• Toxicological Research
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• v.34 no.1
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• pp.7-12
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• 2018

Laboratory animal models have been developed to investigate preventive or therapeutic effect of medicinal products, or occurrence or progression mechanism of atopic dermatitis (AD), a pruritic and persistent inflammatory skin disease. The murine model with immunologic phenomena resembling human AD was introduced, which demonstrated skewedness toward predominance of type-2 helper T cell reactivity and pathophysiological changes similar as human AD following 2,4-dinitrochlorobenzene (DNCB) sensitization and challenge. Molecular mechanism on the DNCB-mediated AD was further evaluated. Skin tissues were collected from mice treated with DNCB, and each tissue was equally divided into two sections; one for protein and the other for mRNA analysis. Expression of filaggrin, an important protein for keratinocyte integrity, was evaluated through SDS-PAGE. Level of mRNA expression for cytokines was determined through semi-quantitative reverse transcriptase polymerase chain reaction. Expression of filaggrin protein was significantly enhanced in the mice treated with DNCB compared with the vehicle (acetone : olive oil = 4 : 1 mixture) treatment group or the normal group without any treatment. Level of tumor necrosis factor-alpha and interleukin-18 mRNA expression, cytokines involved in activity of type-1 helper T ($T_H1$) cell, was significantly downregulated in the AD group compared with other control groups. These results suggest that suppression of $T_H1$ cell-mediated immune response could be reflected into the skin tissue of mice treated with DNCB for AD induction, and disturbance of keratinocyte integrity might evoke a compensatory mechanism.

• The Korean Journal of Physiology and Pharmacology
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• v.14 no.6
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• pp.391-397
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• 2010

E2F transcription factors and their target genes have been known to play an important role in cell growth control. We found that curcumin, a polyphenolic phytochemical isolated from the plant Curcuma longa, markedly suppressed E2F4 expression in HCT116 colon cancer cells. Hydrogen peroxide was also found to decrease E2F4 protein level, indicating the involvement of reactive oxygen species (ROS) in curucmin-induced downregulation of E2F4 expression. Involvement of ROS in E2F4 downregulation in response to curcumin was confirmed by the result that pretreatment of cells with N-acetylcystein (NAC) before exposure of curcumin almost completely blocked the reduction of E2F4 expression at the protein as well as mRNA level. Anti-proliferative effect of curcumin was also suppressed by NAC which is consistent to previous reports showing curcumin-superoxide production and induction of poly (ADP-ribose) polymerase (PARP) cleavage as well as apoptosis. Expression of several genes, cyclin A, p21, and p27, which has been shown to be regulated in E2F4-dependent manner and involved in the cell cycle progression was also affected by curcumin. Moreover, decreased (cyclin A) and increased (p21 and p27) expression of these E2F4 downstream genes by curcumin was restored by pretreatment of cells with NAC and E2F4 overexpression which is induced by doxycycline. In addition, E2F4 overexpression was observed to partially ameliorate curcumin-induced growth inhibition by cell viability assay. Taken together, we found curcumin-induced ROS down-regulation of E2F4 expression and modulation of E2F4 target genes which finally lead to the apoptotic cell death in HCT116 colon cancer cells, suggesting that E2F4 appears to be a novel determinant of curcumin-induced cytotoxicity.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.22
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• pp.9927-9931
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• 2014

The objectives of this study were to examine serum periplakin expression in patients with urothelial carcinoma of the urinary bladder and in normal controls, and to examine relationships with clinicopathological findings. Detection of serum periplakin was performed in 50 patients and 30 normal controls with anti-periplakin antibodies using the automatic dot blot system, and a micro-dot blot array with a 256 solid-pin system. Levels in patients with urothelial carcinoma of the urinary bladder were significantly lower than those in normal controls (0.31 and 5.68, respectively; p<0.0001). The area under the receiver-operator curve level for urothelial carcinoma of the urinary bladder was 0.845. The sensitivity and specificity, using a cut-off point of 4.045, were 83.7% and 73.3%, respectively. In addition, serum periplakin levels were significantly higher in patients with muscle-invasive cancer than in those with nonmuscle-invasive cancer (P = 0.03). In multivariate Cox proportional hazards regression analysis, none of the clinicopathological factors was associated with an increased risk for progression and cancer-specific survival. Examination of the serum periplakin level may play a role as a non-invasive diagnostic modality to aid urine cytology and cystoscopy.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.3929-3937
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• 2016

Gastric cancer (GC) is a major health problem worldwide and is one of the ten most commonly diagnosed cancers in Jordan. GC is usually diagnosed at late aggressive stages in which treatment options are limited. Recently, heat shock proteins (HSPs) were found to be overexpressed in a wide range of malignancies have been considered as promising candidate biomarkers for GC. The aim of this study was to investigate pathogenic roles of a panel of cytosolic HSPs including HSP90, HSP70, HSP60 and HSP27 in GC. Immunohistochemistry was used to assess the level of expression of these proteins in archived tumor samples (N=87) representing various pathological characteristics of GC. HSP90, HSP60 and HSP27 were expressed abundantly in gastric tumors. On the other hand, HSP70 was reduced significantly and also found to be associated with Helicobacter pylori infection in tissues collected from GC patients. Furthermore, HSP27 was found to be associated with the level of differentiation. Our findings indicate a role of HSP70 as a potential prognostic biomarker, patients harboring positive HSP70 expression displaying worse disease free survival than those with negative HSP70 expression. Differential expression of HSPs may play crucial roles in the initiation and progression of GC, and could be exploited as future therapeutic targets.

• International Journal of Oral Biology
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• v.30 no.1
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• pp.1-8
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• 2005

The elderly suffer from an impaired immune function being obvious in a higher susceptibility to infections. Although the inflammatory cells are the major immunomodulatory cells, fibroblasts also secrete a variety of inflammatory cytokines and chemokines. Therefore periodontal tissue aging might playa role in development and progress of periodontitis. In this study, we investigated the effect of in vitro periodontal ligament cellular aging on the inflammatory cytokines, chemokines, and matrix metalloprotease(MMP)-2 expression induced by lipopolysaccharide(LPS) treatment. Three different cell populations were used; passages 4-5, 14-15, and 24-25 (at passage 27, more than 90% cells were replicative senescent). LPS increased the expression of interleukin(IL)-1${\beta}$, IL-6, and tumor necrosis factor-${\alpha}$, IL-8, RANTES, and MMP-2. However, the order of induction folds were passages 14-15 > 4-5 > 24-25. While the expression level of Toll-like receptor(TLR) 4 decreased according to the increase in passage number, the level of TLR2 was highest at passages 14-15 and then decreased at passages 24-25. While the spontaneous expression of IL-8 decreased according to the increase in passage number, that of RANTES and proMMP-2 increased according to the increase in passage number. These results suggest that the aging of periodontal ligament fibroblasts differentially affect the role as immunomodulatory cells in response to periodontopathic bacteria and therefore might be another risk factor of periodontitis progression.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.36 no.1
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• pp.1-6
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• 2010

Purpose: Chemokines are structurally related, small polypeptide signaling molecules that bind to and activate a family of transmembrane G protein-coupled receptors, the chemokine receptors. Recently, interaction between the chemokine receptor CXCR4 and its ligand, stromal cell-derived factor 1 (SDF-1 or CXCL12), has been found to play an important role in tumorigenicity, proliferation, metastasis and angiogenesis in many cancers such as lung cancer, breast cancer, melanoma, glioblastoma, pancreatic cancer and cholangiocarcinoma. Hence, the goal of this study is to identify the correlation of clinicopathological factors and the up-regulation of SDF-1 expression in oral squamous cell carcinoma. Material and methods: We studied the immunohistochemical staining of SDF-1, quantitative RT-PCR (qRT-PCR) of SDF-1 gene in 20 specimens of 20 patients with oral squamous cell carcinoma. Results: 1. In the immunohistochemical study of poor differentiated and invasive oral squamous cell carcinoma, the high level staining of SDF-1 was observed. And the correlation between immunohistochemical SDF-1 expression and tumor nodes metastases (TNM) classification of specimens was significant.($x^2$ test, P < 0.05) 2. In the SDF-1 gene qRT-PCR analysis, SDF-1 expression was more in tumor tissue than in carcinoma in situ tissue. Paired-samples analysis determined the difference of SDF-1 mRNA expression level between the cancer tissue and the carcinoma in situ tissue.(Student's t-test, P < 0.05) Conclusion: These findings suggest that up-regulation of the SDF-1 may play a role in progression and invasion of oral squamous cell carcinoma.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.44 no.3
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• pp.120-127
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• 2018

Objectives: The aim of this study was to reveal how collagenases (matrix metalloproteinase [MMP]-1, 8, 13) and tissue inhibitor of metalloproteinase 1 (TIMP-1) are expressed in immunohistochemistry of retrodiscal tissue in temporomandibular joint disorder patients. Materials and Methods: This study was conducted on 39 patients who underwent discoplasty or discectomy. Immunohistochemical staining was undertaken and expression levels of MMP-1, 8, 13, and TIMP-1 were evaluated. The status of internal derangement of disc, osteoarthritis, and joint effusion were analyzed using magnetic resonance imaging (MRI). Disc status observed during operation was also categorized. Results: The more severe disc derangement was observed on MRI, the more increased expression of MMPs and TIMP-1 appeared. Regarding MMP-13 expression, 86.7% of late-stage disc displacement patients showed grade II or III. Expression level of MMPs or TIMP was not statistically significant associated with joint effusion level. In perforation and/or adhesion groups, all patients showed grade II or III expression of MMP-13. Once perforation occurred, MMP-13 showed increased expression with statistical significance. Conclusion: MMP-1 and MMP-13 expression seem to be related to progression of osteoarthritis whereas MMP-8 does not seem to have a specific role with regard to temporomandibular joint disorders. TIMP-1 is considered to be partly related to internal derangement rather than osteoarthritis, but it is not significant.

• Toxicological Research
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• v.18 no.2
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• pp.205-213
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• 2002

This study was undertaken to develop a subacute murine model for predicting occurrence of systemic anaphylaxis and to evaluate efficacy of various immunological parameters as the monitoring indices for the occurrence of anaphyalxis. The murine anaphyalxis model was developed through intraperitoneally sensitizing 100 $\mu\textrm{g}$ ovalbumin (OVA) in the presence of 1 mg alum and 300 ng cholera toxin twice a week interval followed by challenging 500 $\mu\textrm{g}$. OVA intravenously. Typical anaphylaxis symptoms were demonstrated at the both BALB/c mice, a strain prone to type-2 response, and C57BL/6 mice. a strain prone to type-1 response. Level of plasma histamine was approximately 50-fold or 30-fold higher in the mice sensitized with OVA than the mice sensitized with alum plus cholera toxin or the saline-treated mice after OVA challenge, respectively. Sensitization and challenge with OVA significantly enhanced plasma leukotriene $B_4$ level but not IgE levels in comparison with the control mice, which indicated the role of leukotriene $B_4$ for progression of anaphyalxis. Furthermore, among mice suffered from anaphylaxis, levels of OVA-specific IgGl were significantly higher in the BALB/c mice than in the C57BL/6 mice, which implied the genetic susceptibility for the induction of systemic anaphylaxis. Conclusively, simultaneous evaluation of histamine, leukotriene $B_4$, and allergen-specific IgG isotype may serve as more efficient monitoring tool for vaccine-related anaphyalxis.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.4001-4005
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• 2012

Backgrouds: The hedgehog (Hh) signaling pathway is composed of patched (PTCH) and smoothened (SMO), two transmembrane proteins, and downstream glioma-associated oncogene homolog (Gli) transcription factors. Hh signaling plays a pathological role in the occurrence and development of various cancers. Methods: To investigate the expression of SMO protein in colon cancer and its association with clinicopathological parameters and postoperative liver metastasis, immunohistochemistry was performed with paraffin-embedded specimens of 96 cases. Relationships between SMO protein expression and clinicopathological parameters, postoperative liver metastasis were analyzed. Results: IHC examination showed that SMO protein expression was significantly increased in colon cancer tissues compared to normal colon tissues (P = 0.042), positively related to lymph node metastases (P = 0.018) and higher T stages (P = 0.026). Postoperative live metastasis-free survival was significantly longer in the low SMO expression group than in those with high SMO expression ($48.7{\pm}8.02$ months vs $28.0{\pm}6.86$ months, P=0.036). Multivariate analysis showed SMO expression level to be an independent prognostic factor for postoperative live metastasis-free survival (95% confidence interval [CI] =1.46-2.82, P = 0.008). Conclusions: Our results suggest that in patients with colon cancer, the SMO expression level is an independent biomarker for postoperative liver metastasis, and SMO might play an important role in colon cancer progression.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7603-7609
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• 2014

Glutathione is a thiol compound that plays an important role in the antioxidant defense system of the cell and its deficiency leads to an increased susceptibility to oxidative stress and, thus, progression of many disease states including head and neck cancer. In the present study, alterations of glutathione levels were investigated in study cohort of 500 samples (cohort 1 containing 200 head and neck cancer blood samples along with 200 healthy controls and cohort II with 50 head and neck squamous cell carcinoma tissue samples along with 50 control tissues) by high performance liquid chromatography. The results indicated that mean blood glutathione levels were significantly reduced in head and neck cancer patients (p<0.001) compared to respective controls. In contrast, the levels of glutathione total (p<0.05) and glutathione reduced (p<0.05) were significantly elevated in head and neck squamous cell carcinoma tissues compared to the adjacent cancer-free control tissues. In addition to this, pearson correlation performed to correlate different tissue glutathione levels (GSH) with clinical/pathological parameters demonstrated a significant negative correlation between pT-stage and GSH level ($r=-0.263^{**}$; p<0.01), C-stage and GSH level ($r=-0.335^{**}$; p<0.01), grade and GSH ($r=-0.329^{**}$; p<0.01) and grade versus redox index ($r=-0.213^{**}$; p<0.01) in HNSCC tissues. Our study suggests that dysregulation of glutathione levels in head and neck cancer has the potential to predict metastasis, and may serve as a prognostic marker.