• The Journal of Korean Medicine Ophthalmology and Otolaryngology and Dermatology
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• v.22 no.1
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• pp.11-32
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• 2009

Objective : This study was designed to investigate anti-cancer and whitening activities (LC). So it was investigated the effects of LC on proliferation rates of melanoma genetic profile by LC. Methods : The genetic profile for the effect of LC on human derived melanoma cell, SK-MEL-2, was measured using microarray technique, and the functional analysis on these genes were conducted. Total 441 genes were up-regulated and 830 genes down-regulated in cells treated with LC. Genes induced or suppressed by LC were all mainly concerned with basic signalling pathways, which are involved in cell growth, differentiation and migration. Especially, many genes, which are related in apoptosis and cell cycle arrest were up-regulated by treatment with LC, and genes related in cell cycle were down-regulated. Result : The network of total protein interactions were identified by using cytoscape program, and some key molecules, such as BCL2L1, SIN3A, SMAD2 and c-myc that can be used for elucidation of therapeutical mechanism of medicine in the future. Conclusion : These results suggest possibility of LC as addition drug and whitening cosmetics. In addition, it was also suggested that related mechanisms are involved in BCL2L1, SIN3A, SMAD2 and c-myc related signalling pathways.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.1
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• pp.41-44
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• 2015

Based on genome-wide association studies (GWAS) a linkage between several variants such as single nucleotide polymorphisms (SNPs) in intron 3 of SMAD7 (mothers against decapentaplegic homolog7) were, rs12953717, rs4464148 and rs4939827 has been noted for susceptibility to colorectal cancer (CRC). In this study we investigated the relationship of rs12953717 and rs4464148 with risk of CRC among 487 Iranian individuals based on a case-control study. Genotyping of SNPs was performed by PCR-RFLP and for confirming the outcomes, 10% of genotyping cases were sequenced with RFLP. Comparing the case and control group, we have found significant association between the rs4464148 SNP and lower risk of CRC. The AG genotype showed decreased risk with and odds ratio of 0.635 (adjusted OR=0.635, 95% CI: 0.417-0.967, p=0.034). There was no significant difference in the distribution of SMAD7 gene rs12953717 TT genotype between two groups of the population evaluated (adjusted OR=1.604, 95% CI: 0.978-2.633, p=0.061). On the other hand, rs12953717 T allele showed a statistically significant association with CRC risk (adjusted OR=1.339, 95% CI: 1.017-1.764, p=0.037). In conclusion, we found a significant association between CRC risk and the rs4464148 AG genotype. Furthermore, the rs12953717 T allele may act as a risk factor. This association may be caused by alternative splicing of pre mRNA. Although we observed a strong association with rs4464148 GG genotype in affected women, we did not detect the same association in CRC male patients.

• The Korea Journal of Herbology
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• v.31 no.5
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• pp.71-78
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• 2016

Objectives : Diabetic nephropathy is one of the most common chronic complications of diabetes and a leading cause of end-stage renal failure in the world. Mesangial cell proliferation is known as the major pathologic features such as glomerulosclerosis and renal fibrosis. Wiryeongtang (WRT) is a well-known traditional herbal formula as therapeutic agents for chronic edema and dysuresia of renal homeostasis. In the present study, we investigated whether WRT inhibits high glucose (HG)-induced renal dysfunction by TGF-β/Smads signal regulation in cultured mesangial cells.Methods : Inhibitory effect of WRT (10-50 ㎍/ml) on HG-stimulated mesangial cells proliferation and dysfunction were evaluated by [³H]-thymidine incorporation, Western blot, and RT-qPCR.Results : WRT significantly decreased HG-accelerated thymidine incorporation in human renal mesangial cell in a dose-dependent levels. WRT induced down-regulation of cyclins/CDKs and up-regulation of CDK inhibitor, p21waf1/cip1 and p27kip1 expression. In addition, HG enhanced expression of dysfunction biomarker such as collagen IV and CTGF, which was markedly attenuated by WRT. WRT decreased TGF-β1 and Smad-2/Smad-4 expression, whereas increased Smad-7 expression under HG. Furthermore, WRT inhibited HG-induced inflammatory factors level such as ICAM-1 and MCP-1 as well as NF-κB p65 nuclear translocation and intracellular ROS production.Conclusions : These results suggested that WRT may alleviate mesangial proliferation and inflammation possibly involved in renal fibrotic process, further diabetic nephropathy through disturbing TGF-β1/Smad signaling and NF-κB/ROS pathway. Thus, WRT might prove to be effective in the treatment of renal dysfunction leading to diabetic nephropathy.

• Molecules and Cells
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• v.41 no.12
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• pp.1061-1071
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• 2018

From Xenopus embryo studies, the BMP4/Smad1-targeted gene circuit is a key signaling pathway for specifying the cell fate between the ectoderm and neuro-ectoderm as well as the ventral and dorsal mesoderm. In this context, several BMP4/Smad1 target transcriptional factors have been identified as repressors of the neuro-ectoderm. However, none of these direct target transcription factors in this pathway, including GATA1b, Msx1 and Ventx1.1 have yet been proven as direct repressors of early neuro-ectodermal gene expression. In order to demonstrate that Ventx1.1 is a direct repressor of neuro-ectoderm genes, a genome-wide Xenopus ChIP-Seq of Ventx1.1 was performed. In this study, we demonstrated that Ventx1.1 bound to the Ventx1.1 response cis-acting element 1 and 2 (VRE1 and VRE2) on the promoter for zic3, which is a key early neuro-ectoderm gene, and this Ventx1.1 binding led to repression of zic3 transcription. Site-directed mutagenesis of VRE1 and VRE2 within zic3 promoter completely abolished the repression caused by Ventx1.1. In addition, we found both the positive and negative regulation of zic3 promoter activity by FoxD5b and Xcad2, respectively, and that these occur through the VREs and via modulation of Ventx1.1 levels. Taken together, the results demonstrate that the BMP4/Smad1 target gene, Ventx1.1, is a direct repressor of neuro-ectodermal gene zic3 during early Xenopus embryogenesis.

• CELLMED
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• v.8 no.3
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• pp.13.1-13.8
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• 2018

In the field of osteoporosis, there has been growing interest in anabolic agents that enhance bone formation. The purpose of this study was to examine the effects of NNMBS 246 osteoblastic differentiation with associated signaling pathways. NNMBS 246 markedly increased alkaline phosphatase (ALP) activity and calcium nodule formation. Stimulation with NNMBS 246 not only increased the differentiation markers (ALP, OPN, OCN) level and transcription markers (RUNX2, Osterix) mRNA expression but also upregulated the ECM molecules and OPG mRNA expression. Treatments of NNMBS 246 downregulated MMPs (MMP-1, MMP-2, MMP-9), but RANKL mRNA expression. Furthermore, NNMBS 246 activated osteoblastic differentiation markers and formed calcium nodules in human periodontal ligament cells (hPDLCs) and cementoblast cells. NNMBS 246 induced phosphorylation of MAPKs, Akt, nuclear p65 and IkB-${\alpha}$. BMP-2/Smad and ${\beta}$-catenin signaling pathways were activated by NNMBS 246. Sirtinol (SIRT1 inhibitor) inhibited NNMBS 246-induced osteoblastic differentiation markers mRNA expression. These results suggested that NNMBS 246 has the potential to enhance osteoblastogenesis probably through the activation of BMP/Smad and ${\beta}$-catenin signal pathways, and SIRT1 plays as critical mediator in bone anabolic effect of NNMBS 246.

• Reproductive and Developmental Biology
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• v.30 no.4
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• pp.271-277
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• 2006

Transforming growth $factor-{\beta}\;(TGF-{\beta})$ has been shown to have a positive effect on in vitro fertilization (IVF) and has been reported to stimulate meiosis at follicular level in variety of species. The study was designed to determine the expression patterns of $TGF-{\beta}1,\;TGF-{\beta}$ receptors type I, II and Smads gene in bovine oocytes and embryos. $TGF-{\beta}1$ and their receptors were observed in the unfertilized oocytes. $TGF-{\beta}1$ and type II receptor were not expressed at the blastocyst stage, however, only type I receptor was exclusively observed at the same stage. The blastocyst stage, in particular, showed high levels of mRNA expression patterns containing a $TGF-{\beta}1$ type I receptor. The mRNA expression pattern of Smad 2 at all stages of embryonic development was similar in all respect with $TGF-{\beta}1$ type I receptor. On the contrary, Smad 3 and 4 were expressed with high and low level mRNA at the blastocyst stage. In conclusion. it is suggested that $TGF-{\beta}1$ signaling may be regarded as an important entity during the preimplantation embryo development.

• IMMUNE NETWORK
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• v.9 no.6
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• pp.248-254
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• 2009

[ $TGF-{\beta}1$ ]is well known to induce Ig germ-line ${\alpha}$ ($GL{\alpha}$) transcription and subsequent IgA isotype class switching recombination (CSR). Homeodomain protein TG-interacting factor (TGIF) and E3-ubiquitin ligases TGIF interacting ubiquitin ligase 1 (Tiul1) are implicated in the negative regulation of $TGF-{\beta}$ signaling. In the present study, we investigated the roles of Tiul1 and TGIF in $TGF{\beta}1$-induced IgA CSR. We found that over-expression of Tiul1 decreased $TGF{\beta}1$-induced $GL{\alpha}$ promoter activity and strengthened the inhibitory effect of Smad7 on the promoter activity. Likewise, overexpression of TGIF also diminished $GL{\alpha}$ promoter activity and further strengthened the inhibitory effect of Tiul1, suggesting that Tiul1 and TGIF can down-regulate $TGF{\beta}1$-induced $GL{\alpha}$ expression. In parallel, overexpression of Tiul1 decreased the expression of endogenous IgA CSR-predicitive transcripts ($GLT_{\alpha},\;PST_{\alpha},\;and\;CT_{\alpha}$) and $TGF{\beta}1$-induced IgA secretion, but not $GLT_{\gamma3}$ and IgG3 secretion. Here, over-expressed TGIF further strengthened the inhibitory effect of Tiul1. These results suggest that Tiul1 and TGIF act as negatively regulators in $TGF{\beta}1$-induced IgA isotype expression.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9915-9919
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• 2014

Lamellarin D (LamD) is a marine alkaloid with a pronounced cytotoxicity against a large panel of cancer cells, affecting cell growth and inducing apoptosis. However, the molecular mechanisms of action of this compound are poorly understood. In this study, the anticancer efficacy of LamD was investigated in human leukemia K562 cells. The results showed suppressed cell proliferation and induction of G0/G1-phase arrest,while expression of CDK1, and activity of smad3 and smad5 were reduced, but that of p27, p53 and STGC3 was increased. LamD induced cell apoptosis through activation of caspases-8/-3, inhibition of survivin and Bcl-2, suggesting that this compound may also act through a caspase-independent pathway. Moreover, LamD inhibited the secretion of TGF-${\beta}$, IL-$1{\beta}$, IL-6, IL-8 and other inflammatory cytokines and the transcriptional activity of transcription factor NF-${\kappa}B$ in human leukemia K562 cells.Taken together, our results suggest that LamD-mediated inhibition of leukemia cell proliferation may be related to the induction of apoptosis and the regulation of cell cycle, tumor-related gene expression and cytokine expression, which may provide a new way of thinking for the treatment leukemia.

• Journal of Medicine and Life Science
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• v.16 no.3
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• pp.84-89
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• 2019

Docosahexaenoic acid (DHA), a principal of mackerel-derived fermented fish oil, increases the proliferation of dermal papilla cells (DPCs) via the upregulation of cell cycle-associated proteins such as cyclin D1 and cdc2 p34, and might promote hair-growth. However, the intracellular mechanisms that underlie the action of DHA in the proliferation of DPCs have not been investigated fully. In this study, we addressed the action mechanisms of DHA to trigger the activation of anagen in DPCs. DHA activated β-catenin signaling by the increased phosphorylation at serine 552 and serine 675 as well as the translocation and accumulation of activated β-catenin into the nucleus. In the other hand, DHA inhibited canonical TGF-β/Smad signaling by the decreased phosphorylation of Smad2/3. Taken together, the results indicate that DHA might stimulate anagen signaling via the activation of Wnt/β-catenin pathway, while the inactivation of canonical TGF-β signaling pathway in DPCs.

• Journal of Preventive Medicine and Public Health
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• v.45 no.4
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• pp.251-258
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• 2012

Objectives: The purpose of this paper was to elucidate the potential methylation levels of adjacent normal and cancer tissues by comparing them with normal colorectal tissues, and to describe the correlations between the methylation and clinical parameters in Korean colorectal cancer (CRC) patients. Methods: Hypermethylation profiles of nine genes (RASSF1, APC, $p16^{INK4a}$, Twist1, E-cadherin, TIMP3, Smad4, COX2, and ABCB1) were examined with 100 sets of cancer tissues and 14 normal colorectal tissues. We determined the hypermethylation at a given level by a percent of methylation ratio value of 10 using quantitative methylation real-time polymerase chain reaction. Results: Nine genes' hypermethylation levels in Korean CRC patient tissues were increased more higher than normal colorectal tissues. However, the amounts of $p16^{INK4a}$ and E-cadherin gene hypermethylation in normal and CRC tissues were not significantly different nor did TIMP3 gene hypermethylation in adjacent normal and cancer tissues differ significantly. The hypermethylation of TIMP3, Ecadherin, ABCB1, and COX2 genes among other genes were abundantly found in normal colorectal tissues. The hypermethylation of nine genes' methylation in cancer tissues was not significantly associated with any clinical parameters. In Cohen's kappa test, it was moderately observed that RASSF1 was related with E-cadherin, and Smad4 with ABCB1 and COX2. Conclusions: This study provides evidence for different hypermethylation patterns of cancer-associated genes in normal and CRC tissues, which may serve as useful information on CRC cancer progression.