• The Korean Journal of Physiology and Pharmacology
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• 제28권2호
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• pp.113-120
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• 2024

Solute carrier 40A1 (SLC40A1) encodes ferroportin, which is the only known transmembrane protein that exports elemental iron from mammalian cells and is essential for iron homeostasis. Mutations in SLC40A1 are associated with iron-overload disorders. In addition to ferroportin diseases, SLC40A1 expression is downregulated in various cancer types. Despite the clinical significance of the SLC40A1 transporter, only a few studies have investigated genetic variants in SLC40A1. The present study was performed to identify genetic variations in the SLC40A1 promoter and functionally characterize each variant using in vitro assays. We investigated four haplotypes and five variants in the SLC40A1 promoter. We observed that haplotype 3 (H3) had significantly lower promoter activity than H1, whereas the activity of H4 was significantly higher than that of H1. Luciferase activity of H2 was comparable to that of H1. In addition, four variants of SLC40A1, c.-1355G>C, c.-662C>T, c.-98G>C, and c.-8C>G, showed significantly increased luciferase activity compared to the wild type (WT), whereas c.-750G>A showed significantly decreased luciferase activity compared to the WT. Three transcription factors, cAMP response element-binding protein-1 (CREB-1), chicken ovalbumin upstream promoter transcription factor 1, and hepatic leukemia factor (HLF), were predicted to bind to the promoter regions of SLC40A1 near c.-662C>T, c.-98G>C, and c.-8C>G, respectively. Among these, CREB1 and HLF bound more strongly to the variant sequences than to the WT and functioned as activators of SLC40A1 transcription. Collectively, our findings indicate that the two SLC40A1 promoter haplotypes affect SLC40A1 transcription, which is regulated by CREB-1 and HLF.

• 대한임상검사과학회지
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• 제49권1호
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• pp.40-47
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• 2017

난포 내 난자를 둘러싸고 있는 과립세포는 난자를 위한 성장상태 및 난포의 발달에 중요하다. Solute carrier family 유전자는 스테로이드 호르몬, 다양한 약물, 몇몇 다른 기질을 유입시킨다. 연구에서 획득한 서로 다르게 발현하는 유전자들 (DEGs) 중 일부를 in situ hybridization을 통해 분석하였다. 분석한 결과 SLC23A3과 SLC39A10이 난소에서 높게 발현하였다. SLC39A10 유전자는 원시난포에서 높게 발현하였고, SLC23A3은 일차, 이차 난포에서 높게 발현하였다. 특히 성장하는 난포의 과립막 세포에서 발현하였다. SLC23A3과 SLC39A10은 원시난포와 일차난포에서 다르게 발현하는 것은 각 난포의 분리를 통해 좀 더 확인해야 할 것이다. 본 연구에서는 유전자 발현 정보를 통해 원시난포의 개시와 성장을 위한 전환에 관여하는 기전을 이해하는데 기초정보와 난포발달 촉진을 위한 난소기능부전의 기전을 규명하는데 정보를 제공할 것으로 기대된다.

• Molecules and Cells
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• 제40권10호
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• pp.761-772
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• 2017

Glioblastoma is the most frequent and most aggressive brain tumor in adults. Solute carrier family 8 member 2 (SLC8A2) is only expressed in normal brain, but not present in other human normal tissues or in gliomas. Therefore, we hypothesized that SLC8A2 might be a glioma tumor suppressor gene and detected the role of SLC8A2 in glioblastoma and explored the underlying molecular mechanism. The glioblastoma U87MG cells stably transfected with the lentivirus plasmid containg SLC8A2 (U87MG-SLC8A2) and negative control (U87MG-NC) were constructed. In the present study, we found that the tumorigenicity of U87MG in nude mice was totally inhibited by SLC8A2. Overexpression of SLC8A2 had no effect on cell proliferation or cell cycle, but impaired the invasion and migration of U87MG cells, most likely through inactivating the extracellular signal-related kinases (ERK)1/2 signaling pathway, inhibiting the nuclear translocation and DNA binding activity of nuclear factor kappa B ($NF-{\kappa}B$), reducing the level of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator (uPA)-its receptor (uPAR) system (ERK1/2-$NF-{\kappa}B$-MMPs/uPA-uPAR), and altering the protein levels of epithelial to mesenchymal transitions (EMT)-associated proteins E-cardherin, vimentin and Snail. In addition, SLC8A2 inhibited the angiogenesis of U87MG cells, probably through combined inhibition of endothelium-dependent and endothelium-nondependent angiogenesis (vascular mimicry pattern). Totally, SLC8A2 serves as a tumor suppressor gene and inhibits invasion, angiogenesis and growth of glioblastoma.

• 대한의생명과학회지
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• 제18권4호
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• pp.377-383
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• 2012

Recent genome-wide association studies (GWAS) have identified a number of common variants associated with blood pressure homeostasis and hypertension in population. In the previous study, single nucleotide polymorphisms (SNPs) in the SLC4A4 gene have been reported to be associated with hypertension in Han Chinese population. We aimed to confirm whether the genetic variation of SLC4A4 gene influence the susceptibility to blood pressure and hypertension in Korean population. We genotyped variants in or near SLC4A4 in a population-based cohort including 7,551 unrelated Korean from Ansan and Ansung. Here, we performed association analysis to elucidate the possible relations of genetic polymorphisms in SLC4A4 gene with blood pressure traits. By examining genotype data of a total of 7,551 subjects in the Korean Association REsource (KARE) study, we discovered the SLC4A4 gene polymorphisms are associated with blood pressure and hypertension. The common and highest significant polymorphism was rs6846301 (${\beta}$=0.839, additive P=0.032) with systolic blood pressure (SBP), rs6846301 (${\beta}$=0.588, additive P=0.027) with diastolic blood pressure (DBP), and rs6846301 (OR=1.23, CI: 1.09~1.40, additive $P=1.2{\times}10^{-3}$) with hypertension. Furthermore, the SNP rs6846301 was consistently associated with both blood pressure and hypertension. Consequently, we found statistically significant SNPs in SLC4A4 gene that are associated with both blood pressure and hypertension traits. In addition, these results suggest that the individuals with the minor alleles of the SNP in the SLC4A4 gene may be more susceptible to the development of hypertension in the Korean population.

• Journal of Nutrition and Health
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• 제50권1호
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• pp.32-40
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• 2017

소아기의 과체중 혹은 비만은 성인기의 만성질환의 onset 위험을 증가시키는 대사이상을 야기하므로 관련된 obesogenic 환경 (나트륨 섭취 등)을 제어할 필요가 있다. 본 연구에서는 소아기의 과도한 소금섭취가 신장의 재흡수 기능을 조절하는 SLC12A3기능장애로 이어져 고혈압 및 비만을 야기하는지를 확인하고자 하였다. 서울 구로구에 소재한 8~9세 초등학생 752명 (남학생: 379명 여학생: 373명)을 대상으로 BMI가 85 percentiles이상을 비만군으로, 이하를 정상군으로 분류하였다. SLC12A3 rs11643718 유전자형은 GG (wild)와 GA + AA로 분류하여 신체계측, 혈액검사, 식이조사 등을 비교분석하였다 대상자의 남아가 여아보다, 비만군이 정상군보다 신체지수, 혈액지수, 식사섭취량이 여아보다 높았다. 남녀 모두 비만군에서 높은 TG와 낮은 HDLc를 보여주었지만 비만한 남아는 혈압에, 비만한 여아는 인슐린저항성에 더 민감한 반응을 보였다. 비록 남녀차이는 있지만 비만군 및 정상군 모두에서 SLC12A3의 GA + AA형이 GG형보다 혈압과 체중이 높았다. GG 유전자형을 가지고 있는 소아는 혈중 LDLc, FBS, insulin등이 높거나 식이 콜레스테롤섭취가 증가할수록 비만이 될 위험도가 증가하였고 엽산의 섭취가 증가할수록 비만위험도는 감소하였다. 반면, GA + AA 유전자형을 가지고 있는 소아는 고나트륨 (> 4,000 mg/day)섭취시 비만위험도 (odd ratio)가 15.57배 증가하였고 남아 (22.84배)에서 더욱 위험도가 높았다. HDLc의 경우는 유전자형에 관계없이 증가할수록 비만위험도가 감소하였다. 결론적으로 SLC12A3 (rs11643718) 유전자의 A allele를 가진 형이 나트륨에 특이적으로 반응하여 과체중위험을 증가시키는 것으로 생각된다.

• Journal of Nutrition and Health
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• 제54권5호
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• pp.435-447
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• 2021

Purpose: Body adiposity is negatively correlated with hepatic iron status, and Korean pine nut oil (PNO) has been reported to reduce adiposity. Therefore, we aimed to study the effects of PNO on adiposity, hepatic mineral status, and the expression of genes and proteins involved in iron absorption. Methods: Five-week-old male C57BL/6 mice were fed a control diet containing 10% kcal from PNO (PC) or soybean oil (SBO; SC), or a high-fat diet (HFD) containing 35% kcal from lard and 10% kcal from PNO (PHFD) or SBO (SHFD). Hepatic iron, copper, and zinc content; and expression of genes and proteins related to iron absorption were measured. Results: HFD-fed mice had a higher white fat mass (2-fold; p < 0.001), lower hepatic iron content (25% lower; p < 0.001), and lower hepatic Hamp (p = 0.028) and duodenal Dcytb mRNA levels (p = 0.037) compared to the control diet-fed mice. Hepatic iron status was negatively correlated with body weight (r = -0.607, p < 0.001) and white fat mass (r = -0.745, p < 0.001). Although the PHFD group gained less body weight (18% less; p < 0.05) and white fat mass (18% less; p < 0.05) than the SHFD group, the hepatic iron status impaired by the HFD feeding did not improve. The expression of hepatic and duodenal ferroportin protein was not affected by the fat amount or the oil type. PNO-fed mice had significantly lower Slc11a2 (p = 0.022) and Slc40a1 expression (p = 0.027) compared to SBO-fed mice. However, the PC group had a higher Heph expression than the SC group (p < 0.05). The hepatic copper and zinc content did not differ between the four diet groups, but hepatic copper content adjusted by body weight was significantly lower in the HFD-fed mice compared to the control diet-fed mice. Conclusion: HFD-induced obesity decreased hepatic iron storage by affecting the regulation of genes related to iron absorption; however, the 18% less white fat mass in the PHFD group was not enough to improve the iron status compared to the SHFD group. The hepatic copper and zinc status was not altered by the fat amount or the oil type.

• 운동영양학회지
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• 제23권4호
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• pp.26-31
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• 2019

[Purpose] Numerous epidemiological studies have shown that it is possible to prescribe exercise for neurodegenerative disease, such as Alzheimer's disease and Parkinson's disease. However, despite the availability of diverse scientific knowledge, the effects of exercise in this regard are still unclear. Therefore, this study attempted to investigate a substance, such as black chokeberry (Aronia melanocapa L.) that could improve the ability of the treatment and enhance the benefits of exercising in neurodegenerative diseases. [Methods] The cell viability was tested with 2,3-bis[2-methyloxy-4-nitro-5-sulfophenyl]-2H-tetrazolim-5-carboxanilide and the cells were stained with ethidium homodimer-1 solution. The mRNA expression levels were evaluated by microarray. The active compounds of black chokeberry ethanolic extract (BCE) were analyzed by gas chromatography. The chemical shift analysis in the brain was performed using magnetic resonance spectroscopy. [Results] BCE treatment decreased hydrogen peroxide-induced L6 cell death and beta amyloid induced primary neuronal cell death. Furthermore, BCE treatment significantly reduced the mRNA levels of the inflammatory factors, such as IL-1α, Cxcl13, IL36rn, Itgb2, Epha2, Slamf8, Itgb6, Kdm6b, Acvr1, Cd6, Adora3, Cd27, Gata3, Tnfrsf25, Cd40lg, Clec10a, and Slc11a1, in the primary neuronal cells. Next, we identified 16 active compounds from BCE, including D-mannitol. In vivo, BCE (administered orally at a dosage of 50 mg/kg) significantly regulated chemical shift in the brain. [Conclusion] Our findings suggest that BCE can serve as a candidate for neurodegenerative disease therapy owing to its cyto-protective and anti-inflammatory effects. Therefore, BCE treatment is expected to prevent damage to the muscles and neurons of the athletes who continue high intensity exercise. In future studies, it would be necessary to elucidate the effects of combined BCE intake and exercise.

• Molecules and Cells
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• 제28권6호
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• pp.529-536
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• 2009

Genome sequencing of the pig is being accelerated because of its importance as an evolutionary and biomedical model animal as well as a major livestock animal. However, information on expressed porcine genes is insufficient to allow annotation and use of the genomic information. A series of expressed sequence tags of 5' ends of five full-length enriched cDNA libraries (SUSFLECKs) were functionally characterized. SUSFLECKs were constructed from porcine abdominal fat, induced fat cells, loin muscle, liver, and pituitary gland, and were composed of non-normalized and normalized libraries. A total of 55,658 ESTs that were sequenced once from the 5′ ends of clones were produced and assembled into 17,684 unique sequences with 7,736 contigs and 9,948 singletons. In Gene Ontology analysis, two significant biological process leaf nodes were found: gluconeogenesis and translation elongation. In functional domain analysis based on the Pfam database, the beta transducin repeat domain of WD40 protein was the most frequently occurring domain. Twelve genes, including SLC25A6, EEF1G, EEF1A1, COX1, ACTA1, SLA, and ANXA2, were significantly more abundant in fat tissues than in loin muscle, liver, and pituitary gland in the SUSFLECKs. These characteristics of SUSFLECKs determined by EST analysis can provide important insight to discover the functional pathways in gene networks and to expand our understanding of energy metabolism in the pig.