• IMMUNE NETWORK
• /
• 제1권3호
• /
• pp.230-235
• /
• 2001

Background: Finding of the regulation of various gene expression by cytokine including $IFN-{\gamma}$ in hematopoietic stem cell will light up the understanding of pathogenesis of aplastic anemia in various aspects. To study on aplastic anemia, however, we have to circumvent the difficulty of directly obtaining bone marrow stem cells from the patient. Therefore, we tried to find out a cell can replace the bone marrow stem cells for study on cell signaling pathway and regulation of gene expression by $IFN-{\gamma}$. Materials and Methods: HL-60 cells, of 20 ng/mL of $IFN-{\gamma}$. Total RNA was isolated from the cells and RT-PCR of the indoleamine 2,3-dioxygenase (IDO), $IFN-{\gamma}$, TNF-${\alpha}$, $MIP-1{\alpha}$, and $TGF-{\beta}2$ was carried out for the estimation of the gene expression. Results: $IFN-{\gamma}$ induced IDO gene expression of mononuclear cells from umbilical cord blood showed similar pattern as compared to that of bone marrow. Whether $INF-{\gamma}$ was treated or not, $TNF-{\alpha}$ was expressed in both mononuclear cells from umbilical cord blood and bone marrow. However, HL-60 cells showed different expression patterns. HL-60 cells would express neither IDO nor $TNF-{\alpha}$ even under the culture with 20ng/mL of $IFN-{\gamma}$. Conclusion: Our results showed bone marrow can be replaced with mononuclear cells from umbilical cord blood in the study on the relation between aplastic anemia and $IFN-{\gamma}$ including $IFN-{\gamma}$ cell signaling pathway.

• Molecules and Cells
• /
• 제46권10호
• /
• pp.592-610
• /
• 2023

The Hippo kinase cascade functions as a central hub that relays input from the "outside world" of the cell and translates it into specific cellular responses by regulating the activity of Yes-associated protein 1 (YAP1). How Hippo translates input from the extracellular signals into specific intracellular responses remains unclear. Here, we show that transforming growth factor β (TGFβ)-activated TAK1 activates LATS1/2, which then phosphorylates YAP1. Phosphorylated YAP1 (p-YAP1) associates with RUNX3, but not with TEAD4, to form a TGFβ-stimulated restriction (R)-point-associated complex which activates target chromatin loci in the nucleus. Soon after, p-YAP1 is exported to the cytoplasm. Attenuation of TGFβ signaling results in re-localization of unphosphorylated YAP1 to the nucleus, where it forms a YAP1/TEAD4/SMAD3/AP1/p300 complex. The TGFβ-stimulated spatiotemporal dynamics of YAP1 are abrogated in many cancer cells. These results identify a new pathway that integrates TGFβ signals and the Hippo pathway (TGFβ→TAK1→LATS1/2→YAP1 cascade) with a novel dynamic nuclear role for p-YAP1.

• IMMUNE NETWORK
• /
• 제7권1호
• /
• pp.10-17
• /
• 2007

Autoimmune arthritis, such as rheumatoid arthritis (RA), is a chronic inflammatory disorder that primarily affects the joints and then results in their progressive destruction. Effector Th cells have been classified as Th1 and Th2 subsets based on their cytokine expression profiles and immune regulatory function. Another subset of T cells termed Th17 was recendy discovered and known to selectively produce IL-17. Also, Th17 was shown to be generated by TGF${\beta}$ and IL-6 and maintained by IL-23. IL-17 is a proinflammatory cytokine that is considered to involve the development of various inflammatory autoimmune diseases such as RA, asthma, lupus, and allograft rejection. IL-17 is present in the sera, synovial fluids and synovial biopsies of most RA patient. IL-17 activates RA synovial fibroblasts to synthesize IL-6, IL-8 and VEGF via PI3K/Akt and NF-${\kappa}B$ dependent pathway. IL-17 increases IL-6 production, collagen destruction and collagen synthesis. In addition, it not only causes bone resorption but also increases osteoclastogenesis and fetal cartilage destruction. Inhibition of the IL-17 production may contribute a novel therapeutic approach along with potent anti-inflammatory effect and with less immunosuppressive effect on host defenses.

• BMB Reports
• /
• 제43권8호
• /
• pp.554-560
• /
• 2010

Smad4 is involved in cancer progression and metastasis. Using a pair of human syngeneic epithelial ovarian cancer cells with low (HO-8910) and high (HO-8910PM) metastatic abilities, we aimed to reveal the role of Smad4 in ovarian cancer metastasis in vitro. Smad4 was down-regulated in HO-8910PM cell line relative to HO-8910 by implicating Smad4 was probably a potential tumor suppressor gene for ovarian cancer. Re-expression of Smad4 decreased the migration ability and inhibited the invasion capacity of HO-8910PM, while promoted the cell adhesion capacity for HO-8910PM. The stable expression of Smad4 increased the expression of E-cadherin, reduced the expression of plasminogen activator inhibitor-1 (PAI-1) and slightly down-regulated the expression of VEGF. Smad4 suppresses human ovarian cancer cell metastasis potential through its effect on the expressions of PAI-1, E-cadherin and VEGF. Results from current work implicate Smad4 might suppress the invasion and metastasis of human ovarian tumor cells through a TGF-$\beta$/Smad-mediated pathway.

• International Journal of Oral Biology
• /
• 제33권2호
• /
• pp.51-58
• /
• 2008

A mutation of UNCL, an inner nuclear membrane RNAbinding protein, has been found to eliminate mechanotransduction in Drosophila. UNCL is expressed in human periodontal tissue including in periodontal ligament (PDL) fibroblasts. However, it is unclear how a mechanical stimulus is translated into cellular responses in PDL fibroblasts. The aim of this study was to evaluate the effect of UNCl on mechanical stress related genes in PDL fibroblasts in response to mechanical stress. The mRNA of TGF-$\beta$, COX-2, and MMP-2 was up-regulated after UNCL inactivation in PDL fibroblasts under the compression force. Under the tensile force, inactivation of UNCL decreased the expression of Biglycan, RANKL, MMP-2, and TIMP-2 mRNAs while it increased the expression of TIMP-1. p38-MAPK was expressed in PDL fibroblasts under compression forces whereas phospho-ERK1/2, p65-NFkB, and c-fos were expressed under tension forces. The expression and phosphorylation of the mechanical stress related genes, kinases, and transcription factors were changed according to the types of stress. Furthermore, most of them were regulated by the inactivation of UNCL. This suggests that UNCL is involved in the regulation of mechanical stress related genes through the signaling pathway in PDL fibroblasts.

• Asian Pacific Journal of Cancer Prevention
• /
• 제13권4호
• /
• pp.1297-1303
• /
• 2012

Aims: Primary hepatocellular carcinoma (HCC) is a common malignancy often related to hepatitis viral infection. Smad4 is known to mediate the TGF-${\beta}$ pathway to suppress tumorigenesis. However, the function of Smad4 in HCC is still controversial. In this study we compared levels of Smad4 in HCC tissues with or without hepatitis virus infection and adjacent normal-appearing liver. Methods: Samples from HCC patients were analyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Western blotting. Results: We found that tumor tissues expressed less Smad4 mRNA and protein than the adjacent tissues. Most HCC tumor tissues were negative for Smad4 in IHC staining, while the majority of adjacent tissues were positively stained. Interestingly, protein levels were higher in HCC tissues with viral hepatitis than those without virus infection. Suppression of expression appeared closely related to HCC, so that Smad4 appears to function as a tumor suppressor gene (TSG). Conclusion: Patients with hepatitis viral infection, at higher risk for HCC, exhibited increased Smad4 protein expression suggesting hepatitis virus may modulate Smad4 expression, which is functionally distinct from its putative role as a TSG. Smad4 expression may thus be an applicable marker for diagnosis and/or a target to develop therapeutic agents for HCC.

• Journal of Ginseng Research
• /
• 제36권4호
• /
• pp.375-382
• /
• 2012

Ginsenoside Rp1 (G-Rp1) is a saponin derivate that provides anti-metastatic activities through inhibition of the NF-${\kappa}B$ pathway. In this study, we examined the effects of G-Rp1 on regulatory T cell (Treg) activation. After treatment of splenocytes with G-Rp1, Tregs exhibited upregulation of IL-10 expression, and along with dendritic cells (DCs), these Tregs showed increased cell number compared to other cell populations. The effect of G-Rp1 on Treg number was augmented in the presence of lipopolysaccharide (LPS), which mimics pathological changes that occur during inflammation. However, depletion of DCs prevented the increase in Treg number in the presence of G-Rp1 and/or LPS. In addition, G-Rp1 promoted the differentiation of the memory types of $CD4^+Foxp3^+CD62L^{low}$ Tregs rather than the generation of new Tregs. In vivo experiments also demonstrated that Tregs and DCs from mice that were fed G-Rp1 for 7 d and then injected with LPS exhibited increased activation compared with those from mice that were injected with LPS alone. Expression of TGF-${\beta}$ and CTLA4 in Tregs was increased, and upregulation of IL-2 and CD80/CD86 expression by DCs affected the suppressive function of Tregs through IL-2 receptors and CTLA4. These data demonstrate that G-Rp1 exerts anti-inflammatory effects by activating Tregs in vitro and in vivo.

• Journal of Microbiology and Biotechnology
• /
• 제29권9호
• /
• pp.1349-1360
• /
• 2019

Chronic exposure to ultraviolet (UV) radiation, regarded as a major cause of extrinsic aging or photoaging characterized by wrinkle formation and skin dehydration, exerts adverse effects on skin by causing the overproduction of reactive oxygen species. Agastache rugosa Kuntze, known as Korean mint, possesses a wide spectrum of biological properties including anti-oxidation, anti-inflammation, and anti-atherosclerosis. Previous studies have reported that A. rugosa protected human keratinocytes against UVB irradiation by restoring the anti-oxidant defense system. However, the anti-photoaging effect of A. rugosa extract (ARE) in animal models has not yet been evaluated. ARE was orally administered to hairless mice at doses of 100 or 250 mg/kg/day along with UVB exposure for 12 weeks. ARE histologically improved UVB-induced wrinkle formation, epidermal thickening, erythema, and hyperpigmentation. In addition, ARE recovered skin moisture by improving skin hydration and transepidermal water loss (TEWL). Along with this, ARE increased hyaluronic acid levels by upregulating HA synthase genes. ARE markedly increased the density of collagen and the amounts of hydroxypoline via two pathways. First, ARE significantly downregulated the mRNA expression of matrix metalloproteinases responsible for collagen degradation by inactivating the mitogen-activated protein kinase/activator protein 1 pathway. Second, ARE stimulated the transforming growth factor beta/Smad signaling, consequently raising the mRNA levels of collagen-related genes. In addition, ARE not only increased the mRNA expression of anti-oxidant enzymes but also decreased inflammatory cytokines by blocking the protein expression of nuclear factor kappa B. Collectively, our findings suggest that A. rugosa may be a potential preventive and therapeutic agent for photoaging.

• Journal of Ginseng Research
• /
• 제44권6호
• /
• pp.790-798
• /
• 2020

Background: Beneficial effects of Korean Red Ginseng (KRG) on polycystic ovarian syndrome (PCOS) remains unclear. Methods: We examined whether pretreatment (daily from 2 hours before PCOS induction) with KRG extract in water (KRGE; 75 and 150 mg/kg/day, p.o.) could exert a favorable effect in a dehydroepian-drosterone (DHEA)-induced PCOS rat model. Results: Pretreatment with KRGE significantly inhibited the elevation of body and ovary weights, the increase in number and size of ovarian cysts, and the elevation of serum testosterone and estradiol levels induced by DHEA. Pretreatment with KRGE also inhibited macrophage infiltration and enhanced mRNA expression levels of chemokines [interleukin (IL)-8, monocyte chemoattractant protein-1), proinflammatory cytokines (IL-1β, IL-6), and inducible nitric oxide synthase in ovaries induced by DHEA. It also prevented the reduction in mRNA expression of growth factors (epidermal growth factor, transforming growth factor-beta (EGF, TGF-β)) related to inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cell pathway and stimulation of the nuclear factor erythroid-derived 2-related factor 2 pathway. Interestingly, KRGE or representative ginsenosides (Rb1, Rg1, and Rg3(s)) inhibited the activity of inflammatory enzymes cyclooxygenase-2 and iNOS, cytosolic p-IκB, and nuclear p-nuclear factor kappa-light-chain-enhancer of activated B in lipopolysaccharide-induced RAW264.7 cells, whereas they increased nuclear factor erythroid-derived 2-related factor 2 nuclear translocation. Conclusion: These results provide that KRGE could prevent DHEA-induced PCOS via antiinflammatory and antioxidant activities. Thus, KRGE may be used in preventive and therapeutic strategies for PCOS-like symptoms.

• Asian Pacific Journal of Cancer Prevention
• /
• 제15권11호
• /
• pp.4437-4441
• /
• 2014

SMAD7 has been identified as a functional candidate gene for colorectal cancer (CRC). SMAD7 protein is a known antagonist of the transforming growth factor beta ($TGF-{\beta}$) signaling pathway which is involved in tumorigenesis. Polymorphisms in SMAD7 may thus alter cancer risk. The aim of this study was to investigate the influence of a SMAD7 gene polymorphism (rs2337107) on risk of CRC and clinicopathological features in an Iranian population. In total, 210 subjects including 105 patients with colorectal cancer and 105 healthy controls were recruited in our study. All samples were genotyped by TaqMan assay via an ABI 7500 Real Time PCR System (Applied Biosystems) with DNA from peripheral blood. The polymorphism was statistically analyzed to investigate the relationship with the risk of colorectal cancer and clinicopathological properties. Logistic regression analysis revealed that there was no significant association between rs2337107and the risk of colorectal cancer. In addition, no significant association between genotypes and clinicopathological features was observed (p value>0.05). Although there was not any association between genotypes and disorder, CT was the most common genotype in this population. This genotype prevalence was also higher in the patients with well grade (54.9%) and colon (72.0%) tumors. Our results provide the first evidence that this polymorphism is not a potential contributor to the risk of colorectal cancer and clinicopathological features in an Iranian population, and suggests the need of a large-scale case-control study to validate our results.