• Title/Summary/Keyword: CTGF

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Anti-tumorigenic Effects of Angelica gigase Nakai Extract on MBA-MB-231 through Regulating Lats1/2 Activation (유방암세포에서 LATS1/2 활성에 의한 당귀 추출물의 항암효과)

  • Kim, Cho-Long;Kim, Nambin;Jeong, Han-Sol;Shin, Yu-Su;Mo, Jung-Soon
    • Journal of Physiology & Pathology in Korean Medicine
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    • v.34 no.4
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    • pp.177-183
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    • 2020
  • The Hippo-YAP signaling pathway is critical for cell proliferation, survival, and self-renewal in both Drosophila and mammals. Disorder of Hippo-YAP pathway leads to tumor development, progression and poor prognosis in various cancers. YAP/TAZ are the key downstream effectors of the Hippo pathway and they can be inhibited through LATS1/2, core kinases in the Hippo pathway, mediated phosphorylation. In this study, we investigated the effect of Angelica gigas Nakai extract (AGNE) on Hippo-YAP/TAZ pathway. First, ANGE induced YAP/TAZ phosphorylation and dissociation of the YAP/TAZ-TEAD transcription complex. By qRT-PCR, we found that ANGE inhibits the expression of YAP/TAZ-TEAD target gene, CTGF and CYR61. In addition, the transcriptional activity of YAP/TAZ was not suppressed significantly in LATS1/2 double-knockout (DKO) cells by ANGE compared to LATS1/2 wild-type (WT) cells, which means AGNE inhibits YAP/TAZ signaling through direct action on LATS1/2. Further, it was confirmed that AGNE-induced activation of LATS1/2 inhibited the migration potential of the vector-expressing cells by suppressing YAP/TAZ activity. The reduced migration potential was restored in active YAP-TEAD expressing cells. Taken together, the results of this study indicate that ANGE downregulates YAP/TAZ signaling in cells through the activation of LATS1/2.

Extracellular Vesicles Derived from Adipose Stem Cells Alleviate Systemic Sclerosis by Inhibiting TGF-β Pathway

  • Eunae Kim;Hark Kyun Kim;Jae Hoon Sul;Jeongmi Lee;Seung Hyun Baek;Yoonsuk Cho;Jihoon Han;Junsik Kim;Sunyoung Park;Jae Hyung Park;Yong Woo Cho;Dong-Gyu Jo
    • Biomolecules & Therapeutics
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    • v.32 no.4
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    • pp.432-441
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    • 2024
  • Systemic sclerosis is an autoimmune disease characterized by inflammatory reactions and fibrosis. Myofibroblasts are considered therapeutic targets for preventing and reversing the pathogenesis of fibrosis in systemic sclerosis. Although the mechanisms that differentiate into myofibroblasts are diverse, transforming growth factor β (TGF-β) is known to be a key mediator of fibrosis in systemic sclerosis. This study investigated the effects of extracellular vesicles derived from human adipose stem cells (ASC-EVs) in an in vivo systemic sclerosis model and in vitro TGF-β1-induced dermal fibroblasts. The therapeutic effects of ASC-EVs on the in vivo systemic sclerosis model were evaluated based on dermal thickness and the number of α-smooth muscle actin (α-SMA)-expressing cells using hematoxylin and eosin staining and immunohistochemistry. Administration of ASC-EVs decreased both the dermal thickness and α-SMA expressing cell number as well as the mRNA levels of fibrotic genes, such as Acta2, Ccn2, Col1a1 and Comp. Additionally, we discovered that ASC-EVs can decrease the expression of α-SMA and CTGF and suppress the TGF-β pathway by inhibiting the activation of SMAD2 in dermal fibroblasts induced by TGF-β1. Finally, TGF-β1-induced dermal fibroblasts underwent selective death through ASC-EVs treatment. These results indicate that ASC-EVs could provide a therapeutic approach for preventing and reversing systemic sclerosis.

The Preventive Effect of Dexrazoxane and Pentoxifylline on Adriamycin Induced Cardiomyopathy (Dexrazoxane과 Pentoxifylline의 Adriamycin 유발성심근증에 대한 예방 효과)

  • Zhu, Ling;Bae, Eun-Jung;Ha, Il-Soo;Seo, Jung-Wook;Noh, Chung-Il;Choi, Jung-Yun;Yun, Yong-Soo
    • Clinical and Experimental Pediatrics
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    • v.48 no.12
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    • pp.1378-1384
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    • 2005
  • Purpose : We hypothesized dexrazoxane(DXR) and pentoxifylline(PTX) may prevent myocardial damage in adriamycin(ADR)-induced cardiomyopathic rat model. We also investigated their effects on the myocardial apoptosis and fibrosis in ADR induced cardiomyopathy. Methods : The six-week old female Spregue-Dawley rats were divided into control group(CNT, n=4), ADR group(n=6), ADR+DXR group(DXR, n=5), ADR+PTX group(PTX, n=6), ADR+DXR+PTX group(DXPT, n=5). ADR(5 mg/week, twice) was administrated intravenously to rats except CNT group to induce cardiomyopathy. The PTX(50 mg/kg/day) was administered daily from day-0 to Day-21. The DXR(100 mg/kg) was administered 30 minutes before each ADR injection. On day 21, the rats were sacrificed and the degree of histopathologic changes of hypercontraction band necrosis, cytoplasmic vacuolar change and fibrosis were scored. Immunohistochemical staining for Bcl-2 expression and RT-PCR for $TNF-{\alpha}$ and CTGF were performed. Results : Histopathological scores of myocardial damage were significantly higher in ADR rats than CNT rats(P<0.05), and significantly lower in DXPT rats than ADR rats(P<0.01). Myocardial fibrosis was prevented in both PTX rats and DXPT rats. The expression of Bcl-2 was weaker in ADR rats than that in CNT rats(P<0.05), and stronger in both DXR and DXPT rats than that in ADR rats (P<0.05). $TNF-{\alpha}$ concentration of ADR rats was not different from that of treated groups. Conclusion : DXR prevented myocyte apoptosis with increased Bcl-2 expression, and PTX prevented myocardial fibrosis in ADR induced cardiomyopathic rats. The combination therapy of DXR and PTX showed prevention of cardiomyopathy in ADR induced cardiomyopathy rat model.

Wiryeongtang attenuates diabetic renal dysfunction in human renal mesangial cells (위령탕(胃苓湯) 추출물의 사람 유래 신장 메산지움 세포에서의 당뇨병성 신장 손상 개선 효과)

  • Yoon, Jung Joo;Han, Byung Hyuk;Choi, Eun Sik;NamGung, Seung;Jeong, Da Hye;Kim, Hye Yoom;Ahn, You Mee;Lee, Yun Jung;Kang, Dae Gill;Lee, Ho Sub
    • 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.

Myeloid-specific SIRT1 Deletion Aggravates Hepatic Inflammation and Steatosis in High-fat Diet-fed Mice

  • Kim, Kyung Eun;Kim, Hwajin;Heo, Rok Won;Shi, Hyun Joo;Yi, Chin-ok;Lee, Dong Hoon;Kim, Hyun Joon;Kang, Sang Soo;Cho, Gyeong Jae;Choi, Wan Sung;Roh, Gu Seob
    • The Korean Journal of Physiology and Pharmacology
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    • v.19 no.5
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    • pp.451-460
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    • 2015
  • Sirtuin 1 (SIRT1) is a mammalian $NAD^+$-dependent protein deacetylase that regulates cellular metabolism and inflammatory response. The organ-specific deletion of SIRT1 induces local inflammation and insulin resistance in dietary and genetic obesity. Macrophage-mediated inflammation contributes to insulin resistance and metabolic syndrome, however, the macrophage-specific SIRT1 function in the context of obesity is largely unknown. C57/BL6 wild type (WT) or myeloid-specific SIRT1 knockout (KO) mice were fed a high-fat diet (HFD) or normal diet (ND) for 12 weeks. Metabolic parameters and markers of hepatic steatosis and inflammation in liver were compared in WT and KO mice. SIRT1 deletion enhanced HFD-induced changes on body and liver weight gain, and increased glucose and insulin resistance. In liver, SIRT1 deletion increased the acetylation, and enhanced HFD-induced nuclear translocation of nuclear factor kappa B (NF-${\kappa}B$), hepatic inflammation and macrophage infiltration. HFD-fed KO mice showed severe hepatic steatosis by activating lipogenic pathway through sterol regulatory element-binding protein 1 (SREBP-1), and hepatic fibrogenesis, as indicated by induction of connective tissue growth factor (CTGF), alpha-smooth muscle actin (${\alpha}$-SMA), and collagen secretion. Myeloid-specific deletion of SIRT1 stimulates obesity-induced inflammation and increases the risk of hepatic fibrosis. Targeted induction of macrophage SIRT1 may be a good therapy for alleviating inflammation-associated metabolic syndrome.

Characterization of Genes Related to the Cell Size Growth and CCN Family According to the Early Folliculogenesis in the Mouse (쥐의 초기 난포 발달에 관여하는 Cell Size Growth 및 CCN Family 유전자에 관한 연구)

  • Kim, Kyeoung-Hwa;Park, Chang-Eun;Yoon, Se-Jin;Lee, Kyung-Ah
    • Clinical and Experimental Reproductive Medicine
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    • v.32 no.3
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    • pp.269-277
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    • 2005
  • Objectives: Previously, we sought to compile a list of genes expressed during early folliculogenesis by using cDNA microarray to investigate follicular gene expression and changes during primordialprimary follicle transition and development of secondary follicles (Yoon et al., 2005). Among those genes, a group of genes related to the cell size growth was characterized during the ovarian development in the present study. Methods: We determined ovarian expression pattern of six genes related to the cell size growth (cyr61, emp1, fhl1, socs2, wig1 and wisp1) and extended into CCN family (${\underline{c}}onnective$ tissue growth factor/${\underline{c}}ysteine$-rich 61/${\underline{n}}ephroblastoma$-overexpressed), ctgf, nov, wisp2, wisp3, including cyr61 and wisp1 genes. Expression of mRNA and protein according to the ovarian developmental stage was evaluated by in situ hybridization, and/or semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), and immunohistochemistry, respectively. Results: Among 6 genes related to the cell size growth, cyr61 and wisp1 mRNA was detected only in oocytes in the postnatal day5 mouse ovaries. cyr61 mRNA expression was limited to the nucleolus of oocytes, while wisp1 was expressed in the cytoplasm and nucleolus of oocytes, except nucleus. cyr61 mRNA expression, however, was found in granulosa cells from secondary follicles. The rest 4 genes in the cell size growth group were detected in oocytes, granulosa and theca cells. Cyr61 and Wisp1 proteins were expressed in the oocyte cytoplasm from primordial follicle stage. Especially, Cyr61 protein was detected in pre-granulosa cells, Wisp1 protein was not. By using RT-PCR, we evaluated and decided that Cyr61 protein is produced by their own mRNA in pre-granulosa cells that was not detected by in situ hybridization. cyr61 and wisp1 genes are happen to be the CCN family members. The other members of CCN family were also studied, but their expression was detected in oocytes, granulose and theca cells. Conclusions: We firstly characterized the ovarian expression of genes related to the cell size growth and CCN family according to the early folliculogenesis. Cyr61 protein expression in the pre-granulosa cells is profound in meaning. Further functional analysis for cyr61 in early folliculogenesis is under investigation.

GENE EXPRESSION PATTERNS INDUCED BY $TAXOL^{(R)}$ AND CYCLOSPORIN A IN ORAL SQUAMOUS CELL CARCINOMA CELL LINE USING CDNA MICROARRAY (cDNA Microarray를 이용한 구강편평세포암종 세포주에서 $Taxol^{(R)}$과 Cyclosporin A로 유도된 유전자 발현양상)

  • Kim, Yong-Kwan;Lee, Jae-Hoon;Kim, Chul-Hwan
    • Maxillofacial Plastic and Reconstructive Surgery
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    • v.28 no.3
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    • pp.202-212
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    • 2006
  • It is well-known that paclitaxel($Taxol^{(R)}$), which is extracted from the pacific and English yew, has been used as a chemotherapeutic agent for ovarian carcinoma and advanced breast carcinoma and Cyclosporin A, which is highly lipophilic cyclic peptide and isolated from a fungus, has been also used as an useful immunosuppressive drug after transplantation and is associated with cellular apoptosis. Since 1953, in which James Watson, Rosalind Franklin and Francis Crick discovered the double helical structure of DNA, a few kinds of techniques for identifying gene expression have been developed. In postgenomic period, many of researchers have used the DNA microarray which is high throughput screening technique to screen large numbers of gene expression simultaneously. In this study, we searched and screened the gene expression in the oral squamous cell carcinoma cell lines treated with $Taxol^{(R)}$, cyclosporin or cyclosporin combined with $Taxol^{(R)}$ using cDNA microarray. The results were as following; 1. It was useful that the appropriate concentration of Cyclosporin A and $Taxol^{(R)}$ used in oral squamous cell carcinoma cell line was under 1${\mu}g/ml$ and 3${\mu}g/ml$. 2. In the experimental group in which $Taxol^{(R)}$ and $Taxol^{(R)}$ + Cyclosporin A were used, the cell growth was extremely decreased. 3. In the group in which Cyclosporin A was used, the MTT assay was rarely decreased which means the activity of succinyl dehydrogenase is remained in mitochondria but in the group in which the mixture of Cyclosporin A and $Taxol^{(R)}$ were used, the MTT assay was extremely decreased. 4. In the each group in which Cyclosporin A(3 ${\mu}g/ml$) and $Taxol^{(R)}$(1 ${\mu}g/ml$) were used, the cell arrest was appeared in $G_2/M$ phase and in the group in which $Taxol^{(R)}$(3 ${\mu}g/ml$) was used, the cell arrest was appeared in both S phase and $G_2/M$ phase. 5. In the oral squamous cell carcinoma cell line treated with $Taxol^{(R)}$, several genes including ANGPTL4, RALBP1 and TXNRD1, associated with apoptosis, SUI1, MAC30, RRAGA and CTGF, related with cell growth, HUS1 and DUSP5, related with cell cycle and proliferation, ATF4 and CEBPG, associated with transcription factor, BTG1 and VEGF, associated with angiogenesis, FDPS, FCER1G, GPA33 and EPHA4 associated with signal transduction and receptor activity and AKR1C2 and UGTA10 related with carcinogenesis were detected in increased levels. The genes that showed increaced expression in the oral squamous cell carcinoma cell line treated with Cyclosporin A were CYR61, SERPINB2, SSR3 and UPA3A which are known as genes associated with cell growth, carcinogenesis, receptor activity and transcription factor. The genes expressed in the HN22 cell line treated with cyclosporin combined with $taxol^{(R)}$ were ALCAM and GTSE1 associated with cancer invasiveness and cell cycle regulation.

THE ANTICANCER EFFECT OF PACLITAXEL($Taxol^{(R)}$) IN ORAL SQUAMOUS CELL CARCINOMA XENOGRAFT (이종 이식된 구강편평세포 암종에서 Paclitaxel ($Taxol^{(R)}$)의 항암 효과)

  • Kim, Ki-Hwan;Kim, Chul-Hwan;Han, Se-Jin;Lee, Jae-Hoon
    • Maxillofacial Plastic and Reconstructive Surgery
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    • v.28 no.2
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    • pp.95-110
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    • 2006
  • The treatment for oral and maxillofacial carcinoma with chemotherapeutic agents is evaluated by many effective methods to reduce the tumor mass and cancer cell proliferation. However these chemotherapy have many serious side effects, such as bone marrow suppression, renal toxicity, G-I troubles. Therefore a possible approach to develop a clinically applicable chemotherapeutic agent is to screen anticancer activity of Taxol which is known to have very little side effect and have been used to breast cancer and ovarian carcinoma. Taxol is a new anti-microtubular anti-cancer agent extracted from the bark of the Pacific yew, Taxus brevifolia. Paclitaxel(Taxol) acts by promoting tubulin polymerization and over stabilizing microtubules agianst depolymerization. Despite the constant improvements of methods of the cancer treatment especially chemotherapy, the rate of cancer metastasis and recurrent are not decreased. Thus the investigation of new drug which have very little side effect and a possible clinically application continues to be a high priority. Considering that the Taxol have shown very effective chemotherapeutic agent with relatively low toxicity in many solid tumors, it deserves to evaluate its efficacy in oral squamous cell carcinoma. In this study, to investigate the in-vivo and in-vitro anti-cancer efficacy of Taxol in oral squamous cell carcinoma and lastly, the potency of Paclitaxel in the clinical application for oral cancer was evaluated. In vivo study, after HN22 cell line were xenografted in nude mice, the growth of tumor mass was observed, 3 mg/Kg taxol was injected intraperitoneally into nude mice containing tumor mass. The methods of these study were measurement of total volume of tumor mass, histopathologic study, immunohistochemical study, drug resistance assay, growth curve, MTT assay, flow cytometry, cDNA microarray in vivo and in vitro. The results were obtained as following. 1. The visual inspection of the experimental group showed that the volume of the tumor mass was slightly decreased but no significant difference with control group. 2. Ki-67 index was decreased at weeks 4 in experimental group. 3. Microscopic view of the xenografted tumor mass showed well differentiated squamous cell carcinoma and after Taxol injection, some necrotic tissue was seen weeks 4. 4. The growth curve of the tumor cells were decreased after 1day Taxol treatment. 5. According to the MTT assay, HN22 cell line showed relative drug resistancy above $5\;{\mu}g/ml$ concentrations of Taxol. 6. In drug resistance assay, the decrease of cell counts was seen relatively according to concentration. 7. In Flow cytometry, G2M phase cell arrests were seen in low concentration of the Taxol, while S phase cell arrests were seen in high concentration of the Taxol. 8. Using cDNA microarray technique, variable gene expression of ANGPTL4, TXNRD1, FAS, RRAGA, CTGF, CYCLINEA, P19, DUSP5, CEBPG, BTG1 were detacted in the oral squamous cell carcinoma cell after taxol treatment. In this study paclitaxel is effective against oral squamous cell carcinoma cell lines in vitro, but week effect was observed in vivo. So we need continuous study about anticancer effect of taxol in vivo in oral squamous cell carcinoma.