• Journal of Ginseng Research
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• v.47 no.6
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• pp.743-754
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• 2023

Background: Myocardial fibrosis post-myocardial infarction (MI) can induce maladaptive cardiac remodeling as well as heart failure. Although 20(S)-ginsenoside Rg3 (Rg3) has been applied to cardiovascular diseases, its efficacy and specific molecular mechanism in myocardial fibrosis are largely unknown. Herein, we aimed to explore whether TGFBR1 signaling was involved in Rg3's anti-fibrotic effect post-MI. Methods: Left anterior descending (LAD) coronary artery ligation-induced MI mice and TGF-β1-stimulated primary cardiac fibroblasts (CFs) were adopted. Echocardiography, hematoxlin-eosin and Masson staining, Western-blot and immunohistochemistry, CCK8 and Edu were used to study the effects of Rg3 on myocardial fibrosis and TGFBR1 signaling. The combination mechanism of Rg3 and TGFBR1 was explored by surface plasmon resonance imaging (SPRi). Moreover, myocardial Tgfbr1-deficient mice and TGFBR1 adenovirus were adopted to confirm the pharmacological mechanism of Rg3. Results: In vivo experiments, Rg3 ameliorated myocardial fibrosis and hypertrophy and enhanced cardiac function. Rg3-TGFBR1 had the 1.78×10^-7 M equilibrium dissociation constant based on SPRi analysis, and Rg3 inhibited the activation of TGFBR1/Smads signaling dose-dependently. Cardiac-specific Tgfbr1 knockdown abolished Rg3's protection against myocardial fibrosis post-MI. In addition, Rg3 downregulated the TGF-β1-mediated CFs growth together with collagen production in vitro through TGFBR1 signaling. Moreover, TGFBR1 adenovirus partially blocked the inhibitory effect of Rg3. Conclusion: Rg3 improves myocardial fibrosis and cardiac function through suppressing CFs proliferation along with collagen deposition by inactivation of TGFBR1 pathway.

• Clinical and Experimental Pediatrics
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• v.54 no.6
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• pp.272-275
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• 2011

A recently recognized connective tissue disorder, Loeys-Dietz syndrome (LDS) is a genetic aortic aneurysm syndrome caused by mutations in the transforming growth factor-receptor type I or II gene (TGFBR1 or TGFBR2). They have distinctive phenotypic abnormalities including widely spaced eyes (hypertelorism), bifid uvula or cleft palate, and arterial tortuosity with aortic aneurysm or dissection throughout the arterial tree. LDS is characterized by aggressive and rapid progression of aortic aneurysm. Therefore, the patients with distinct phenotype, marked aortic dilatation and aneurysm at early age should be suspected to be affected by LDS and rapid TGFBR gene analysis should be done. We report one child diagnosed as LDS due to typical phenotypes and two novel missense mutations of the TGFBR2 gene (c.1526G>T and c.1528A>T).

• Clinical and Experimental Pediatrics
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• v.55 no.1
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• pp.18-23
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• 2012

Purpose: Transforming growth factor beta receptor 2 ($TGFBR2$) is a tumor suppressor gene that plays a role in the differentiation of striated cells and remodeling of coronary arteries. Single nucleotide polymorphisms (SNPs) of this gene are associated with Marfan syndrome and sudden death in patients with coronary artery disease. Cardiovascular remodeling and T cell activation of $TGFBR2$ gene suggest that the $TGFBR2$ gene SNPs are related to the pathogenesis of Kawasaki disease (KD) and coronary artery lesion (CAL). Methods: The subjects were 105 patients with KD and 500 healthy adults as controls. Mean age of KD group was 32 months age and 26.6% of those had CAL. We selected $TGFBR2$ gene SNPs from serum and performed direct sequencing. Results: The sequences of the eleven SNPs in the $TGFBR2$ gene were compared between the KD group and controls. Three SNPs (rs1495592, rs6550004, rs795430) were associated with development of KD ($P$=0.019, $P$=0.026, $P$=0.016, respectively). One SNP (rs1495592) was associated with CAL in KD group ($P$=0.022). Conclusion: Eleven SNPs in $TGFBR2$ gene were identified at that time the genome wide association. But, with the change of the data base, only six SNPs remained associated with the $TGFBR2$ gene. One of the six SNPs (rs6550004) was associated with development of KD. One SNP associated with CAL (rs1495592) was disassociated from the $TGFBR2$ gene. The other five SNPs were not functionally identified, but these SNPs are notable because the data base is changing. Further studies involving larger group of patients with KD are needed.

• Journal of Chest Surgery
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• v.52 no.5
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• pp.376-379
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• 2019

Concomitant Loeys-Dietz syndrome (LDS) and hematologic malignancies are exceptionally rare. This is the first report of a patient operated on for aortic root dilation who had been previously diagnosed with LDS and B-cell-lymphoma. After completion of chemotherapy and complete remission, an elective valve-sparing aortic root replacement (using the David-V method) was performed. Due to the positive family history, preoperative genetic counseling was conducted, and revealed LDS with a TGFBR1 (transforming growth factor beta receptor type I) mutation in 6 probands of the family, albeit in 1 of them posthumously. This missense mutation has been previously described in relation to aortic dissection, but a causative relationship to malignancy has so far neither been proposed nor proven.

• Archives of Plastic Surgery
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• v.49 no.1
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• pp.115-120
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• 2022

Background In addition to vascular endothelial cells, vascular smooth muscle cells (VSMCs) are subject to continuous shear stress because of blood circulation. The angiogenic properties of VSMCs in extracranial arteriovenous malformations (AVMs) may exceed those of normal blood vessels if the body responds more sensitively to mechanical stimuli. This study was performed to investigate the hypothesis that rapid angiogenesis may be achieved by mechanical shear stress. Methods VSMCs were obtained from six patients who had AVMs and six normal controls. The target genes were set to angiopoietin-2 (AGP2), aquaporin-1 (AQP1), and transforming growth factor-beta receptor 1 (TGFBR1). Reverse-transcriptase polymerase chain reaction (RT-PCR) and real-time PCR were implemented to identify the expression levels for target genes. Immunofluorescence was also conducted. Results Under the shear stress condition, mean relative quantity values of AGP2, AQP1, and TGFBR1 in AVM tissues were 1.927±0.528, 1.291±0.031, and 2.284±1.461 when compared with neutral conditions. The expression levels of all three genes in AVMs were higher than those in normal tissue except for AQP1 under shear stress conditions. Immunofluorescence also revealed increased staining of shear stress-induced genes in the normal tissue and in AVM tissue. Conclusions Shear stress made the VSMCs of AVMs more sensitive. Although the pathogenesis of AVMs remains unclear, our study showed that biomechanical stimulation imposed by shear stress may aggravate angiogenesis in AVMs.

• Korean Journal of Ichthyology
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• v.23 no.1
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• pp.21-29
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• 2011

Expression analysis of development-related genes was conducted using differential screening of 6-month-old [18M(-), 6M-18M] specific and 18-month-old [6M(-), 18M-6M] specific subtracted cDNA libraries constructed by subtractive hybridization using skeletal muscle of 6- and 18-month-old dark-banded rockfish Sebastes inermis. A total 202 cDNA clones displaying different expression levels in each stage were obtained; among them, 32 clones showing up-regulation were finally selected for further expression analysis. We sequenced the clones and analyzed individual sequences. Genes expressed specifically in 6-month-old skeletal muscle were identified as myosin, adenylate kinase, calsequestrin, dystrobrevin beta, and diphosphate kinase-Z1. Genes showing strong expression in 18-month-old rockfish were identified as desmin, TGFBR2 (transforming growth factor-beta receptor), muscle-type creatine kinase, and cathepsin D. Expression of these genes was checked further in 6-18-30-42 month-old dark-banded rock fish. Rapid reduction of expression was observed in dystrobrevin beta and diphosphate kinase. However, expression of creatine kinase (muscle type) and cathepsin D increased as dark-banded rockfish grew, and remained even after 18 months. The results reported here demonstrate that genes related to muscles contract are expressed at an early stage of development, and genes controlling energy in muscles are predominantly expressed at a late developmental stage.

• Journal of Genetic Medicine
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• v.10 no.1
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• pp.47-51
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• 2013

Loeys-Dietz syndrome (LDS) is an autosomal dominant disorder caused by heterozygous mutations in the genes encoding transforming growth factor-${\beta}$ receptor type 1 or 2. It is typically characterized by a triad of hypertelorism, cleft palate or bifid uvula, and arterial tortuosity with aneurysm or dissection. Characteristic vascular abnormalities such as tortuosity, aneurysms, dissections, and stenosis are the most severe complications of LDS and can occur in the neurovascular system. We report a 5-year-old boy who presented with headaches and neurovascular abnormalities and was diagnosed with LDS with a novel mutation of the TGFBR1 gene. It is the first Korean report of neurovascular abnormalities in LDS.

• Journal of Interdisciplinary Genomics
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• v.4 no.2
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• pp.31-34
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• 2022

Background: Arteriovenous malformations (AVMs) are rare diseases comprising abnormally dilated arteries and veins with an absence of a capillary network. Since these diseases are intractable after diagnosis, various treatment strategies have been examined, with continuous efforts to identify target genes. Here, we report relevant new target genes selected via gene microarray. Methods: Endothelial cells were isolated from samples collected from three patients with AVM and three healthy individuals, followed by microarray analysis. Additionally, quantitative PCR was performed to select genes highly relevant to AVM. Results: In the vascular endothelial cells derived from the tissues of patients with AVM, the expression of ANGPT1, ANGPT2, DLL4, IL6, NRG1, TGFBR1, and VEGFA was typically higher compared to those derived from normal tissues. Conclusion: Seven candidate genes were selected to analyze the pathophysiological mechanism of AVM. These results may aid in future directions of diagnosis and treatment.

• Genomics & Informatics
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• v.7 no.2
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• pp.85-96
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• 2009

The differentiation of neural precursor cells (NPCs) into neurons and astrocytes is a process that is tightly controlled by complicated and ill-defined gene networks. To extend our knowledge to gene networks, we performed a temporal analysis of gene expression during the differentiation (2, 4, and 8 days) of spinal cord-derived NPCs using oligonucleotide microarray technology. Out of 32,996 genes analyzed, 1878 exhibited significant changes in expression level (fold change>2, p<0.05) at least once throughout the differentiation process. These 1878 genes were classified into 12 groups by k-means clustering, based on their expression patterns. K-means clustering analysis revealed that the genes involved in astrogenesis were categorized into the clusters containing constantly upregulated genes, whereas the genes involved in neurogenesis were grouped to the cluster showing a sudden decrease in gene expression on Day 8. Functional analysis of the differentially expressed genes indicated the enrichment of genes for Pax6- NeuroD signaling.TGFb-SMAD and BMP-SMAD.which suggest the implication of these genes in the differentiation of NPCs and, in particular, key roles for Nova1 and TGFBR1 in the neurogenesis/astrogenesis of mouse spinal cord.

• Molecular & Cellular Toxicology
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• v.2 no.4
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• pp.266-272
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• 2006

Carpal tunnel syndrome (CTS) is one of the most common disorders by under pressure of the median nerve at the wrist in these days. However, pathological mechanism of CTS is unknown. We carried out this study to identify the changes of gene expression and to evaluate possible mechanism in CTS. 120 CTS patients and 30 control patients were included in this study. Patients with a history of diabetes, hypertension, thyroid diseases, and arthritis were excluded. CTS patients were divided to three experimental groups-Mild, Moderate, and Severe group-according to elecrodiagnosis. Radioactive cDNA microarrays (Nylon membrane including 1,152 genes) were used to examine the difference of gene expression profile in CTS. We identified up-regulated genes by more than 2.0 value of z-ratio, and down-regulated genes by less than-2.0 value of z-ratio. 20 genes such as the ITGAL, ITGAM, PECAM1, VIL2, TGFBR2, RAB7, RNF5 and NFKB1 were up-regulated, and 28 genes such as PRG5, CASP8, CDH1, IGFBP5, CBX3, HREV107, PIN, and WINT2 were down-regulated. These genes were related with TGF beta signaling pathway, NF-Kb signaling pathway, antiapoptotic pathway and T cell receptor signaling pathway. However, there were no differences in gene expression profiles according to severities of symptoms. We suggest that CTS could be related with proinflammatory mechanism and antiapoptotic mechanism.