Publications by authors named "Eui-Ju Hong"

79 Publications

Activation of TCA cycle restrains virus-metabolic hijacking and viral replication in mouse hepatitis virus-infected cells.

Cell Biosci 2022 Jan 18;12(1). Epub 2022 Jan 18.

College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea.

Background: One of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused coronavirus disease 2019 (COVID-19) pandemic and threatened worldwide. However, therapy for COVID-19 has rarely been proven to possess specific efficacy. As the virus relies on host metabolism for its survival, several studies have reported metabolic intervention by SARS-CoV-2.

Results: We investigated the coronavirus-metabolic hijacking using mouse hepatitis virus (MHV) as a surrogate for SARS-CoV-2. Based on the altered host metabolism by MHV infection, an increase of glycolysis with low mitochondrial metabolism, we tried to investigate possible therapeutic molecules which increase the TCA cycle. Endogenous metabolites and metabolic regulators were introduced to restrain viral replication by metabolic intervention. We observed that cells deprived of cellular energy nutrition with low glycolysis strongly suppress viral replication. Furthermore, viral replication was also significantly suppressed by electron transport chain inhibitors which exhaust cellular energy. Apart from glycolysis and ETC, pyruvate supplement suppressed viral replication by the TCA cycle induction. As the non-glucose metabolite, fatty acids supplement decreased viral replication via the TCA cycle. Additionally, as a highly possible therapeutic metabolite, nicotinamide riboside (NR) supplement, which activates the TCA cycle by supplying NAD+, substantially suppressed viral replication.

Conclusions: This study suggests that metabolite-mediated TCA cycle activation suppresses replication of coronavirus and suggests that NR might play a role as a novel therapeutic metabolite for coronavirus.
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http://dx.doi.org/10.1186/s13578-021-00740-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764321PMC
January 2022

Letrozole Accelerates Metabolic Remodeling through Activation of Glycolysis in Cardiomyocytes: A Role beyond Hormone Regulation.

Int J Mol Sci 2022 Jan 4;23(1). Epub 2022 Jan 4.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Estrogen receptor-positive (ER+) breast cancer patients are recommended hormone therapy as a primary adjuvant treatment after surgery. Aromatase inhibitors (AIs) are widely administered to ER+ breast cancer patients as estrogen blockers; however, their safety remains controversial. The use of letrozole, an AI, has been reported to cause adverse cardiovascular effects. We aimed to elucidate the effects of letrozole on the cardiovascular system. Female rats exposed to letrozole for four weeks showed metabolic changes, i.e., decreased fatty acid oxidation, increased glycolysis, and hypertrophy in the left ventricle. Although lipid oxidation yields more ATP than carbohydrate metabolism, the latter predominates in the heart under pathological conditions. Reduced lipid metabolism is attributed to reduced β-oxidation due to low circulating estrogen levels. In letrozole-treated rats, glycolysis levels were found to be increased in the heart. Furthermore, the levels of glycolytic enzymes were increased (in a high glucose medium) and the glycolytic rate was increased in vitro (H9c2 cells); the same was not true in the case of estrogen treatment. Reduced lipid metabolism and increased glycolysis can lower energy supply to the heart, resulting in predisposition to heart failure. These data suggest that a letrozole-induced cardiac metabolic remodeling, i.e., a shift from β-oxidation to glycolysis, may induce cardiac structural remodeling.
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http://dx.doi.org/10.3390/ijms23010547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745349PMC
January 2022

Cryptocotyle lata (Trematoda: Heterophyidae) Adult from a Korean Raccoon Dog, Nyctereutes procyonoides koreensis.

Korean J Parasitol 2021 Dec 22;59(6):645-649. Epub 2021 Dec 22.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Total 513 heterophyid flukes were collected from a carcass of wild Korean raccoon dog, Nyctereutes procyonoides koreensis, in Korea. With morphological and molecular characteristics, the flukes were identified to Cryptocotyle lata. The adult C. lata were minute, transparent, pentagonal, 522 µm long by 425 µm wide. Ceca extended into post-testicular region. Ventrogenital sac elliptical, 79 µm by 87 µm with genital pore and ventral sucker. Two testes semielliptical and slightly lobed, located in the posterior region, right testis 173 µm by 155 µm, left testis 130 µm by 134 µm. In a phylogenetic tree, the fluke specimen of this study was grouped with C. lata divergent from Cryptocotyle lingua. We report here N. procyonoides koreensis first as a natural definitive host of C. lata.
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http://dx.doi.org/10.3347/kjp.2021.59.6.645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8721310PMC
December 2021

Case Report: A Case of Caprine Arthritis Encephalitis in Dairy Goat Farms in South Korea.

Front Vet Sci 2021 7;8:773039. Epub 2021 Dec 7.

College of Veterinary Medicine at Chungnam National University, Daejeon, South Korea.

One Saanen dairy goat () farm in Korea reported that some goats showed clinical signs such as arthritis, paralysis, carpal joint swelling, and even death. We monitored clinical signs and pathological lesions. In the laboratory, we confirmed caprine arthritis encephalitis virus (CAEV) infection by polymerase chain reaction (PCR). We examined all the dairy goats on the farm and found that many of them were positive. In conclusion, CAEV infection was detected in the majority of the goats in this farm, and it induced severe clinical signs impacting productivity and causing important economic shortfalls. We need to regularly investigate all dairy goat farms, and, more importantly, inspection of the quarantine stage should be required before importation. Interestingly, we found all negative results in Korean native black goats ().
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http://dx.doi.org/10.3389/fvets.2021.773039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688911PMC
December 2021

Lipid signatures reflect the function of the murine primary placentation.

Biol Reprod 2021 Nov 30. Epub 2021 Nov 30.

Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

The placenta regulates maternal-fetal communication, and its defect leads to significant pregnancy complications. The maternal and embryonic circulations are primitively connected in early placentation, but the function of the placenta during this developmentally essential period is relatively unknown. We thus performed a comparative proteomic analysis of the placenta before and after primary placentation and found that the metabolism and transport of lipids were characteristically activated in this period. The placental fatty acid (FA) carriers in specific placental compartments were upregulated according to gestational age, and metabolomic analysis also showed that the placental transport of FAs increased in a time-dependent manner. Further analysis of two mutant mice models with embryonic lethality revealed that lipid-related signatures could reflect the functional state of the placenta. Our findings highlight the importance of the nutrient transport function of the primary placenta in the early gestational period and the role of lipids in embryonic development.
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http://dx.doi.org/10.1093/biolre/ioab219DOI Listing
November 2021

Dietary Intake of 17α-Ethinylestradiol Promotes HCC Progression in Humanized Male Mice Expressing Sex Hormone-Binding Globulin.

Int J Mol Sci 2021 Nov 22;22(22). Epub 2021 Nov 22.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Hepatocellular carcinoma (HCC) is a male-oriented malignancy; its progression is affected by sex hormones. 17α-ethinylestradiol (EE2) is a synthetic estrogen widely used as an oral contraceptive; however, it is unknown whether EE2 regulates sex hormone action in HCC. We investigated whether EE2 influences HCC risk in male androgenic environments, using mice expressing human sex hormone-binding globulin (SHBG). Two-week-old male mice were injected with diethyl-nitrosamine (DEN, 25 mg/kg) and fed an EE2 diet for 10 weeks from 30 weeks of age. Development and characteristics of liver cancer were evaluated in 40-week-old mice via molecular and histological analyses. Although EE2 did not increase HCC progression in wild-type mice, SHBG mice exhibited remarkably higher HCC risk when fed EE2. The livers of EE2-treated SHBG mice exhibited substantially increased pro-inflammatory necrosis with high plasma levels of ALT and HMGB1, and intrahepatic injury and fibers. Additionally, increased androgen response and androgen-mediated proliferation in the livers of EE2-treated SHBG mice and EE2-exposed hepatocytes under SHBG conditions were observed. As a competitor of SHBG-androgen binding, EE2 could bind with SHBG and increase the bioavailability of androgen. Our results revealed that EE2 is a novel risk factor in androgen-dominant men, predisposing them to HCC risk.
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http://dx.doi.org/10.3390/ijms222212557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620028PMC
November 2021

RICTULARIA JIYEONI N. SP. (NEMATODA: RICTULARIIDAE) FROM THE STRIPED FIELD MOUSE, APODEMUS AGRARIUS, IN KOREA.

J Parasitol 2021 11;107(6):831-837

Laboratory of Veterinary Internal Medicine, BK21 FOUR Future Veterinary Medicine Leading Education and Research Centre, Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul 08826, Republic of Korea.

Rictularia jiyeoni n. sp. from the small intestine of the striped field mouse, Apodemus agrarius, in Korea, is described and illustrated. Specimens were studied using light and scanning electron microscopies. This rictulariid nematode is closest to the Rictularia species that have a reduced number of combs and spines. However, the new species can be differentiated from the other species of Rictularia by having 36-58 perioral denticles, a buccal capsule with a single esophageal tooth, and 37-44 pairs of combs and spines of which 32-37 are prevulvar and 5-11 are postvulvar.
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http://dx.doi.org/10.1645/20-111DOI Listing
November 2021

Heat shock protein 70 could enhance porcine epidemic diarrhoea virus replication by interacting with membrane proteins.

Vet Res 2021 Oct 30;52(1):138. Epub 2021 Oct 30.

College of Veterinary Medicine, Chungnam National University, Daejeon, 13434, Republic of Korea.

In this study, we investigated the role of heat shock protein 70 (HSP70) in porcine epidemic diarrhoea virus (PEDV) replication. We found that PEDV infection induced strong HSP70 overexpression in the very early stage of infection. We also confirmed that HSP70 overexpression increased the speed of PEDV replication, resulting in the generation of more virions. In contrast, knockout of HSP70 in cells significantly downregulated PEDV protein expression, resulting in a significant reduction in PEDV replication. Most importantly, we confirmed that among the structural proteins of PEDV, membrane (M) proteins have this important role. We found that membrane proteins control cellular HSP70 expression in PEDV-infected cells. We confirmed HSP70/M complex formation by both immunoprecipitation and immunofluorescence assays. Additionally, PEDV M overexpression induced strong HSP70 expression. All our results clearly confirmed that in PEDV-infected cells, the M protein plays a very important role in PEDV replication in collaboration with HSP70.
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http://dx.doi.org/10.1186/s13567-021-01006-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557036PMC
October 2021

Hepatic LKB1 Reduces the Progression of Non-Alcoholic Fatty Liver Disease via Genomic Androgen Receptor Signaling.

Int J Mol Sci 2021 Jul 23;22(15). Epub 2021 Jul 23.

Department of Veterinary Biochemistry, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

The incidence of non-alcoholic fatty liver disease (NAFLD) increases in males aged >45 years, which indicates that androgens are associated with the development and/or progression of NAFLD, although excess dietary intake is the primary causative factor. However, it is uncertain how androgens are involved in the metabolic process of NAFLD, which is associated with the state of steatosis in hepatocytes. To investigate whether androgen receptor (AR) signaling influences NAFLD development, the state of steatosis was monitored in mouse livers and hepatocytes with or without androgens. As a result, hepatic lipid droplets, expression of AR, and phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) increased in the presence of testosterone. Concurrently, the expression of LKB1, an upstream regulator of AMPK, was increased by testosterone treatment. We observed that the fluctuation of AMPK-ACC signaling, which plays an important role in lipogenesis, depends on the presence of testosterone and AR. Additionally, we demonstrated that testosterone bound AR was recruited to the promoter of the gene and induced LKB1 expression. Our study highlights a novel mechanism by which testosterone modulates NAFLD development by inducing the mRNA expression of .
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http://dx.doi.org/10.3390/ijms22157904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348493PMC
July 2021

Euryhelmis squamula (Digenea: Heterophyidae) Recovered from Korean Raccoon Dog, Nyctereutes procyonoides koreensis, in Korea.

Korean J Parasitol 2021 Jun 21;59(3):303-309. Epub 2021 Jun 21.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

In this study, we intended to describe an unrecorded species of heterophyid trematode recovered from the small intestine of a Korean raccoon dog, Nyctereutes procyonoides koreensis, in Korea. A total of 13 small flukes were collected from a deceased Korean raccoon dog which was found in Chuncheon-si, Gangwon-do, Korea in May 2017. The trematode body were covered with many small spines, rectangular, broader than long, 807-1,103 µm long and 1,270-1,550 µm wide. Oral sucker in the anterior end slightly smaller than acetabulum. Pharynx muscular and well developed. Esophagus relatively long and sigmoid. Acetabulum small and located at median in anterior 2/5 portion. Ceca bifurcated at the anterior of genital pore and acetabulum and terminated at testis level. Testes larger, deeply lobed and located at the near of posterior end of body. Ovary small, triangular and located at the slight left of median and the anterior of left testis. Vitelline follicles dendritic and extend from the middle level of esophagus to the posterior portion of body. Eggs embryonated, operculated, small and 33-35×15-16 µm in size. Based on the morphological characteristics, the small heterophyid flukes recovered from the small intestines of Korean raccoon dog, N. procyonoides koreensis, were identified as Euryhelmis squamula (Digenea: Heterophyidae). Accordingly, this species of heterophyid flukes is to be a new trematode fauna in Korea by this study.
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http://dx.doi.org/10.3347/kjp.2021.59.3.303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255488PMC
June 2021

The Carboxy Terminal Region on Spike Protein of Porcine Epidemic Diarrhea Virus (PEDV) Is Important for Evaluating Neutralizing Activity.

Pathogens 2021 May 31;10(6). Epub 2021 May 31.

Laboratory of Infectious Diseases, College of Veterinary Medicine, Chungnam National University, Daejon 34134, Korea.

In this study, we evaluated 62 sow sera samples from PED-vaccinated sows to compare the serum neutralizing test (SNT) and enzyme-linked immunosorbent assay (ELISA). We performed protein ELISA (pELISA) using fragments of spike proteins S1, S2, S3 and entire nucleocapsid proteins, and found a correlation between the SNT and ELISA in PEDV-vaccinated sera. Sera with higher neutralizing activity showed higher titers of IgG. In the antibody profiling, the neutralizing activities are correlated with the levels of the spike antibody, especially the S3 region. We confirmed that the carboxy-terminal region, including the endodomain of the S protein, induced stronger neutralizing activity than the ectodomain. This region of the S protein could be useful for evaluating PED vaccine efficacy, and it is a strong neutralizing epitope of PEDV. The S3 protein could be useful for evaluating PED vaccine efficacy, and it is a strong neutralizing epitope of PEDV.
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http://dx.doi.org/10.3390/pathogens10060683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226889PMC
May 2021

Loss of PGRMC1 Delays the Progression of Hepatocellular Carcinoma via Suppression of Pro-Inflammatory Immune Responses.

Cancers (Basel) 2021 May 18;13(10). Epub 2021 May 18.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Pgrmc1 is a non-canonical progesterone receptor related to the lethality of various types of cancer. PGRMC1 has been reported to exist in co-precipitated protein complexes with epidermal growth factor receptor (EGFR), which is considered a useful therapeutic target in hepatocellular carcinoma (HCC). Here, we investigated whether is involved in HCC progression. In clinical datasets, transcription level was positively correlated with levels; importantly, level was inversely correlated with the survival duration of HCC patients. In a diethylnitrosamine (DEN)-induced murine model of HCC, the global ablation of suppressed the development of HCC and prolonged the survival of HCC-bearing mice. We further found that increases in hepatocyte death and suppression of compensatory proliferation in the livers of DEN-injured -null mice were concomitant with decreases in nuclear factor κB (NF-κB)-dependent production of interleukin-6 (IL-6). Indeed, silencing of in murine macrophages led to reductions in NF-κB activity and IL-6 production. We found that the anti-proinflammatory effect of loss was mediated by reductions in EGFR level and its effect was not observed after exposure of the EGFR inhibitor erlotinib. This study reveals a novel cooperative role of in supporting the EGFR-mediated development of hepatocellular carcinoma, implying that pharmacological suppression of may be a useful strategy in HCC treatment.
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http://dx.doi.org/10.3390/cancers13102438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157610PMC
May 2021

Korean Red Ginseng attenuates ultraviolet-mediated inflammasome activation in keratinocytes.

J Ginseng Res 2021 May 13;45(3):456-463. Epub 2021 Feb 13.

College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon, Republic of Korea.

Background: Keratinocytes form a physical barrier and act as an innate immune cell in skin. Keratinocytes secrete pro-inflammatory cytokines, such as interleukin (IL)-1β, resulting from inflammasome activation when exposed to ultraviolet (UV) irradiation. Korean Red Ginseng extracts (RGE) have been well-studied as modulators of inflammasome activation in immune cells, such as macrophages. In the study, we elucidated the role of RGE on the UV-mediated inflammasome activation in keratinocytes compared with that in macrophages.

Methods: Human skin keratinocyte cells (HaCaT), human epidermal keratinocytes (HEK), human monocyte-like cells (THP-1), and mouse macrophages were treated with RGE or a saponin fraction (SF) or non-saponin fraction (NS) of RGE before and after UV irradiation. The secretion levels of IL-1β, as an indicator of inflammasome activation, were analyzed.

Results: The treatment of RGE or SF in macrophages after UV irradiation inhibited IL-1β secretion, but similar treatment in HaCaT cells did not. However, the treatment of RGE or SF in HaCaT cells in the presence of poly I:C, a toll-like receptor (TLR) 3 ligand, before UV exposure elicited the inhibition of the IL-1β secretion. The inhibition was caused by the disruption by RGE or SF of the TLR mediating up-regulation of the β and genes during the priming step.

Conclusion: RGE and its saponins inhibit IL-1β secretion in response to UV exposure in both keratinocytes and macrophages. In particular, RGE treatment interrupted only the priming step in keratinocytes, although it did attenuate both the priming and activation steps in macrophages.
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http://dx.doi.org/10.1016/j.jgr.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134848PMC
May 2021

Suppressed estrogen supply extra-ovarian progesterone receptor membrane component 1 in menopause.

J Biomed Res 2021 Jan;35(3):228-237

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.

In post-menopausal women, intra-mammary estrogen, which is converted from extra-ovarian estrone (E1), promotes the growth of breast cancer. Since the aromatase inhibitor letrozole does not suppress 17β-estradiol (E2) production from E1, high intra-mammary E1 concentrations impair letrozole's therapeutic efficacy. Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with breast cancer progression. In the present study, we introduced a heterozygous knockout (hetero KO) murine model exhibiting low Pgrmc1 expression, and observed estrogen levels and steroidogenic gene expression. Naïve hetero KO mice exhibited low estrogen (E2 and E1) levels and low progesterone receptor (PR) expression, compared to wild-type mice. In contrast, hetero KO mice that have been ovariectomized (OVX), including letrozole-treated OVX mice (OVX-letrozole), exhibited high estrogen levels and PR expression. Increased extra-ovarian estrogen production in hetero KO mice was observed with the induction of steroid sulfatase (STS). In MCF-7 cell, letrozole suppressed PR expression, but knockdown increased PR and STS expression. Our presented results highlight the important role of in modulating estrogen production when ovary-derived estrogen is limited, thereby suggesting a potential therapeutic approach for letrozole resistance.
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http://dx.doi.org/10.7555/JBR.35.20200172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193715PMC
January 2021

Progesterone receptor membrane component 1 reduces cardiac steatosis and lipotoxicity via activation of fatty acid oxidation and mitochondrial respiration.

Sci Rep 2021 04 22;11(1):8781. Epub 2021 Apr 22.

College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Suite 401 Veterinary medicine Bldg., Yuseong, Daejeon, 34134, Korea.

Obesity is implicated in cardiovascular disease and heart failure. When fatty acids are transported to and not adequately oxidized in cardiac cells, they accumulate, causing lipotoxicity in the heart. Since hepatic progesterone receptor membrane component 1 (Pgrmc1) suppressed de novo lipogenesis in a previous study, it was questioned whether cardiac Pgrmc1 protects against lipotoxicity. Hence, we focused on the role of cardiac Pgrmc1 in basal (Resting), glucose-dominant (Refed) and lipid-dominant high-fat diet (HFD) conditions. Pgrmc1 KO mice showed high FFA levels and low glucose levels compared to wild-type (WT) mice. Pgrmc1 KO mice presented low number of mitochondrial DNA copies in heart, and it was concomitantly observed with low expression of TCA cycle genes and oxidative phosphorylation genes. Pgrmc1 absence in heart presented low fatty acid oxidation activity in all conditions, but the production of acetyl-CoA and ATP was in pronounced suppression only in HFD condition. Furthermore, HFD Pgrmc1 KO mice resulted in high cardiac fatty acyl-CoA levels and TG level. Accordingly, HFD Pgrmc1 KO mice were prone to cardiac lipotoxicity, featuring high levels in markers of inflammation, endoplasmic reticulum stress, oxidative stress, fibrosis, and heart failure. In vitro study, it was also confirmed that Pgrmc1 enhances rates of mitochondrial respiration and fatty acid oxidation. This study is clinically important because mitochondrial defects in Pgrmc1 KO mice hearts represent the late phase of cardiac failure.
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http://dx.doi.org/10.1038/s41598-021-88251-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062525PMC
April 2021

Absence of progesterone receptor membrane component 1 reduces migration and metastasis of breast cancer.

Cell Commun Signal 2021 04 8;19(1):42. Epub 2021 Apr 8.

College of Veterinary Medicine, Chungnam National University, Suite 401, Veterinary Medicine Bldg., 99, Daehak-ro, Yuseong-gu, Daejeon, 34134, Republic of Korea.

Background: Progesterone receptor membrane component 1 (Pgrmc1) is a non-classical progesterone receptor associated with the development of the mammary gland and xenograft-induced breast cancer. Importantly, Pgrmc1 is associated with the expression of estrogen receptor alpha and can be used for predicting the prognosis of breast cancer. Whether the genetic deletion of Pgrmc1 affects the progression of breast cancer is still unclear.

Methods: We used MMTV-PyMT transgenic mice that spontaneously develop breast tumors. In backcrossed FVB Pgrmc1 knockout (KO) mice, we monitored the development of the primary tumor and lung metastasis. In MCF-7 and MDA-MB-231 tumor cell lines, the migratory activity was evaluated after Pgrmc1 knockdown.

Results: There was no significant difference in the development of breast cancer in terms of tumor size at 13 weeks of age between WT and Pgrmc1 KO mice. However, Pgrmc1 KO mice had a significantly longer survival duration compared with WT mice. Furthermore, Pgrmc1 KO mice exhibited a significantly lower degree of lung metastasis. Compared with those of WT mice, the tumors of Pgrmc1 KO mice had a low expression of focal adhesion kinase and epithelial-mesenchymal transition markers. PGRMC1 knockdown resulted in a significantly reduced migration rate in breast cancer cell lines.

Conclusions: Pgrmc1 KO mice with breast cancer had a prolonged survival, which was accompanied by a low degree of lung metastasis. PGRMC1 showed a significant role in the migration of breast cancer cells, and may serve as a potential therapeutic target in breast cancer. Video Abstract.
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http://dx.doi.org/10.1186/s12964-021-00719-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034092PMC
April 2021

Comparison of steroid hormones in three different preeclamptic models.

Mol Med Rep 2021 04 4;23(4). Epub 2021 Feb 4.

Department of Biomaterials Science (BK21 FOUR Program), College of Natural Resources and Life Science/Life and Industry Convergence Research Institute, Pusan National University, Miryang, Gyeongsangnam 50463, Republic of Korea.

Preeclampsia (PE) is a complication of pregnancy and is characterized by hypertension and proteinuria, threatening both the mother and the fetus. However, the etiology of PE has not yet been fully understood. Since the imbalance of steroid hormones is associated with the pathogenesis of PE, investigating steroidogenic mechanisms under various PE conditions is essential to understand the entire spectrum of pregnancy disorders. Therefore, the current study established three PE and models, and compared the levels of steroid hormones and steroidogenic enzymes within them. In cellular PE models induced by hypoxia, N‑nitro‑L‑arginine methyl ester hydrocholride (L‑NAME) and catechol‑o‑methyltransferase inhibitor, the levels of steroid hormones, including pregnenolone (P5), progesterone (P4), dehydroepiandrosterone (DHEA) and testosterone tended to decrease during steroidogenesis. Injection of L‑NAME in pregnant rats led to a reduction in the levels of estradiol and P4 through regulation of cholesterol side‑chain cleavage enzyme (CYP11A1) and 3β‑hydroxysteroid dehydrogenase/δ5 4‑isomerase type 1 (HSD3B1), whereas rats treated with COMT‑I exhibited elevated levels of P5 and DHEA by regulation of the CYP11A1 and aromatase cytochrome P450 (CYP19A1) in the placenta and plasma. The reduced uterine perfusion pressure operation decreased CYP11A1 and increased CYP19A1 expression in placental tissues, whereas steroid hormone levels were not altered. In conclusion, the results of the present study suggest that the induction of PE conditions dysregulates the steroid hormones via regulation of steroidogenic enzymes, depending on specific PE symptoms. These findings can contribute to the development of novel diagnostic and therapeutic modalities for PE, by monitoring and supplying appropriate levels of steroid hormones.
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http://dx.doi.org/10.3892/mmr.2021.11891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893799PMC
April 2021

Progesterone increases blood glucose via hepatic progesterone receptor membrane component 1 under limited or impaired action of insulin.

Sci Rep 2020 10 1;10(1):16316. Epub 2020 Oct 1.

College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Suite 401Veterinary medicine Bldg., Yuseong, Daejeon, 34134, Republic of Korea.

Hepatic gluconeogenesis is the main pathway for blood glucose maintenance activated during fasting. Retardation of insulin action, such as in diabetes mellitus, activates gluconeogenesis during the fed state. While the role of progesterone (P4) in diabetes is controversial, the P4 receptor, progesterone receptor membrane component 1 (PGRMC1), is known to stimulate pancreatic insulin secretion. We investigated the role of P4, via hepatic PGRMC1, during gluconeogenesis. The PGRMC1 binding chemical, AG-205, induced PGRMC1 monomer (25 kDa) abundance, and increased PEPCK expression and glucose production in parallel with cyclic AMP (cAMP) induction in Hep3B cells. PGRMC1-mediated cyclic AMP was inhibited by an adenylate cyclase inhibitor (MDL-12,330A). PEPCK suppression in Pgrmc1 KO hepatocyte was not observed after treatment of MDL-12,330A. PGRMC1 knockdown or overexpression systems in Hep3B cells confirmed that PGRMC1 mediates PEPCK expression via phosphorylation of cAMP-response element binding protein (CREB). CREB phosphorylation and PEPCK expression in primary hepatocytes were greater than that in PGRMC1 knock-out hepatocytes. Progesterone increased PGRMC1 expression, which induced cAMP and PEPCK induction and glucose production. In vivo, P4 suppressed gluconeogenesis following plasma insulin induction under normal conditions in a mouse model. However, P4 increased blood glucose via gluconeogenesis in parallel with increases in PGRMC1 and PEPCK expression in mice in both insulin-deficient and insulin-resistant conditions. We conclude that P4 increases hepatic glucose production via PGRMC1, which may exacerbate hyperglycaemia in diabetes where insulin action is limited.
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http://dx.doi.org/10.1038/s41598-020-73330-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529793PMC
October 2020

Progesterone receptor membrane component 1 is required for mammary gland development†.

Biol Reprod 2020 12;103(6):1249-1259

ConveRgence mEDIcine research cenTer (CREDIT), Asan Institute for Life Sciences, Seoul, Republic of Korea.

The physiological functions of progesterone (P4) in female reproductive organs including the mammary glands are mediated via the progesterone receptor (PR), but not all P4 functions can be explained by PR-mediated signaling. Progesterone receptor membrane component 1 (PGRMC1), a potential mediator of P4 actions, plays an important role in the ovary and uterus in maintaining female fertility and pregnancy, but its function in mammary glands has not been elucidated. This study investigated the role of PGRMC1 in mouse mammary gland development. Unlike in the uterus, exogenous estrogen (E2) and/or P4 did not alter PGRMC1 expression in the mammary gland, and Pgrmc1-knockout (KO) mice displayed reduced ductal elongation and side branching in response to hormone treatment. During pregnancy, PGRMC1 was expressed within both the luminal and basal epithelium and gradually increased with gestation and decreased rapidly after parturition. Moreover, although lactogenic capacity was normal after parturition, Pgrmc1 KO resulted in defective mammary gland development from puberty until midpregnancy, while the expression of PR and its target genes was not significantly different between wild-type and Pgrmc1-KO mammary gland. These data suggest that PGRMC1 is essential for mammary gland development during puberty and pregnancy in a PR-independent manner.
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http://dx.doi.org/10.1093/biolre/ioaa164DOI Listing
December 2020

Morphological and Molecular Characterization of Toxocara apodemi (Nematoda: Ascarididae) from Striped Field Mice, Apodemus agrarius, in Korea.

Korean J Parasitol 2020 Aug 25;58(4):403-411. Epub 2020 Aug 25.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Adult ascarid worms from the field mice, Apodemus agrarius, were observed with a light and scanning electron microscope, and molecularly analized with 18S rRNA gene. In the scanning electron microscope, 3 prominent labia were present in the anterior end of male and female worms, but the interlabia and gubernaculum were absent. Scanning electron micrographs showed cervical alae as vestigial organs that looked like a slightly uplifted superficial sewing stitch. Total 6 pairs of post-cloacal papillae were observed on the tail of the male worms. The tail of female worms was blunt and conical shape with a spine-like structure, mucron. The eggs were sub-globular, coated with the albuminous layer and 73 by 82 μm in average size. The superficial pits of T. apodemi egg (mean 8.6×6.7 μm) are obviously bigger than those of Toxocara spp. The partial sequence of 18S rRNA showed the sequence homology of Toxocara canis (99.6%), Toxocara cati (99.4%), Toxascaris leonina (99.4%), and Toxocara vitulorum (99.2%). Conclusively, it was confirmed that ascarid nematodes, Toxocara apodemi, recovered from striped field mice in Korea are taxonomically conspecific relationship with genus Toxocara and genetic divergence from other Toxocara species.
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http://dx.doi.org/10.3347/kjp.2020.58.4.403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462795PMC
August 2020

Calbindin-D is a Novel Risk Gene for Neurodegenerative Disease.

Cell Physiol Biochem 2020 May;54(3):438-456

Laboratory of Veterinary Biochemistry and Molecular Biology, Veterinary Medical Center and College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk, Republic of Korea,

Background/aims: Calcium homeostasis plays a crucial role in neuronal development and disease. Calbindin-D (CaBP-9k) acts as calcium modulators and sensors in various tissues. However, the neurobiological functions of CaBP-9k are unknown.

Methods: We used CaBP-9k knockout (KO) mice to investigate the roles of these gene in neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. We used anatomical and biochemical approaches to characterize functional abnormalities of the brain in the CaBP-9k KO mice.

Results: We found that the brains of CaBP-9k KO mice have increased APP/β-amyloid, Tau, and α-synuclein accumulation and endoplasmic reticulum (ER) stress-induced apoptosis. Neurons deficient for these CaBP-9k had abnormal intracellular calcium levels and responses. ER stress inhibitor TUDCA reduced ER stress-induced apoptosis and restored ER stress- and apoptosis-related proteins expression to wild-type levels in CaBP-9k KO mice. Furthermore, treatment with TUDCA rescued the abnormal memory and motor behaviors exhibited by older CaBP-9k KO mice.

Conclusion: Our results suggest that a loss of CaBP-9k may contribute to the onset and progression of neurodegenerative diseases.
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http://dx.doi.org/10.33594/000000229DOI Listing
May 2020

IκBζ controls NLRP3 inflammasome activation via upregulation of the Nlrp3 gene.

Cytokine 2020 03 7;127:154983. Epub 2020 Jan 7.

College of Veterinary Medicine and Institute of Veterinary Science, College of Pharmacy, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea. Electronic address:

Inflammasome activation induces the maturation and secretion of interleukin (IL)-1β and -18, and is dependent on NF-κB signaling to induce the transcription of the inflammasome components, called the priming step. This study elucidated the role of IκBζ, an atypical IκBs (inhibitor of κB) and a coactivator of NF-κB target genes, on the activation of inflammasome. Bone marrow-derived macrophages (BMDMs) that originated from IκBζ-encoding Nfkbiz gene depletion mice presented a defect in NLRP3 inflammasome activation. In addition, the Nfkbiz and Nfkbiz mice significantly attenuated serum IL-1β secretion in response to a monosodium urate injection, a NLRP3 trigger, when compared with Nfkbiz mice. The lack of IκBζ in BMDMs produced a disability in the expression of Nlrp3 and pro-Il1β mRNAs during the priming step. In addition, ectopic IκBζ expression enhanced the Nlrp3 promoter activity, and Nlrp3 and pro-Il1β transcription. Overall, IκBζ controlled the activation of NLRP3 inflammasome by upregulating the Nlrp3 gene during the priming step.
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http://dx.doi.org/10.1016/j.cyto.2019.154983DOI Listing
March 2020

The Protective Role of Calbindin-D on Endoplasmic Reticulum Stress-Induced Beta Cell Death.

Int J Mol Sci 2019 Oct 25;20(21). Epub 2019 Oct 25.

Laboratory of Veterinary Biochemistry and Molecular Biology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 28644, Korea.

Intracellular calcium ion content is tightly regulated for the maintenance of cellular functions and cell survival. Calbindin-D (CaBP-9k) is responsible for regulating the distribution of cytosolic free-calcium ions. In this study, we aimed to investigate the effect of CaBP-9k on cell survival in pancreatic beta cells. Six-month-old wildtype CaBP-9k, CaBP-28k, and CaBP-9k/28k knockout (KO) mice were used to compare the pathological phenotypes of calcium-binding protein-deleted mice. Subsequently, the endoplasmic reticulum (ER) stress reducer tauroursodeoxycholic acid (TUDCA) was administered to wildtype and CaBP-9k KO mice. In vitro assessment of the role of CaBP-9k was performed following CaBP-9k overexpression and treatment with the ER stress inducer thapsigargin. Six-month-old CaBP-9k KO mice showed reduced islet volume and up-regulation of cell death markers resulting from ER stress, which led to pancreatic beta cell death. TUDCA treatment recovered islet volume, serum insulin level, and abdominal fat storage by CaBP-9k ablation. CaBP-9k overexpression elevated insulin secretion and recovered thapsigargin-induced ER stress in the INS-1E cell line. The results of this study show that CaBP-9k can protect pancreatic beta cell survival from ER stress and contribute to glucose homeostasis, which can reduce the risk of type 1 diabetes and provide the molecular basis for calcium supplementation to diabetic patients.
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http://dx.doi.org/10.3390/ijms20215317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862009PMC
October 2019

Urogonimus turdi (Digenea: Leucochloridiidae) from the White's Thrush, Zoothera aurea, in the Republic of Korea.

Korean J Parasitol 2019 Oct 31;57(5):461-467. Epub 2019 Oct 31.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Avian trematodes, Urogonimus turdi (Digenea: Leucochloridiidae), were collected from the intestine of wild birds, Zoothera aurea, 2013-2017 in the Daejeon Metropolitan City, Korea. The body was ellipsoidal, attenuated and/or round ends, 1,987-2,120 long and 819-831 µm wide. The oral sucker was subterminal, rounded anteriorly, and 308- 425×351-432 µm in size; the prepharynx and esophagus were almost lacking; pharynx was well-developed, 142- 179×78-170 µm in size; intestine narrow, bifurcating just after pharynx, ascending to the oral sucker before looping posteriorly and terminating near the posterior end; ventral sucker larger, in almost median, 536-673×447-605 µm and approximately 1.5 times larger than oral sucker. A phylogenetic tree constructed with 18S ribosomal RNA showed inter- and intraspecific relationships. Based on these morphological and molecular findings, we report here a U. turdi from White's thrushes in Korea.
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http://dx.doi.org/10.3347/kjp.2019.57.5.461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851249PMC
October 2019

Traditional Medicine (Mahuang-Tang) Improves Ovarian Dysfunction and the Regulation of Steroidogenic Genes in Letrozole-Induced PCOS Rats.

J Ethnopharmacol 2020 Feb 10;248:112300. Epub 2019 Oct 10.

Herbal Medicine Research Division Korea Institute of Oriental Medicine, Daejeon, 34054, South Korea. Electronic address:

Ethnopharmacological Relevance: Mahuang-Tang (MHT) has traditionally been used in Asia to treat a variety of diseases, such as fever without sweating, joint pain, lower back pain, asthma, and gynecological conditions. Polycystic ovary syndrome (PCOS) is a kind of gynecological disease that causes amenorrhea, infertility, and menopausal and urogenital disorders that could benefit from MHT treatment.

Aim Of The Study: In this study, we examined the effects of MHT on ovarian hormones and steroidogenic enzymes in female PCOS rats.

Methods And Results: The PCOS rat model was induced by Letrozole, and an in vivo evaluation of whether the dietary consumption of MHT improved the PCOS-like symptoms was conducted. The luteinizing hormone (LH) level and luteinizing hormone/follicular-stimulating hormone (LH/FSH) ratio increased in PCOS rats but decreased following MHT treatment. In the PCOS rats, the reduced estrogen level was restored to that of normal controls with MHT treatment in serum. The transcription level(s) of gonadotropin receptors (Fshr and Lhr), steroid receptors (Pgr, and Esr1) and steroidogenic enzymes (Cyp19a1, Hsd3b1, Hsd17a1, and Cyp11a1) changed under the PCOS condition, and were regulated by MHT treatment in the ovaries of PCOS rats. The reproductive tissues of Letrozole-induced PCOS rats were restored into estrogenic condition from androgen environments.

Conclusion: These results suggest that MHT ameliorates the symptoms of PCOS by improving the dysregulation of ovarian steroids and steroidogenic enzymes in PCOS rats.
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http://dx.doi.org/10.1016/j.jep.2019.112300DOI Listing
February 2020

Sex hormone-binding globulin suppresses NAFLD-triggered hepatocarcinogenesis after menopause.

Carcinogenesis 2019 08;40(8):1031-1041

College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.

It is generally accepted that androgen receptors increase the risk of hepatocellular carcinoma (HCC), and that estrogen reduces risk of HCC. Many studies regarding this have involved males. We, therefore, have focused our attention on females, especially postmenopausal females, who typically have limited supplies of estrogen. By using sex hormone-binding globulin (SHBG) transgenic mice, we produced a humanoid environment, and facilitated deposition and modulation of sex hormones. After exposure to diethylnitrosamine to induce HCC and upon reaching the age of 40 weeks, mice were fed the fat-rich diet for 5 months. Fat-rich diet fed or ovariectomized (OVX) wild-type mice aged 62 weeks showed HCC progression, whereas fat-rich diet fed SHBG mice or OVX SHBG mice displayed fewer tumors. In the liver of fat-rich diet fed SHBG mice, estrogenic conditions including high levels of 17β-estradiol and estrogen receptor alpha led to the induction of the lipogenesis inhibitor, phosphorylated acetyl-CoA carboxylase, and consequently suppressed fatty liver. The presence of plasma SHBG in HCC bearing mice suppressed the levels of steatosis and inflammation in a process mediated by estrogens and estrogen receptor alpha. Conversely, in the liver of OVX SHBG mice, lipogenic inhibition was also observed under conditions where the supply of estrogens is limited. Through in vitro experiment, it was confirmed SHBG suppresses lipogenesis via inhibition of acetyl-CoA carboxylase level. In conclusion, our results show that plasma SHBG might have a clinical impact on lipid-mediated hepatic diseases.
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http://dx.doi.org/10.1093/carcin/bgz107DOI Listing
August 2019

Antidepressant Effect of Extract on Serotonin Turnover.

Evid Based Complement Alternat Med 2019 3;2019:7312842. Epub 2019 Feb 3.

Herbal Medicine Research Division, Korea Institute of Oriental Medicine (KIOM), Daejeon 34054, Republic of Korea.

(TTK) is a groundcover found along coastal areas of the Korean peninsula. TTK is traditionally used to improve women's health and treat gastrointestinal diseases. Use of herbal medicines in the treatment of mood disorders has recently been suggested as an alternative therapeutic strategy. In the present study, we determined that consumption of TTK extract ameliorated progression of depressive-like symptoms in ovariectomized (OVX) rats and further examined the mechanisms involved, i.e., synthesis, release, and reuptake(s) of serotonin (also known as 5-HT). We assessed the mRNA expression levels of tryptophan hydroxylases (TPH-1 and TPH-2) and serotonin transporter (SERT) as well as the reuptake activity of serotonin in RBL-2H3 cells. We also determined whether or not TTK extract regulates the serum level of serotonin and improves depressive-like symptoms in 0.5, 1, and 2% TTK-fed OVX female rats in a forced swimming test. Our results show that the mRNA levels of TPH-1 and SERT were significantly reduced, whereas the mRNA level of TPH-2 was dose-dependently elevated by TTK (50 and 100 g/mL) in RBL-2H3 cells. TTK significantly inhibited LPS- (lipopolysaccharide-) induced serotonin uptake in RBL-2H3 cells in a dose-dependent manner. The serum level(s) of serotonin was elevated by 1% and 2% TTK treatment in OVX female rats. Moreover, immobility time in the forced swimming test was reduced by 1% and 2% TTK treatment but not altered by 0.5% TTK treatment in OVX female rats. Taken together, these results indicate that TTK may significantly inhibit depressive-like symptoms due to upregulation of serotonin level(s) and regulation of serotonin reuptake activity. Thus, TTK may exert beneficial effects on depression during pre- or/and postmenopausal periods modulation of serotonin synthesis and metabolism.
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http://dx.doi.org/10.1155/2019/7312842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378020PMC
February 2019

Curcumae Radix Extract Decreases Mammary Tumor-Derived Lung Metastasis via Suppression of C-C Chemokine Receptor Type 7 Expression.

Nutrients 2019 Feb 15;11(2). Epub 2019 Feb 15.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Curcumae radix is the dry root of (turmeric) that can be used either as a spice or traditional medicine. The aim of this study was to investigate the survival benefits and the anti-metastatic activity of curcumae radix extract (CRE) in MCF7 cells and in MMTV-PyMT transgenic mice-a mouse model of breast cancer metastasis. In vitro wound scratch assay revealed that CRE treatment inhibited cell motility and cell migration in a dose-dependent manner. To investigate the effect of CRE in breast cancer metastasis, MMTV-PyMT transgenic female virgin mice were used and randomly divided into two groups. For survival curve analysis, CRE was administered in a dose of 50 mg/kg to 8⁻20-week-old mice. Interestingly, CRE treatment significantly increased the median and prolonged survival of MMTV-PyMT mice. Furthermore, CRE treatment decreased tumor burden and inhibited cell proliferation in primary breast tumor, and also suppressed mammary tumor-derived lung metastasis. The size of the lung metastases substantially decreased in the CRE-treated group compared with the ones in the control group. Curcumae radix extract showed anti-metastatic activity through regulating the expression of metastasis markers including C-C Chemokine Receptor Type 7, Matrix Metalloproteinase 9 and the proto-oncogenes c-fos and c-jun. We demonstrated that these metastatic regulators were decreased when CCR7 expression was suppressed in MCF7 cells transfected with CCR7 siRNA. The results of this study show that curcumae radix exerts antitumor and anti-metastatic activities, and we suggest that curcumae radix might be a potential supplement for the treatment and prevention of breast cancer metastasis.
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http://dx.doi.org/10.3390/nu11020410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412318PMC
February 2019

Morphological and Molecular Characterization of Toxocara tanuki (Nematoda: Ascaridae) from Korean Raccoon Dog, Nyctereutes procyonoides koreensis.

Korean J Parasitol 2018 Dec 31;56(6):567-575. Epub 2018 Dec 31.

College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Korea.

Present study was performed to describe the morphological and molecular characterization of Toxocara tanuki (Nematoda: Ascaridae) from Korean raccoon dog, Nyctereutes procyonoides koreensis, naturally infected in the Republic of Korea (Korea). Juvenile and adult worms of T. tanuki were recovered in 5 out of 10 raccoon dogs examined and the larval worms were detected in 15 out of 20 muscle samples (75%). Small lateral alae were observed on the cranial end of the body in male and female adults and 2 long spicules (3.0-3.5 mm) were characteristically observed in the posterior end of males. In SEM observation, 18 pairs of proximal precloacal, a precloacal median, a postcloacal median and 5 pairs of postcloacal papillae were uniquely revealed in the posterior portion of males, but the proximal papillae were not shown in the lateral ends of females. Molecular analysis on the 18S rRNA partial DNA sequences was revealed the same finding in both samples, adult worms and muscle larvae, which are closely related to T. tanuki. In conclusion, it was confirmed for the first time that T. tanuki is indigenously distributed, the Korean raccoon dog is acted as the natural definitive host of this nematode in Korea and the morphological characteristics of T. tanuki were shown in specific structure for single postcloacal median papilla in male.
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http://dx.doi.org/10.3347/kjp.2018.56.6.567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327194PMC
December 2018

Dietary intake of genistein suppresses hepatocellular carcinoma through AMPK-mediated apoptosis and anti-inflammation.

BMC Cancer 2019 Jan 3;19(1). Epub 2019 Jan 3.

College of Veterinary Medicine, Chungnam National University, 99 Daehak-ro, Suite 401Veterinary medicine Bldg., Yuseong, Daejeon, 34134, South Korea.

Background: Women have a lower risk of hepatocellular carcinoma (HCC) than men, and the decreased possibility of HCC in women is thought to depend on estrogen levels. As a soybean-isoflavone product, genistein has estrogenic activity in various reproductive tissues, because it mimics 17β-estradiol and binds the estrogen receptor. Though genistein is a known liver cancer suppressor, its effects have not been studies in long-term experiment, where genistein is fed to a female animal model of HCC.

Methods: Mice were treated with diethylnitrosamine (DEN) to induce HCC at 2 weeks of age and fed with supplemental genistein for 5 months, from 40 to 62 weeks of age.

Results: The dietary intake of genistein decreased the incidence of HCC and suppressed HCC development. Genistein induced phospho-AMPK in total liver extracts, Hep3B cells, and Raw 264.7 cells, and phospho-AMPK promoted apoptosis in liver and Hep3B cells. Moreover, phospho-AMPK down-regulated pro-inflammatory responses and ameliorated liver damage. A suppressed pro-inflammatory response with increased mitochondrial respiration was concomitantly observed after genistein treatment.

Conclusions: Genistein-mediated AMPK activation increases hepatocyte apoptosis through energy-dependent caspase pathways, suppresses the inflammatory response in resident liver macrophages by increased cellular respiration, and consequently inhibits the initiation and progression of HCC.
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http://dx.doi.org/10.1186/s12885-018-5222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318960PMC
January 2019
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