• Journal of the Korean Association of Oral and Maxillofacial Surgeons
• /
• 제36권6호
• /
• pp.460-465
• /
• 2010

Introduction: A cleft palate is a common birth defect in humans with an incidence of 1/500 to 1/1,000 births. It appears to be caused by multiple genetic and environmental factors during palatogenesis. Many molecules are involved in palate formation but the biological mechanisms underlying the normal palate formation and cleft palate are unclear. Accumulating evidence suggests that transforming growth factor $\beta$/bone morphogenetic proteins (TGF-$\beta$/BMP) family members mediate the epithelial-mesenchymal interactions during palate formation. However, their roles in palatal morphogenesis are not completely understood. Materials and Methods: To understand the roles of TGF-$\beta$/BMP signaling in vivo during palatogenesis, mice with a palatal mesenchyme- specific deletion of Smad4, a key intracellular mediator of TGF-$\beta$/BMP signaling, were generated and analyzed using the Osr2Ires-Cre mice. Results: The mutant mice were alive at the time of birth with open eyelids and complete cleft palate but died within 24 hours after birth. In skeletal preparation, the horizontal processes of the palatine bones in mutants were not formed and resulted in a complete cleft palate. At E13.5, the palatal shelves of the mutants were growing as normally as those of theirwild type littermates. However, the palatal shelves of the mutants were not elevated at E14.5 in contrast to the elevated palatal shelves of the wild type mice. At E15.5, the palatal shelves of the mutants were elevated over the tongue but did not come in contact with each other, resulting in a cleft palate. Conclusion: These results suggest that mesenchymal Smad4 mediated signaling is essential for the growth of palatal processes and suggests that TGF-$\beta$/BMP family members are essential regulators during palate development.

• 대한의생명과학회지
• /
• 제19권3호
• /
• pp.195-205
• /
• 2013

Obesity may cause metabolic syndrome and adult diseases. This study was undertaken to investigate the ameliorative or useful effects of beanleaves on inflammation and liver damage in obese rat models. Rats were divided into three groups: a control group (normal diet, n=6), a fat diet group (45%-fat diet, n=7), and a bean leaf group (45%-fat+Korean bean leaves diet, n=7). Body weights in the bean leaf group were lower than those of the fat group (P<0.05). Serum tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) and prostaglandin $E_2$ ($PGE_2$) concentrations were lower in both the control and bean leaf groups than in the fat group (P<0.001). TNF-${\alpha}$ concentrations in the bean leaf group were slightly higher than in the control group but statistically significant (P<0.05). The bean leaf group histologically exhibited lower fatty degeneration, spotty necrosis, and leukocyte infiltrations in hepatic tissues than those of the fat group. In the homogenized liver tissues, the cyclooxygenase-2 (COX-2) gene was only expressed in the fat group. The gene expression levels of hepatic TNF-${\alpha}$, inducible nitric-oxide synthase, peroxiome proliferator-activated receptor-${\alpha}$ (PPAR-${\alpha}$), poly (ADP-ribose) polymerase (PARP), and transforming growth factor-${\beta}1$ (TGF-${\beta}1$) were weaker in the bean leaf group than in the fat group. These results suggest that adding bean-leaves to the diet may ameliorate obesity-induced systemic inflammation and liver damage and that bean leaves may be a useful food for preventing obesity and thereby metabolic syndrome and adult diseases.

• Archives of Plastic Surgery
• /
• 제42권2호
• /
• pp.179-185
• /
• 2015

Background Capsular contracture is the most troublesome complication in breast implant surgery. Although capsule formation can be seen as a normal reaction to a foreign body, it can induce pain, hardness, deformity, and other pathologic problems. Surgical intervention is required in severe cases, but even surgery cannot guarantee a successful outcome without recurrence. This experimental study confirms that single topical administration of leukotriene antagonist zafirlukast (Accolate, Astrazeneca) reduces peri-implant capsule formation and prevents capsular contracture. Methods Twelve smooth-surfaced cohesive gel implants were implanted in New Zealand White rabbits. These miniature implants were designed to be identical to currently used products for breast augmentation. The rabbits were divided into 2 groups. In the experimental group (n=6), the implant and normal saline with zafirlukast were inserted in the submuscular pocket. In the control group (n=6), the implant and normal saline alone were used. Two months later, the implants with peri-implant capsule were excised. We evaluated capsule thickness and collagen pattern and performed immunohistochemical staining of myofibroblasts, transforming growth factor $(TGF)-{\beta}1$, 2. Results The thickness of the capsules in the experimental group was reduced in both dorsal and ventral directions. The collagen pattern showed parallel alignment with low density, and the number of myofibroblasts as well as the amounts of $TGF-{\beta}1$ and $TGF-{\beta}2$ were reduced in the experimental group. Conclusions We suggest that single topical administration of leukotriene antagonist zafirlukast can be helpful in reducing capsule formation and preventing capsular contracture via myofibroblast suppression, modulation of fibroblastic cytokines, and anti-inflammatory effect.

• Archives of Pharmacal Research
• /
• 제21권2호
• /
• pp.120-127
• /
• 1998

Peroxisome proliferators induce hepatic peroxisome proliferation and hepatic tumors in rodents. These chemicals increase the expression of the peroxisomal $\beta$-oxidation pathway and the cytochrome P-450 4A family, which metabolizes lipids, including eicosanoids. Peroxisome proliferators transiently induce increased cell proliferation in vivo. However, peroxisome proliferators are weakly mitogenic and are not co-mitogenic with epidermal growth factor (EGF) in cultured hepatocytes. Earlier study found that the peroxisome proliferator ciprofibrate is cornitogenic with eicosanoids. In order to study possible mechanisms of the comitogenicity of peroxisome proliferator ciprofibrate and eicosanoids' we hypothesized that the co-mitogenicity may result from synergistic or additive increases of second messengers in mitogenic signal pathways. We therefore examined the effect of the peroxisome proliferator ciprofibrate, prostaglandin $F_2_{\alpha}$($PGF_2{\alpha}$) and the combination of ciprofibrate and $PGF_2{\alpha}$ with or without growth factors on the protein kinase C (PKC) activity, and inositol-1, 4, 5-triphosphate ($IP_{3-}$) and intracellular calcium ($[Ca^{2+}]_i$) concentrations in cultured rat hepatocytes. The combination of ciprofibrate and $PGF_2{\alpha}$ significantly increased particulate PKC activity. The combination of ciprofibrate and $PGF_2{\alpha}$ also significantly increased EGF, transforming growth factor-$\alpha$ ($TGF_2{\alpha}$) and hepatic growth factor (HGF)-induced particulate PKC activity. The combination of ciprofibrate and $PGF_2_\alpha$greatly increased $[Ca^{2+}]_i$. However, the increases of PKC activity and $[Ca^{2+}]_i$ by ciprofibrate and $PGF_2{\alpha}$ alone were much smaller. Neither ciprofibrate or $PGF_2{\alpha}$ alone nor the combination of ciprofibrate and $PGF_2{\alpha}$ significantly increased the formation of $IP_3$. The combination of ciprofibrate and $PGF_2{\alpha}$, however, blocked the inhibitory effect of $TGF-{\beta}$ on particulate PKC activity and formation of $IP_3$ induced by EGF. These results show that co-mitogenicity of the peroxisome proliferator ciprofibrate and eicosanoids may result from the increase in particulate PKC activity and intracellular calcium concentration but not from the formation of $IP_3$.

• International Journal of Industrial Entomology and Biomaterials
• /
• 제27권1호
• /
• pp.159-165
• /
• 2013

Bone morphogenetic proteins (BMPs) belong to the transforming growth factor (TGF-${\beta}$) superfamily and are involved in osteoblastic differentiation. The largest TGF-${\beta}$ superfamily subgroup shares genetic homology with human BMPs (hBMPs) and silkworm decapentaplegic (dpp). In addition, hBMPs are functionally interchangeable with Drosophila dpp. Bombyx mori dpp may induce bone formation in mammalian cells. To test this hypothesis, we synthesized the 1,285-base pairs cDNA of full-length B. mori dpp using total RNAs obtained from the fat body of 3-day-old of the $5^{th}$ instar larvae and cloned the cDNA into the pCEP4 mammalian expression vector. Next, B. mori dpp was expressed in C3H10T1/2 cells. The target cells transfected with the pCEP4-Bm dpp plasmid showed biological functions similar to those of osteogenic differentiation induction growth factors such as hBMPs. We determined the relative mRNA expression rates of Runt-related transcription factor 2 (RUNX2), osterix, osteocalcin, and alkaline phosphatase (ALP) to validate the osteoblast-specific differentiation effects of B. mori dpp by performing quantitative real-time RT-PCR. Interestingly, mRNA expression levels of the 3 marker genes except RUNX2, in cells expressing B. mori dpp were much higher than those in control cells and C3H10T1/2 cells transfected with pCEP4. These results suggested that B. mori dpp signaling regulates osterix expression during osteogenic differentiation via RUNX2-independent mechanisms.

• BMB Reports
• /
• 제55권4호
• /
• pp.192-197
• /
• 2022

Cell signals for growth factors depend on the mechanical properties of the extracellular matrix (ECM) surrounding the cells. Microtubule acetylation is involved in the transforming growth factor (TGF)-β-induced myofibroblast differentiation in the soft ECM. However, the mechanism of activation of α-tubulin acetyltransferase 1 (α-TAT1), a major α-tubulin acetyltransferase, in the soft ECM is not well defined. Here, we found that casein kinase 2 (CK2) is required for the TGF-β-induced activation of α-TAT1 that promotes microtubule acetylation in the soft matrix. Genetic mutation and pharmacological inhibition of CK2 catalytic activity specifically reduced microtubule acetylation in the cells cultured on a soft matrix rather than those cultured on a stiff matrix. Immunoprecipitation analysis showed that CK2α, a catalytic subunit of CK2, directly bound to the C-terminal domain of α-TAT1, and this interaction was more prominent in the cells cultured on the soft matrix. Moreover, the substitution of alanine with serine, the 236th amino acid located at the C-terminus, which contains the CK2-binding site of α-TAT1, significantly abrogated the TGF-β-induced microtubule acetylation in the soft matrix, indicating that the successful binding of CK2 and the C-terminus of α-TAT1 led to the phosphorylation of serine at the 236th position of amino acids in α-TAT1 and regulation of its catalytic activity. Taken together, our findings provide novel insights into the molecular mechanisms underlying the TGF-β-induced activation of α-TAT1 in a soft matrix.

• The Korean Journal of Physiology and Pharmacology
• /
• 제14권6호
• /
• pp.377-384
• /
• 2010

The present study examined whether metformin treatment prevents isoporterenol-induced cardiac hypertrophy in mice. Chronic subcutaneous infusion of isoproterenol (15 mg/kg/24 h) for 1 week using an osmotic minipump induced cardiac hypertrophy measured by the heart-to-body weight ratio and left ventricular posterior wall thickness. Cardiac hypertrophy was accompanied with increased interleukin-6 (IL-6), transforming growth factor (TGF)-${\beta}$, atrial natriuretic peptide (ANP), collagen I and III, and matrix metallopeptidase 2 (MMP-2). Coinfusion of metformin (150 mg/kg/24 h) with isoproterenol partially inhibited cardiac hypertrophy that was followed by reduced IL-6, TGF-${\beta}$, ANP, collagen I and III, and MMP-2. Chronic subcutaneous infusion of metformin did not increase AMP-activated protein kinase (AMPK) activity in heart, although acute intraperitoneal injection of metformin (10 mg/kg) increased AMPK activity. Isoproterenol increased nitrotyrosine levels and mRNA expression of antioxidant enzyme glutathione peroxidase and metformin treatment normalized these changes. These results suggest that metformin inhibits cardiac hypertrophy through attenuating oxidative stress.

• Toxicological Research
• /
• 제26권4호
• /
• pp.245-252
• /
• 2010

Epithelial-mesenchymal transition (EMT) is a complex process in which epithelial cells acquire the characteristics of invasive mesenchymal cells. EMT has been implicated in cancer progression and metastasis as well as the formation of many tissues and organs during development. Epithelial cells undergoing EMT lose cell-cell adhesion structures and polarity, and rearrange their cytoskeletons. Several oncogenic pathways such as transforming growth factor (TGF)-$\beta$, Wnt, and Notch signaling pathways, have been shown to induce EMT. These pathways have activated transcription factors including Snail, Slug, and the ZEB family which work as transcriptional repressors of E-cadherin, thereby making epithelial cells motile and resistant to apoptosis. Mounting evidence shows that EMT is associated with cell invasion and tumor progression. In this review, we summarize the characteristic features of EMT, pathways leading to EMT, and the role of EMT in cell invasion. Three topics are addressed in this review: (1) Definition of EMT, (2) Signaling pathways leading to EMT, (3) Role of EMT in cell invasion. Understanding the role of EMT in cell invasion will provide valuable information for establishing strategies to develop anti-metastatic therapeutics which modulate malignant cellular processes mediated by EMT.

• 대한본초학회지
• /
• 제39권4호
• /
• pp.19-28
• /
• 2024

Objectives : Ephedrae Herba has been used in the East Asian traditional medicine, for treatment of asthma, cold and influenza. Silymarin is an effective antioxidant and its anti-fibrogenic, anti-inflammatory, and hepatoprotective properties have been reported. This study was performed to explore an anti-fibrogenic potential of Ephedrae Herba extract (EHE) + silymarin on immortalized human hepatic stellate cell line, LX-2 cells. Methods : We studied the anti-fibrogenic effects of EHE + silymarin on transforming growth factor β1 (TGF-β1) signaling pathway in LX-2 cells. Cell viability was measured using the MTT assay. mRNA levels were detected by real-time PCR. TGF-β1 signaling-related proteins expression were detected by Western blot. Results : Silymarin 30 ㎍/mL and EHE 100 ㎍/mL showed cytotoxicity on LX-2 cells. Therefore, the concentrations of silymarin and EHE were studied at 10 ㎍/mL, respectively. Silymarin significantly reduced PAI-1 protein expression, Smad binding element (SBE) luciferase activity, and mRNA (PAI-1, MMP2 and 9) expression compared to TGF-β1. EHE significantly reduced SBE luciferase activity and mRNA (PAI-1, MMP2 and 9) expression compared to TGF-β1. More importantly, EHE + silymarin significantly reduced all parameters compared to TGF-β1, and also significantly reduced compared to EHE alone and silymarin alone. Conclusion : The results indicate that EHE + silymarin has anti-fibrogenic effect in LX-2 cells induced by TGF-β1. Additionally, EHE + silymarin shows more effective anti-fibrogenic effect than EHE alone and silymarin alone.

• 대한임상검사과학회지
• /
• 제39권3호
• /
• pp.210-216
• /
• 2007

There is increasing evidence that stromal reaction in cancer has an important diagnostic and prognostic significance. The aim of our study is to analyze the relation between the increase in mast cell number and the expression CD34 and alpha-smooth muscle actin (${\alpha}$-SMA) in the stroma of cervical intraepithelial neoplasia (CIN) and squamous cell carcinoma (SCC). We investigated a total of 29 CIN (1,2,3) and 21 SCC (microinvasive and invasive) specimens and compared the distribution of $CD34^+$ stromal cells, ${\alpha}-SMA^+$ cells, transforming growth factor-${\beta}1$ $(TGF-{\beta}1)^+$ cells, and the density of mast cells using immunohistochemistry with antibodies against CD34, ${\alpha}$-SMA, TGF-${\beta}1$, and c-Kit (CD117) respectively. Computerized image analysis was to evaluate the positive area (%) and density of the respective immunoreactive cells. In CIN $CD34^+$ cells were abundant in the stroma but no ${\alpha}-SMA^+$ cells were identified except the wall of blood vessels. $CD34^+$ cells were progressively decreased along the continuum from CIN 2 to microinvasive SCC and not observed in the stroma of invasive SCC. Whereas ${\alpha}-SMA^+$ cells were only observed in the stroma of microinvasive and invasive SCC. We found more intense TGF-${\beta}1$ expression in the increased mast cells in the stroma of invasive SCCs than that in the stroma of CIN. These results indicate that disappearance of $CD34^+$ stromal cells and appearance of ${\alpha}-SMA^+$ cells are associated with the stromal change of CIN to SCC and the transformation of $CD34^+$ stromal cells into ${\alpha}-SMA^+$ cells is mediated by TGF-${\beta}1$ secretions in the stromal mast cell of SCC.