Publications by authors named "Sang R Lee"

23 Publications

  • Page 1 of 1

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms23010547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8745349PMC
January 2022

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms222212557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8620028PMC
November 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 .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms22157904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8348493PMC
July 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers13102438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157610PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12964-021-00719-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034092PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-73330-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529793PMC
October 2020

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/carcin/bgz107DOI Listing
August 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu11020410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412318PMC
February 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-018-5222-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6318960PMC
January 2019

Therapeutic Effect of Extract in Letrozole-Induced Polycystic Ovary Syndrome Rats.

Front Pharmacol 2018 19;9:1325. Epub 2018 Nov 19.

Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, South Korea.

Polycystic ovary syndrome (PCOS) is an endocrinal disorder that afflicts mainly women of childbearing age. The symptoms of PCOS are irregular menstrual cycles, weight gain, subfertility and infertility. However, because the etiology is unclear, management and treatment methods for PCOS are not well established. Recently, natural substances have been used for PCOS therapy. () is a well-known natural substance that attenuates the effects of inflammation, allergies, and cancer. In this study, we investigated the effects of extract in rats with PCOS. When rats with letrozole-induced PCOS were exposed to the extract, the regular estrus cycle was restored, similar to that in placebo rats. Hormone levels, including the levels of testosterone, estrogen, luteinizing hormone (LH), follicle stimulating hormone (FSH), and anti-Müllerian hormone (AMH), were restored to their normal states. Histological analysis revealed that the polycystic ovary symptoms were significantly decreased in the -treated rats and were comparable to those of normal ovaries. At the transcriptional and translational levels, , and levels were markedly increased in the -treated rats with PCOS compared with the rats with letrozole-induced PCOS. These results suggest that the extract inhibits the symptoms of PCOS by restoring imbalanced hormonal levels and irregular ovarian cycles in letrozole-induced female rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2018.01325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262357PMC
November 2018

Loss of progesterone receptor membrane component 1 promotes hepatic steatosis via the induced de novo lipogenesis.

Sci Rep 2018 10 24;8(1):15711. Epub 2018 Oct 24.

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

Non-alcoholic fatty liver disease (NAFLD) results from triglyceride accumulation within the liver and some of them advances to non-alcoholic steatohepatitis (NASH). It is important to note that in NAFLD development, hepatic de novo lipogenesis (DNL) derives from excess carbohydrates and fats under a condition of excess energy through β-oxidation. As a main regulator for DNL, sterol regulatory element-binding protein 1 (Srebp-1) forms complex with progesterone receptor membrane component 1 (Pgrmc1). To investigate whether Pgrmc1 may have a notable effect on DNL via SREBP-1 activation, we generated Pgrmc1 knockout (KO) mice and fed a high fat diet for one month. High-fat-fed Pgrmc1 KO mice showed a substantial increase in levels of hepatic TG accumulation, and they were predisposed to NAFLD when compared to WT mice. Loss of Pgrmc1 increased mature SREBP-1 protein level, suggesting that induction of hepatic steatosis in Pgrmc1 KO mice might be triggered by de novo lipogenesis. Moreover, Pgrmc1 KO mice were also more vulnerable to early stage of NASH, showing high levels of alanine aminotransferase, obesity-linked pro-inflammatory cytokines, and fibrosis markers. This is interesting because Pgrmc1 involves with the first step in regulating the hepatic de novo lipogenesis under an excess energy condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-34148-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6200820PMC
October 2018

Welsh Onion Root () Restores Ovarian Functions from Letrozole Induced-Polycystic Ovary Syndrome.

Nutrients 2018 Oct 4;10(10). Epub 2018 Oct 4.

Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon 34054, Korea.

Polycystic ovarian syndrome (PCOS) is an endocrine, metabolic, and systemic disease. It is mainly characterized by hyperandrogenism, oligomenorrhea, and high levels of luteinizing hormone (LH). There is no obvious therapy for PCOS, so patients have received symptomatic therapy. Welsh onion () is well-known in Asian countries for its usage in food ingredients and traditional medicines. It is also studied for its many effects. These include activation of immune responses, antihypertensive effects, and antioxidant effects. Using letrozole-induced PCOS rats, we focused on herbal therapy using extract of (AF; ) roots to improve ovarian functions. As a nonsteroidal aromatase inhibitor, letrozole blocks conversion of testosterone to estrogen and subsequently induces PCOS phenomenon. We divided six-week-old female rats into four groups, including control, letrozole, letrozole + AF extract, and temporary letrozole groups. In our study, treatment with AF extract shows a low plasma LH/FSH ratio, and reveals high estrogen levels, ovarian morphology, folliculogenesis-related genes, and aromatase expression under PCOS mimic conditions. We concluded that AF extract administration influenced aromatase production, enhanced the estrogen steroid synthesis, and consequently restored the estrogenic feedback mechanism on the pituitary-ovary system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu10101430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6213865PMC
October 2018

5α-dihydrotestosterone reduces renal expression suppression of progesterone receptor.

J Mol Endocrinol 2018 02;60(2):159-170

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

Androgens act in concert with vitamin D to influence reabsorption of calcium. However, it is unclear whether androgens directly regulate vitamin D homeostasis or control other cellular events that are related to vitamin D metabolism. To examine whether the expression of vitamin D-related genes in mouse kidney is driven by androgens or androgen-dependent effects, the androgen receptor and other sex steroid receptors were monitored in orchidectomized mice treated with 5α-dihydrotestosterone (DHT). Our results revealed that exposing orchidectomized mice to DHT inhibited the expression of progesterone receptor (Pgr) with or without estrogen receptor α expression, the latter was confirmed by ER-positive (MCF7 and T47D) or -negative (PCT) cells analysis. The loss of Pgr in turn decreased the expression of renal 24-hydroxylase transcriptional regulation because gene has a progesterone receptor-binding site on promoter. When male kidneys preferentially hydroxylate 25-hydroxyvitamin D using 24-hydroxylase rather than 25-hydroxyvitamin D-1-alpha hydroxylase, DHT suppressed the Pgr-mediated 24-hydroxylase expression, and it is important to note that DHT increased the blood 25-hydroxyvitamin D levels. These findings uncover an important link between androgens and vitamin D homeostasis and suggest that therapeutic modulation of Pgr may be used to treat vitamin D deficiency and related disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1530/JME-17-0187DOI Listing
February 2018

Hydroxylation and sulfation of sex steroid hormones in inflammatory liver.

J Biomed Res 2017 Sep;31(5):437-444

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

Sex steroids, also known as gonadal steroids, are oxidized with hydroxylation by cytochrome P450, glucuronidation by UDP-glucuronosyltransferase, sulfation by sulfotransferase, andO-methylation by catechol O-methyltransferase. Thus, it is important to determine the process by which inflammation influences metabolism of gonadal hormones. Therefore, we investigated the mechanism of metabolic enzymes against high physiologic inflammatory responsein vivo to study their biochemical properties in liver diseases. In this study, C57BL/6N mice were induced with hepatic inflammation by diethylnitrosamine (DEN) exposure. We observed upregulation of Cyp19a1, Hsd17b1, Cyp1a1, Sult1e1 in the DEN-treated livers compared to the control-treated livers using real time PCR. Moreover, the increased Cyp19a1 and Hsd17b1 levels support the possibility that estrogen biosynthesis from androgens are accumulated during inflammatory liver diseases. Furthermore, the increased levels of Cyp1a1 and Cyp1b1 in the hydroxylation of estrogen facilitated the conversion of estrogen to 2- or 4-hydroxyestrogen, respectively. In addition, the substantial increase in the Sult1e1 enzyme levels could lead to sulfate conjugation of hydroxyestrogen. The present information supports the concept that inflammatory response can sequester sulfate conjugates from the endogenous steroid hormones and may suppress binding of sex steroid hormones to their receptors in the whole body.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7555/JBR.31.20170031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706436PMC
September 2017

STAT2 Knockout Syrian Hamsters Support Enhanced Replication and Pathogenicity of Human Adenovirus, Revealing an Important Role of Type I Interferon Response in Viral Control.

PLoS Pathog 2015 Aug 20;11(8):e1005084. Epub 2015 Aug 20.

Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America.

Human adenoviruses have been studied extensively in cell culture and have been a model for studies in molecular, cellular, and medical biology. However, much less is known about adenovirus replication and pathogenesis in vivo in a permissive host because of the lack of an adequate animal model. Presently, the most frequently used permissive immunocompetent animal model for human adenovirus infection is the Syrian hamster. Species C human adenoviruses replicate in these animals and cause pathology that is similar to that seen with humans. Here, we report findings with a new Syrian hamster strain in which the STAT2 gene was functionally knocked out by site-specific gene targeting. Adenovirus-infected STAT2 knockout hamsters demonstrated an accentuated pathology compared to the wild-type control animals, and the virus load in the organs of STAT2 knockout animals was 100- to 1000-fold higher than that in wild-type hamsters. Notably, the adaptive immune response to adenovirus is not adversely affected in STAT2 knockout hamsters, and surviving hamsters cleared the infection by 7 to 10 days post challenge. We show that the Type I interferon pathway is disrupted in these hamsters, revealing the critical role of interferon-stimulated genes in controlling adenovirus infection. This is the first study to report findings with a genetically modified Syrian hamster infected with a virus. Further, this is the first study to show that the Type I interferon pathway plays a role in inhibiting human adenovirus replication in a permissive animal model. Besides providing an insight into adenovirus infection in humans, our results are also interesting from the perspective of the animal model: STAT2 knockout Syrian hamster may also be an important animal model for studying other viral infections, including Ebola-, hanta-, and dengue viruses, where Type I interferon-mediated innate immunity prevents wild type hamsters from being effectively infected to be used as animal models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1005084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546297PMC
August 2015

Efficient gene targeting in golden Syrian hamsters by the CRISPR/Cas9 system.

PLoS One 2014 9;9(10):e109755. Epub 2014 Oct 9.

Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, Utah, United States of America; Auratus Bio, LLC., Canton, South Dakota, United States of America.

The golden Syrian hamster is the model of choice or the only rodent model for studying many human diseases. However, the lack of gene targeting tools in hamsters severely limits their use in biomedical research. Here, we report the first successful application of the CRISPR/Cas9 system to efficiently conduct gene targeting in hamsters. We designed five synthetic single-guide RNAs (sgRNAs)--three for targeting the coding sequences for different functional domains of the hamster STAT2 protein, one for KCNQ1, and one for PPP1R12C--and demonstrated that the CRISPR/Cas9 system is highly efficient in introducing site-specific mutations in hamster somatic cells. We then developed unique pronuclear (PN) and cytoplasmic injection protocols in hamsters and produced STAT2 knockout (KO) hamsters by injecting the sgRNA/Cas9, either in the form of plasmid or mRNA, targeting exon 4 of hamster STAT2. Among the produced hamsters, 14.3% and 88.9% harbored germline-transmitted STAT2 mutations from plasmid and mRNA injection, respectively. Notably, 10.4% of the animals produced from mRNA injection were biallelically targeted. This is the first success in conducting site-specific gene targeting in hamsters and can serve as the foundation for developing other genetically engineered hamster models for human disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0109755PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192357PMC
December 2015

Coupling of soil solarization and reduced rate fumigation: effects on methyl iodide emissions from raised beds under field conditions.

J Agric Food Chem 2013 Dec 13;61(51):12510-5. Epub 2013 Dec 13.

USDA-ARS, United States Salinity Laboratory, 450 West Big Springs Road, Riverside, California 92507, United States.

Using field plots, we studied the effect on methyl iodide (MeI) emissions of coupling soil solarization (passive and active) and reduced rate fumigation (70% of a standard fumigation) in raised beds under virtually impermeable film (VIF). The results showed that for the standard fumigation and the passive solarization + fumigation treatments, emissions from the nontarped furrow were very high (∼50%). Emissions from the bed top and sidewall of these treatments were relatively low but were increased in the latter due to the longer environmental exposure of the VIF covering with the coupled approach (increased tarp permeability). Overall, this approach offered no advantage over fumigation-only in terms of emission reduction. With active solarization + fumigation, the large application of hot water during solarization apparently led to severely limited diffusion causing very low total emissions (<1%). Although this suggests a benefit in terms of air quality, a lack of diffusion could limit the pesticidal efficacy of the treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/jf403702kDOI Listing
December 2013

Optimization of cryoprotectant loading into murine and human oocytes.

Cryobiology 2014 Feb 15;68(1):18-28. Epub 2013 Nov 15.

Institute of Molecular Medicine and Genetics, Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA; Department of Obstetrics and Gynecology, and Cancer Center, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA. Electronic address:

Loading of cryoprotectants into oocytes is an important step of the cryopreservation process, in which the cells are exposed to potentially damaging osmotic stresses and chemical toxicity. Thus, we investigated the use of physics-based mathematical optimization to guide design of cryoprotectant loading methods for mouse and human oocytes. We first examined loading of 1.5 M dimethyl sulfoxide (Me(2)SO) into mouse oocytes at 23°C. Conventional one-step loading resulted in rates of fertilization (34%) and embryonic development (60%) that were significantly lower than those of untreated controls (95% and 94%, respectively). In contrast, the mathematically optimized two-step method yielded much higher rates of fertilization (85%) and development (87%). To examine the causes for oocyte damage, we performed experiments to separate the effects of cell shrinkage and Me(2)SO exposure time, revealing that neither shrinkage nor Me(2)SO exposure single-handedly impairs the fertilization and development rates. Thus, damage during one-step Me(2)SO addition appears to result from interactions between the effects of Me(2)SO toxicity and osmotic stress. We also investigated Me(2)SO loading into mouse oocytes at 30°C. At this temperature, fertilization rates were again lower after one-step loading (8%) in comparison to mathematically optimized two-step loading (86%) and untreated controls (96%). Furthermore, our computer algorithm generated an effective strategy for reducing Me(2)SO exposure time, using hypotonic diluents for cryoprotectant solutions. With this technique, 1.5 M Me(2)SO was successfully loaded in only 2.5 min, with 92% fertilizability. Based on these promising results, we propose new methods to load cryoprotectants into human oocytes, designed using our mathematical optimization approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cryobiol.2013.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4036103PMC
February 2014
-->