Korea University, Seoul 02841, Republic of Korea; Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea. Electronic address:

Organophosphate and organochlorine pesticides are banned in most countries because they cause high toxicity and bioaccumulation in non-target organisms. Pyrethroid pesticides have been applied to agriculture and aquaculture since the 1970s to replace traditional pesticides. However, pyrethroids are approximately 1000 times more toxic to fish than to mammals and birds. Fish-specific organs such as the gills and their late metabolic action against this type of pesticide make fish highly susceptible to the toxicity of pyrethroid pesticides. Oxidative stress plays an important role in the neurological, reproductive, and developmental toxicity caused by pyrethroids. Deltamethrin, cypermethrin, and lambda-cyhalothrin are representative pyrethroid pesticides that induce oxidative stress in tissues such as the gills, liver, and muscles of fish and cause histopathological changes. Although they are observed in low concentrations in aquatic environments such as rivers, lakes, and surface water they induce DNA damage and apoptosis in fish. Pyrethroid pesticides cause ROS-mediated oxidative stress in fish species including carp, tilapia, and trout. They also cause lipid peroxidation and alter the state of DNA, proteins, and lipids in the cells of fish. Moreover, changes in antioxidant enzyme activity following pyrethroid pesticide exposure make fish more susceptible to oxidative stress caused by environmental pollutants. In this review, we examine the occurrence of pyrethroid pesticides in the aquatic environment and oxidative stress-induced toxicity in fish exposed to pyrethroids.
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http://dx.doi.org/10.1016/j.cbpc.2020.108758DOI Listing
August 2020

Effects of endocrine disrupting chemicals in pigs.

Environ Pollut 2020 Aug 3;263(Pt B):114505. Epub 2020 Apr 3.

Department of Food and Nutrition, Kookmin University, Seoul, 02707, Republic of Korea. Electronic address:

Endocrine-disrupting chemicals (EDCs) are compounds that interfere with the expression, synthesis, and activity of hormones in organisms. They are released into the environment from flame retardants and products containing plasticizers. Persistent pesticides, such as dichlorodiphenyltrichloroethane (DDT) and hexachlorobenzene, also disrupt the endocrine system through interaction with hormone receptors. Endogenous hormones, such as 17β-estradiol (E2), are released in the urine and feces of farm animals and seep into terrestrial and aquatic ecosystems through sewage. Pigs are widely used as animal models to determine the effects of EDCs because they are physiologically, biochemically, and histologically similar to humans. EDCs primarily disrupt the reproductive and nervous systems of pigs. Moreover, embryonic development during the prenatal and early postnatal periods is particularly sensitive to EDCs. Mycotoxins, such as zearalenone, are food contaminants that alter hormonal activities in pigs. Mycotoxins also alter the innate immune system in pigs, making them vulnerable to diseases. It has been reported that farm animals are exposed to various types of EDCs, which accumulate in tissues, such as those of gonads, livers, and intestines. There is a lack of an integrated understanding of the impact of EDCs on porcine reproduction and development. Thus, this article aims to provide a comprehensive review of literature regarding the effects of EDCs in pigs.
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http://dx.doi.org/10.1016/j.envpol.2020.114505DOI Listing
August 2020

Methiothepin mesylate causes apoptosis of human prostate cancer cells by mediating oxidative stress and mitochondrial dysfunction.

Free Radic Biol Med 2020 04 5;150:12-22. Epub 2020 Feb 5.

Department of Food and Nutrition, Kookmin University, Seoul, 02707, Republic of Korea. Electronic address:

Prostate cancer is difficult to treat if it metastasizes to other organs. The development of prostate cancer independent of androgen is closely related to the action of neuroendocrine products. Serotonin promotes cell growth in various cancers, and antagonists for serotonin receptors are known to inhibit proliferation and induce cell death in various carcinomas. However, little is known about how antagonists for serotonin receptor function in prostate cancer. We verified apoptotic cell death in prostate cancer cell lines after treatment with methiothepin mesylate (MET), an antagonist for serotonin receptor 5-HT. MET induced hydrogen peroxide (HO) production and mitochondrial Ca overload. Moreover, MET induced changes in the expression of proteins associated with endoplasmic reticulum stress, autophagy, and mitochondrial membrane potential. MET also promoted phosphorylation of JNK, which induced cell death mediated by oxidant production, as evidenced by the JNK inhibitor and oxidant scavenger. Finally, MET has the potential to prevent metastasis by inhibiting the migration of prostate cancer cells. Thus, we show that MET is a potentially novel anticancer agent that can suppress the development of prostate cancer caused by neuroendocrine differentiation.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.01.187DOI Listing
April 2020

Improving Temperature Generator in Parallel Tempering Simulation in the NPT Condition.

J Chem Theory Comput 2020 Mar 19;16(3):1827-1833. Epub 2020 Feb 19.

Department of Chemistry and Institute of Functional Materials, Pusan National University, Busandaehak-ro 63beon-gil, Geumjeong-gu, Busan 46241, South Korea.

Parallel tempering (PT) simulations provide a powerful computational tool to accelerate conformational searches of complex molecular systems. In this method, multiple replica systems assigned to different temperatures run in parallel and undergo tandem replica exchange events to enhance conformational mixing in temperature space. Efficient PT simulations require a uniform acceptance ratio across all the replicas. In the context of a previous energy distribution-based temperature generation (TG) scheme, we propose an improved TG protocol to maintain such a uniform exchange probability in general PT simulations.
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http://dx.doi.org/10.1021/acs.jctc.9b00984DOI Listing
March 2020

Effects of mycotoxin-contaminated feed on farm animals.

J Hazard Mater 2020 05 20;389:122087. Epub 2020 Jan 20.

Department of Food and Nutrition, Kookmin University, Seoul, 02707, Republic of Korea. Electronic address:

Mycotoxins are secondary products produced by fungi in cereals and are frequently found in the livestock industry as contaminants of farm animal feed. Studies analyzing feed mycotoxins have been conducted worldwide and have confirmed the presence of mycotoxins with biological activity, including aflatoxin, ochratoxin A, fumonisin, zearalenone, and deoxynivalenol, in a large proportion of feed samples. Exposure to mycotoxins can cause immunotoxicity and impair reproductive function in farm animals. In addition, exposure of tissues, such as the kidneys, liver, and intestines, to mycotoxins can exert histopathological changes that can interfere with animal growth and survival. This review describes previous studies regarding the presence of major mycotoxins in the feed of farm animals, especially pigs and poultry. Moreover, it describes the adverse effects of mycotoxins in farm animals following exposure, as well as the biological activity of mycotoxins in animal-derived cells. Mycotoxins have been shown to regulate signaling pathways, oxidative stress, endoplasmic reticulum stress, apoptosis, and proliferation in porcine and bovine cells. A clear understanding of the effects of mycotoxins on farm animals will help reduce farm household economic loss and address the health concerns of people who consume these meat and dairy products.
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http://dx.doi.org/10.1016/j.jhazmat.2020.122087DOI Listing
May 2020

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

Mar Drugs 2020 Jan 9;18(1). Epub 2020 Jan 9.

Department of Food and Nutrition, College of Science and Technology, Kookmin University, Seoul 02707, Korea.

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 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.
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http://dx.doi.org/10.3390/md18010045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7024155PMC
January 2020

Inhibition of miR-214-3p Aids in Preventing Epithelial Ovarian Cancer Malignancy by Increasing the Expression of LHX6.

Cancers (Basel) 2019 Dec 2;11(12). Epub 2019 Dec 2.

Department of Food and Nutrition, Kookmin University, Seoul 02707, Korea.

In human epithelial ovarian cancer (EOC), various miRNAs can function as either oncogenes or tumor suppressor genes. We investigated miRNAs known to be involved in EOC progression and analyzed their expression in tissues and serum-derived exosomes from benign serous cystadenoma, borderline serous tumor, low-grade serous ovarian cancer, and high-grade serous ovarian cancer patients (HGSO). The HGSO group was divided based on the platinum-free interval, which is defined as the duration from the completion of platinum-based chemotherapy to recurrence. We also analyzed the mRNA levels of target genes that candidate miRNAs might regulate in patient tissues. miR-214-3p was highly expressed in tissues and exosomes derived from EOC with high malignancy and also found to regulate the expression of LIM homeobox domain 6 (LHX6) mRNA. Serum exosomal levels of miR-214-3p were significantly increased in platinum-resistant HGSO (25.2-fold, < 0.001) compared to the exosomal expression of benign tumor patients. On transfection of miR-214-3p inhibitor in EOC cells, cell proliferation was inhibited while apoptotic cell death was increased. Collectively, we suggest that miR-214-3p in serum exosomes can be a potential biomarker for the diagnosis and prognosis of ovarian tumor, and its inhibition can be a supportive treatment for EOC.
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http://dx.doi.org/10.3390/cancers11121917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966693PMC
December 2019

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

Mol Hum Reprod 2019 11;25(11):755-771

Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 02841, Republic of Korea.

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.
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http://dx.doi.org/10.1093/molehr/gaz054DOI Listing
November 2019

Effects of extracellular vesicles on placentation and pregnancy disorders.

Reproduction 2019 11;158(5):R189-R196

Department of Food and Nutrition, Kookmin University, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1530/REP-19-0147DOI Listing
November 2019

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

J Cell Physiol 2019 12 29;234(12):21493-21503. Epub 2019 May 29.

Department of Food and Nutrition, Kookmin University, Seoul, Republic of Korea.

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.
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http://dx.doi.org/10.1002/jcp.28905DOI Listing
December 2019

A mechanism for the effect of endocrine disrupting chemicals on placentation.

Chemosphere 2019 Sep 18;231:326-336. Epub 2019 May 18.

Department of Food and Nutrition, Kookmin University, Seoul, 02707, Republic of Korea. Electronic address:

Numerous recent studies have shown that endocrine disrupting chemicals (EDCs) in the body of pregnant women can pass through the placenta and be exposed to the fetus, leading to fetal development and cognitive impairment. Placentation through invasion of trophoblast cells and vascular remodeling is essential to maintaining maternal and fetal health throughout the pregnancy. Abnormal placentation can lead to pregnancy disorders such as preeclampsia (PE) and intrauterine growth retardation (IUGR). However, many studies have not been conducted on whether EDCs can inhibit the development and function of the placenta. Isolating placental tissues to analyze the effect of EDCs on placentation has several limitations. In this review, we discussed the types of EDCs that can pass through the placental barrier and accumulate in the placenta with relative outcome. EDCs can be released from a variety of products including plasticizers, pesticides, and retardant. We also discussed the development and dysfunction of the placenta when EDCs were treated on trophoblast cells or pregnant rodent models. The effects of EDCs on the placenta of livestock are also discussed, together with the molecular mechanism of EDCs acting in trophoblast cells. We describe how EDCs cross the membrane of trophoblasts to regulate signaling pathways, causing genetic and epigenetic changes that lead to changes in cell viability and invasiveness. Further studies on the effects of EDCs on placenta may draw attention to the correct use of products containing EDCs during pregnancy.
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http://dx.doi.org/10.1016/j.chemosphere.2019.05.133DOI Listing
September 2019

4-Methylbenzylidene-camphor inhibits proliferation and induces reactive oxygen species-mediated apoptosis of human trophoblast cells.

Reprod Toxicol 2019 03 28;84:49-58. Epub 2018 Dec 28.

Department of Biotechnology, Korea University, Seoul, 02841, Republic of Korea. Electronic address:

4-Methylbenzylidene-camphor (4-MBC) is an estrogenic compound used in a variety of personal care products and is associated with water pollution. In this study, we verified that exposure to 4-MBC suppresses the proliferation and invasiveness of the HTR8/SVneo human trophoblast cell line. Moreover, HTR8/SVneo cells treated with 4-MBC underwent apoptosis with increased DNA fragmentation. 4-MBC also activated the PI3K/AKT and ERK1/2 signaling pathways in HTR8/SVneo cells. Furthermore, 4-MBC induced oxidative stress mediated by reactive oxygen species production, which was associated with HTR8/SVneo cell death. 4-MBC promoted lipid peroxidation and loss of mitochondrial membrane potential in HTR8/SVneo cells and activated the expression of genes encoding a protein expressed on the surface of human trophoblast cells, including the EPH receptor B4 and G protein-coupled receptor 56 genes. Therefore, 4-MBC may retard the normal growth and survival of human trophoblast cells and may hamper normal placental formation during early pregnancy.
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http://dx.doi.org/10.1016/j.reprotox.2018.12.011DOI Listing
March 2019

Computational Probing of Watson-Crick/Hoogsteen Breathing in a DNA Duplex Containing N1-Methylated Adenine.

J Chem Theory Comput 2019 Jan 14;15(1):751-761. Epub 2018 Dec 14.

Department of Chemistry and Institute of Functional Materials , Pusan National University , Busan 46241 , South Korea.

DNA breathing is a local conformational fluctuation spontaneously occurring in double-stranded DNAs. In particular, the possibility of individual base pairs (bps) in duplex DNA to flip between alternate bp modes, i.e., Watson-Crick (WC)-like and Hoogsteen (HG)-like, at relevant time scales has impacted DNA research fields for many years. In this study, to computationally probe effects of chemical modification on the DNA breathing, we present a free energy landscape of spontaneous thermal transitions between WC and HG bps in a free DNA duplex containing N1-methylated adenine (m1A). For the current free energy computation, a variant of well-tempered metadynamics simulation was extensively performed for a total of 40 μs to produce free energy surfaces. The free energy profile indicated that, upon the chemical modification of adenine, the HG bp (m1A·T) was located in the most favorable conformation (96.7%); however, the canonical WC bp (m1A·T) was distorted into two WC-like bps of WC* (2.8%) and WC** (0.5%). The conformational exchange between these two minor WC-like bps occurs with the first hundred nanoseconds. The transition between WC-like and HG bp features multiple transition pathways displaying various extents of base flipping in combination with glycosidic rotation. Analysis of the simulated ensemble showed that the m1A-induced changes of the backbone and sugar pucker were in a reasonable agreement with previous results inferred from NMR experiments. Also, this study revealed that the formation of the stable HG bp upon the mutation alters the characteristics of dynamic fluctuations of the neighboring WC residues of m1A. We expect this simulation approach to be a robust computational scheme to complement and guide future high-resolution experiments on many outstanding issues of duplex DNA breathing.
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http://dx.doi.org/10.1021/acs.jctc.8b00936DOI Listing
January 2019

Homosalate aggravates the invasion of human trophoblast cells as well as regulates intracellular signaling pathways including PI3K/AKT and MAPK pathways.

Environ Pollut 2018 Dec 21;243(Pt B):1263-1273. Epub 2018 Sep 21.

Institute of Animal Molecular Biotechnology and Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul, 02841, Republic of Korea. Electronic address:

Homosalate is an organic ultraviolet filter used in most sunscreens but has been reported to be toxic to marine organisms. The estrogenic activity of homosalate has also been reported, but its endocrine-disrupting effect remains unclear. Although homosalate has been detected in human placental tissues, its effect on the survival of human trophoblast cells needs to be investigated. Therefore, in this study, we evaluated if HTR8/SVneo, a human trophoblast cell line, treated with homosalate showed decreasing proliferative activity in a dose-dependent manner. Homosalate promoted the death of HTR8/SVneo cells with elevated lipid peroxidation and intracellular Ca concentration. It also induced endoplasmic reticulum stress and mitochondrial morphological disturbances associated with the differentiation of human trophoblast cells. However, when the intracellular Ca or reactive oxygen species were removed using BAPTA-AM or N-acetyl-L-cysteine (NAC), the cell proliferation suppressed by homosalate was restored. Homosalate also significantly inhibited the invasion of HTR8/SVneo cells. Furthermore, it modulated phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) signaling pathways, which were involved in the cross-talk between both signaling pathways in HTR8/SVneo cells. Thus, homosalate adversely affects the survival, proliferation, and invasiveness of human trophoblast cells and therefore pregnant women should practice caution while using personal care products containing homosalate.
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http://dx.doi.org/10.1016/j.envpol.2018.09.092DOI Listing
December 2018
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