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1.
Korean J Ophthalmol ; 34(5): 347-352, 2020 10.
Article in English | MEDLINE | ID: mdl-33099555

ABSTRACT

PURPOSE: To evaluate the effects of each subgroup of prostaglandin analogues (PGAs) on central corneal thickness (CCT) in patients with normal tension glaucoma (NTG). METHODS: We retrospectively reviewed 55 eyes of 55 patients with NTG who were receiving PGA therapy. Patients who were treated with 0.005% latanoprost (16 eyes), 0.0015% tafluprost (16 eyes), or 0.004% travoprost (23 eyes) monotherapy were included. CCT assessments were performed at baseline and 1, 2, and 3 years after initiation of treatment. RESULTS: In the NTG group, the mean CCT showed a decreasing trend, and there was a significant difference in mean CCT at 1, 2, and 3 years compared with baseline (baseline, 538.16 ± 32.14; 1 year, 526.55 ± 37.30 µm [p = 0.00]; 2 years, 521.67 ± 36.79 µm [p = 0.00]; 3 years, 520.43 ± 36.88 µm [p = 0.00]). The reduction of CCT was confirmed by subgroup analysis. In the 0.005% latanoprost group, mean CCT was decreased at 1 year (p = 0.11), 2 years (p = 0.00), and 3 years (p = 0.02). In the 0.0015% tafluprost group and the 0.004% travoprost group, mean CCT was also significantly decreased at all years (p = 0.00). No statistical difference was observed between the NTG subgroups (p = 0.06). CONCLUSIONS: Topical therapy with PGAs appeared to cause a significant decrease in CCT reduction in patients with NTG. A long-term follow-up study including more participants is needed.


Subject(s)
Cornea/diagnostic imaging , Intraocular Pressure/drug effects , Low Tension Glaucoma/diagnosis , Prostaglandins, Synthetic/administration & dosage , Cornea/drug effects , Female , Follow-Up Studies , Humans , Low Tension Glaucoma/drug therapy , Male , Middle Aged , Ophthalmic Solutions , Retrospective Studies , Time Factors , Ultrasonography
2.
J Ocul Pharmacol Ther ; 33(1): 57-61, 2017.
Article in English | MEDLINE | ID: mdl-27828721

ABSTRACT

PURPOSE: To assess the impact of latanoprost on central corneal thickness (CCT) after ceasing medication in patients with normal tension glaucoma (NTG). METHODS: A total of 46 eyes from 46 NTG patients, and 44 eyes from 44 individuals with glaucoma suspect (controls), were included in this retrospective study. Newly diagnosed early NTG patients (visual field mean deviation >-6.00) were administered latanoprost 0.005% monotherapy once a day. CCTs were measured by ultrasound pachymetry before treatment, for 5 years during treatment, and for 2 years after ceasing treatment. RESULTS: Mean CCT was reduced significantly in the NTG group during treatment [544.4 ± 35.8 µm vs. 531.4 ± 32.5 µm (n = 46), P < 0.001]. After ceasing latanoprost treatment, mean CCT increased [531.4 ± 32.5 µm vs. 544.6 ± 37.1 µm (n = 46), P < 0.01] over the course of 2 years. In the control group, however, mean CCT was not significantly different [553.5 ± 27.5 µm vs. 561.8 ± 24.7 µm (n = 44), P = 0.06] at the 7-year follow-up. CONCLUSIONS: Latanoprost significantly reduced CCT in NTG patients after 5 years of treatment; however, the reduction was reversed 2 years after discontinuation of treatment.


Subject(s)
Cornea/drug effects , Low Tension Glaucoma/drug therapy , Prostaglandins F, Synthetic/pharmacology , Cornea/pathology , Female , Humans , Latanoprost , Low Tension Glaucoma/pathology , Male , Middle Aged , Prostaglandins F, Synthetic/administration & dosage , Retrospective Studies
3.
Korean J Ophthalmol ; 29(2): 102-8, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25829826

ABSTRACT

PURPOSE: To investigate the risk factors for initial central scotoma (ICS) compared with initial peripheral scotoma (IPS) in normal-tension glaucoma (NTG). METHODS: Fifty-six NTG patients (56 eyes) with an ICS and 103 NTG patients (103 eyes) with an IPS were included. Retrospectively, the differences were assessed between the two groups for baseline characteristics, ocular factors, systemic factors, and lifestyle factors. Also, the mean deviation of visual field was compared between the two groups. RESULTS: Patients from both ICS and IPS groups were of similar age, gender, family history of glaucoma, and follow-up periods. Frequency of disc hemorrhage was significantly higher among patients with ICS than in patients with IPS. Moreover, systemic risk factors such as hypotension, migraine, Raynaud's phenomenon, and snoring were more prevalent in the ICS group than in the IPS group. There were no statistical differences in lifestyle risk factors such as smoking or body mass index. Pattern standard deviation was significantly greater in the ICS group than in the IPS group, but the mean deviation was similar between the two groups. CONCLUSIONS: NTG Patients with ICS and IPS have different profiles of risk factors and clinical characteristics. This suggests that the pattern of initial visual field loss may be useful to identify patients at higher risk of central field loss.


Subject(s)
Intraocular Pressure , Low Tension Glaucoma/complications , Optic Disk/pathology , Risk Assessment/methods , Scotoma/epidemiology , Visual Fields/physiology , Female , Humans , Incidence , Low Tension Glaucoma/diagnosis , Low Tension Glaucoma/physiopathology , Male , Middle Aged , Republic of Korea/epidemiology , Retrospective Studies , Risk Factors , Scotoma/diagnosis , Scotoma/etiology
4.
J Ocul Pharmacol Ther ; 31(3): 152-5, 2015 Apr.
Article in English | MEDLINE | ID: mdl-25621500

ABSTRACT

PURPOSE: To evaluate the long-term effect of latanoprost on central corneal thickness (CCT) in patients with normal-tension glaucoma (NTG). METHODS: This retrospective study included 41 eyes of 41 NTG patients and 40 eyes of 40 individuals with glaucoma suspect (controls). Newly diagnosed NTG patients with no previous glaucoma treatment were administered latanoprost 0.005% monotherapy once a day. CCTs were measured by ultrasound pachymetry before treatment and followed up annually for 5 years. RESULTS: A significant reduction in mean CCT was observed in the NTG group [542.3±36.2 µm vs. 533.7±32.9 µm (n=41), P<0.001], but not in the control group [547.4±24.7 µm vs. 546.8±25.0 µm (n=40), P=0.59] at 5-year follow-up. In the NTG group, the CCT reduction mainly occurred during the first year of treatment (542.3±36.2 µm vs. 536.9±32.8 µm, P=0.001), and no significant correlation was found between CCT and intraocular pressure reductions (r=0.16, P=0.32). CONCLUSIONS: Latanoprost significantly reduced CCT in NTG patients after 5 years of treatment. Serial observations of CCT might be helpful for the proper interpretation of glaucoma status in NTG patients.


Subject(s)
Antihypertensive Agents/administration & dosage , Cornea/drug effects , Intraocular Pressure/drug effects , Low Tension Glaucoma/drug therapy , Ocular Hypertension/drug therapy , Prostaglandins F, Synthetic/administration & dosage , Aged , Antihypertensive Agents/adverse effects , Cornea/diagnostic imaging , Cornea/pathology , Corneal Pachymetry/methods , Female , Follow-Up Studies , Humans , Latanoprost , Low Tension Glaucoma/diagnostic imaging , Low Tension Glaucoma/pathology , Male , Middle Aged , Prostaglandins F, Synthetic/adverse effects , Retrospective Studies , Ultrasonography
5.
Immunol Lett ; 150(1-2): 145-51, 2013 Feb.
Article in English | MEDLINE | ID: mdl-23370368

ABSTRACT

Erythroid differentiation regulator 1 (Erdr1) suppressed cell motility in vitro and has anti-metastatic effect in vivo on melanoma. The current study investigated the effect of recombinant Erdr1 on the migration and invasion ability of SNU-216 cell, a gastric cancer cell line. The expression of Erdr1 is inversely correlated with IL-18 expression, which has a pro-cancer effect in gastric cancer. Treatment with rErdr1 markedly suppressed the ability of SNU-216 cells to migrate and invade, indicating that recombinant Erdr1 inhibited the motility of gastric cancer cells. E-cadherin expression levels were measured to determine the factor involved in the rErdr1-suppressed motility. E-cadherin is a representative of the cadherin family, known as cell motility enhancement adhesion molecule. Our results revealed that E-cadherin levels were increased by rErdr1 treatment, suggesting the involvement of E-cadherin in rErdr1-reduced cell migration. The cells were treated with specific MAPK inhibitors such as SP600125, SB203580 or PD98059 to identify the signaling mechanism involved with rErdr1 suppressed cell migration. The results indicated that the rErdr1 inhibited migration was primarily reversed by SP600125, a JNK inhibitor. In addition, the level of JNK phosphorylation was markedly increased by recombinant Erdr1. Taken together, these findings suggest that rErdr1 suppressed the ability of gastric cancer cells to metastasis by up regulating E-cadherin through a JNK pathway activation. Furthermore, it can be suggested that the inhibitory effect of recombinant Erdr1 on SNU-216 cell's metastatic potential was through cell motility suppression.


Subject(s)
Cell Movement/drug effects , MAP Kinase Signaling System/drug effects , Membrane Proteins/metabolism , Stomach Neoplasms/metabolism , Stomach Neoplasms/pathology , Tumor Suppressor Proteins/metabolism , Cadherins/metabolism , Cell Line, Tumor , Humans , Interleukin-18/pharmacology , Membrane Proteins/pharmacology , Neoplasm Invasiveness , Tumor Suppressor Proteins/pharmacology
6.
J Ocul Pharmacol Ther ; 29(3): 335-8, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23075402

ABSTRACT

PURPOSE: To evaluate the effect of latanoprost on central corneal thickness (CCT) in patients with unilateral normal-tension glaucoma (NTG). METHODS: A total of 38 patients, with unilateral NTG, who were being treated in our glaucoma clinic and were receiving 0.005% latanoprost monotherapy over 24 months, were included in this study. The data were collected, retrospectively, with reviewing of the charts. The mean CCT and the CCT reduction from the baseline were assessed before the treatment, and at 3, 6, 9, 12, and 24 months after the initiation of the treatment. An unaffected eye was also evaluated for the control group. All the measurements were performed with a commercially available ultrasound pachymeter. RESULTS: There were no significant differences between the eyes for the baseline intraocular pressure and CCT. The mean CCT trend decreased, except at 9 months after the treatment in the latanoprost group (affected eye), but only statistically significant after 24 months of treatment by using paired-sample t-test [544.6±38.4 vs. 540.3±37.8 µm (P=0.013)]. There was no statistically significant changes of CCT between the groups with repeated measures analysis of variance (P=0.635). CONCLUSION: Topical therapy with latanoprost may decrease the CCT, over a period of 24 months, in patients with NTG. These data should be taken into consideration in a long-standing latanoprost treatment of NTG.


Subject(s)
Antihypertensive Agents/adverse effects , Cornea/drug effects , Low Tension Glaucoma/drug therapy , Prostaglandins F, Synthetic/adverse effects , Administration, Ophthalmic , Adult , Aged , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/therapeutic use , Cornea/metabolism , Corneal Pachymetry , Female , Follow-Up Studies , Humans , Intraocular Pressure , Latanoprost , Male , Middle Aged , Prostaglandins F, Synthetic/administration & dosage , Prostaglandins F, Synthetic/therapeutic use , Retrospective Studies , Time Factors
7.
Int Ophthalmol ; 31(5): 355-61, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21901560

ABSTRACT

To evaluate the potential benefit of intraocular pressure (IOP) reduction in normal-tension glaucoma (NTG) patients in South Korea. A retrospective, multi-center analysis of Korean NTG patients with 5-years follow-up, typical glaucomatous optic disc and/or visual field changes and no recorded IOP >21 mmHg. Progression was identified by Advanced Glaucoma Intervention Study visual field scoring. There were 90 (42%) progressed patients and 127 (58%) stable patients included in the study. Mean IOP measured higher in the progressed (14.3 ± 2.2 mmHg) than stable patients (14.0 ± 1.9 mmHg), but was not statistically different between the groups (P = 0.29). The mean IOP that best discriminated stable patients was ≤15 mmHg, but no statistical difference existed in the numbers of progressed versus stable patients at ≤15 mmHg compared to >15 mmHg (P = 0.07). Multivariate regression analysis showed that the baseline number of glaucoma medicines and visual field as well as mean, peak and fluctuation of IOP were significant risk factors for glaucomatous progression (P < 0.01). This study suggests that in Korean NTG patients, despite relatively similar IOPs between progressed and stable patients, and based on multivariate regression analysis, IOP may be a risk factor for glaucomatous progression.


Subject(s)
Intraocular Pressure/physiology , Low Tension Glaucoma/physiopathology , Adult , Aged , Disease Progression , Female , Follow-Up Studies , Humans , Low Tension Glaucoma/drug therapy , Male , Middle Aged , Prevalence , Regression Analysis , Republic of Korea , Retrospective Studies , Risk Factors
8.
J Invest Dermatol ; 131(10): 2096-104, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21697887

ABSTRACT

Erythroid differentiation regulator (Erdr1) was first discovered in mouse leukemia cell lines and functions as a stress-related survival factor. This study investigated whether Erdr1 regulates murine melanoma progression, as well as the mechanism involved in Erdr1-regulated metastasis. The expression of Erdr1 is negatively correlated with IL-18 expression, which has a pro-cancer effect in melanoma. To study the role of Erdr1 as an anti-cancer factor, cell migration, invasion, and proliferation were measured. Erdr1 overexpression markedly inhibited the level of cell migration, invasion, and proliferation in B16F10 cells in vitro. In addition, Erdr1 overexpression significantly suppressed melanoma lung colonization, metastasis, and tumor growth in vivo. To identify the factors involved in Erdr1-reduced metastasis, heat shock protein 90 (HSP90), a well-known stress protein and contributor to tumor metastasis, was examined. We found that HSP90 was significantly decreased in Erdr1-overexpressing cells. Functional analysis demonstrated that HSP90 small-interfering RNA transfection reduced the migration ability and metastasis of melanoma. In conclusion, Erdr1 shows a powerful anti-metastasis effect that leads to the ability to reduce the metastatic potential of murine malignant melanoma cells. Erdr1 is an anti-metastatic factor that may be a possible therapeutic target for treatment of melanoma.


Subject(s)
Interleukin-18/metabolism , Melanoma/genetics , Membrane Proteins/physiology , Skin Neoplasms/genetics , Tumor Suppressor Proteins/physiology , Animals , Cell Movement , Cell Proliferation , HSP90 Heat-Shock Proteins/metabolism , Humans , Lung Neoplasms/secondary , Melanoma/therapy , Melanoma, Experimental , Membrane Proteins/genetics , Mice , Neoplasm Invasiveness , Neoplasm Metastasis , RNA, Small Interfering/metabolism , Skin Neoplasms/therapy , Tumor Suppressor Proteins/genetics
9.
Korean J Ophthalmol ; 25(3): 166-73, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21655041

ABSTRACT

PURPOSE: To compare the peripapillary retinal nerve fiber layer (RNFL) thickness of normal patients and those with various glaucoma diseases by time domain (Stratus) and spectral domain (Spectralis) optical coherence tomography (OCT). METHODS: The RNFL thickness as measured by the Stratus and Spectral OCT was compared (paired t-test). The relationship and agreement of RNFL thickness between the two OCT modalities were evaluated by Pearson correlation, Bland-Altman plot, and area under the receiver operating characteristic curve. RESULTS: Two-hundred seventeen eyes of 217 patients, including twenty-four normal eyes, ninety-one glaucoma suspects, seventy-six normal tension glaucoma cases, and twenty-six primary open angle glaucoma cases (POAG) were analyzed. The peripapillary RNFL thicknesses as measured by Stratus OCT were significantly greater than those measured by Spectralis OCT. However, in quadrant comparisons, the temporal RNFL thickness obtained using Stratus OCT were significantly less than those obtained using Spectralis OCT. Correlations between RNFL parameters were strong (Pearson correlation coefficient for mean RNFL thickness = 0.88); a high degree of correlation was found in the POAG group. Bland-Altman plotting demonstrated that agreement in the temporal quadrant was greater than any other quadrant. CONCLUSIONS: Both OCT systems were highly correlated and demonstrated strong agreement. However, absolute measurements of peripapillary RNFL thickness differed between Stratus OCT and Spectralis OCT. Thus, measurements with these instruments should not be considered interchangeable. The temporal quadrant was the only sector where RNFL thickness as measured by Spectralis OCT was greater than by Stratus OCT; this demonstrated greater agreement than other sectors.


Subject(s)
Glaucoma, Open-Angle/pathology , Low Tension Glaucoma/pathology , Nerve Fibers/pathology , Retina/pathology , Tomography, Optical Coherence/methods , Adolescent , Adult , Aged , Aged, 80 and over , Area Under Curve , Female , Humans , Male , Middle Aged , ROC Curve , Young Adult
10.
J Biol Chem ; 286(14): 12049-55, 2011 Apr 08.
Article in English | MEDLINE | ID: mdl-21321117

ABSTRACT

IL-32 was recently identified as a proinflammatory cytokine that is induced by IL-18 in natural killer (NK) cells and is highly correlated with inflammatory disorders. However, the relationship between IL-32 and tumor progression is still unknown. In this study, we investigated whether overexpression of IL-32 affects susceptibility of chronic myeloid leukemia (CML) cells to NK cells. Interestingly, IL-32α-overexpressing CML cell lines, K562, Kcl22, and BV173, showed higher NK cell-mediated killing. Flow cytometry analysis revealed that overexpression of IL-32α induced increased expression of Fas and UL16-binding protein 2 (ULBP2) in CML cells. The direct relationship between overexpression of surface molecules by IL-32α and increased NK cell-mediated killing was confirmed by Fas or ULBP2 siRNA transfection. IL-32α-induced Fas and ULBP2 expression are regulated p38 MAPK. In addition, the transcription factor Ets1 plays a key role in ULBP2 specific expression by IL-32α overexpression in ULBP family members. Taken together, these data show that IL-32α stimulates Fas and ULBP2 expression via activation of p38 MAPK, which increases NK susceptibility of CML cells. Enhanced NK cell susceptibility of CML cells by IL-32α overexpression may improve the efficiency of NK cell-based immunotherapy.


Subject(s)
Intercellular Signaling Peptides and Proteins/metabolism , Interleukins/metabolism , Killer Cells, Natural/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , fas Receptor/metabolism , Blotting, Western , Cell Line , Cell Line, Tumor , Flow Cytometry , GPI-Linked Proteins/genetics , GPI-Linked Proteins/metabolism , Humans , Intercellular Signaling Peptides and Proteins/genetics , Interleukins/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Proto-Oncogene Protein c-ets-1/genetics , Proto-Oncogene Protein c-ets-1/metabolism , RNA, Small Interfering , Reverse Transcriptase Polymerase Chain Reaction , fas Receptor/genetics , p38 Mitogen-Activated Protein Kinases/genetics , p38 Mitogen-Activated Protein Kinases/metabolism
11.
J Cell Biochem ; 112(3): 894-901, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21328462

ABSTRACT

It is known that vitamin C induces apoptosis in several kinds of tumor cells, but its effect on the regulation of the angiogenic process of tumors is not completely studied. Vascular endothelial growth factor (VEGF) is the most well-known angiogenic factor, and it has a potent function as a stimulator of endothelial survival, migration, as well as vascular permeability. Therefore, we have investigated whether vitamin C can regulate the angiogenic process through the modulation of VEGF production from B16F10 melanoma cells. VEGF mRNA expression and VEGF production at protein levels were suppressed by vitamin C. In addition, we found that vitamin C suppressed the expression of cyclooxygenase (COX)-2 and that decreased VEGF production by vitamin C was also restored by the administration of prostaglandin E2 which is a product of COX-2. These results suggest that vitamin C suppresses VEGF expression via the regulation of COX-2 expression. Mitogen-activated protein kinases are generally known as key mediators in the signaling pathway for VEGF production. In the presence of vitamin C, the activation of p42/44 MAPK was completely inhibited. Taken together, our data suggest that vitamin C can down-regulate VEGF production via the modulation of COX-2 expression and that p42/44 MAPK acts as an important signaling mediator in this process.


Subject(s)
Ascorbic Acid/pharmacology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Vascular Endothelial Growth Factor A/biosynthesis , Animals , Cell Line, Tumor , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/pharmacology , Dinoprostone/pharmacology , Down-Regulation , Enzyme Activation/drug effects , Melanoma, Experimental , Mice , Nitrobenzenes/pharmacology , Phosphorylation , Sulfonamides/pharmacology
12.
Antivir Ther ; 16(1): 17-26, 2011.
Article in English | MEDLINE | ID: mdl-21311105

ABSTRACT

BACKGROUND: Alloferon, an immunomodulatory peptide, has antiviral capability against herpesvirus. In this research, we aimed to investigate the effect of alloferon on the regulation of the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), and its mechanisms. We also assessed the antiviral activity of alloferon on natural killer (NK) cells as an early antiviral immune responder. METHODS: We first examined the change in cell proliferation and the expression of the viral genes in a KSHV-infected cell line, body-cavity-based B lymphoma (BCBL)-1, under the lytic cycle by 12-O-tetradecanoyl-phorbol-13-acetate (TPA) treatment. To elucidate the antiviral mechanism of alloferon, we tested calcium influx and the activation of the extracellular signal-regulated kinase (ERK) pathway. Furthermore, we evaluated the cytotoxicity of NK cells against BCBL-1 by alloferon. RESULTS: Alloferon effectively recovered the suppressed proliferation of BCBL-1 by TPA, which was achieved by the down-regulation of lytic-cycle-related viral genes, RTA, K8 and vIRF2. To clarify the signal transduction pathways related to the regulation of the viral genes by alloferon, we confirmed that the calcium influx into BCBL-1 was apparently inhibited by alloferon, which preceded the suppression of the phosphorylation of ERK and the activation of AP-1 by TPA. Moreover, when NK cells were exposed to alloferon, their cytolytic activity was improved, and this was mediated by the enhancement of perforin/granzyme secretion. CONCLUSIONS: The results of this study suggest that alloferon can be used as an effective antiviral agent for the regulation of the KSHV life cycle by the down-regulation of AP-1 activity and for the the enhancement of antiviral immunity by up-regulation of NK cell cytotoxicity.


Subject(s)
Antiviral Agents/pharmacology , Herpesviridae Infections/metabolism , Herpesvirus 8, Human/metabolism , Peptides/pharmacology , Antiviral Agents/immunology , Calcium/antagonists & inhibitors , Calcium/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation , Extracellular Signal-Regulated MAP Kinases/metabolism , Gene Expression/drug effects , Genes, Viral/drug effects , Genes, Viral/immunology , Granzymes/metabolism , Herpesviridae Infections/genetics , Herpesviridae Infections/immunology , Herpesviridae Infections/virology , Herpesvirus 8, Human/genetics , Herpesvirus 8, Human/immunology , Humans , Immunomodulation/drug effects , Immunomodulation/genetics , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Peptides/immunology , Perforin/metabolism , Phosphorylation/drug effects , Signal Transduction/drug effects , Signal Transduction/immunology , Tetradecanoylphorbol Acetate/immunology , Tetradecanoylphorbol Acetate/pharmacology , Transcription Factor AP-1/antagonists & inhibitors , Transcription Factor AP-1/genetics , Transcription Factor AP-1/metabolism , Up-Regulation , Virus Activation/genetics
13.
Oncol Rep ; 25(1): 23-31, 2011 Jan.
Article in English | MEDLINE | ID: mdl-21109953

ABSTRACT

Intratumoral hypoxia has been correlated with distant metastatic potential. Two hypoxia inducible factors (HIFs), HIF-1α and HIF-2α, are induced by hypoxia, and high expression of these proteins has been correlated to angiogenesis and distant metastasis. Thymosin ß4 (Tß4) is frequently highly expressed in cancer, and this overexpression correlates with malignant progression. The objective of this study was to investigate the clinical correlation of HIF-α with Tß4 and the intracellular functional roles of Tß4 on HIF-α activation. We examined HIF-1α, HIF-2α and Tß4 expressions in clinical human breast carcinoma (n=70) by immunohistochemistry. We show that high expression of HIF-1α and HIF-2α strongly correlates with Tß4 expression (P≤0.0001) and overexpression of Tß4 correlates significantly with patients with lymph node metastasis (P<0.05) of human breast cancer. Additionally, we demonstrate that hypoxia up-regulates intracellular Tß4 protein, which then affects HIF-α activity, which is the key in regulating VEGF expression. We confirmed that hypoxia-induced intracellular Tß4 and HIF-α activities were reduced by interference of Tß4 expression using Tß4 shRNA lentivirus. Vascular epidermal growth factor (VEGF)-A, a well-recognized lymphangiogenic cytokine, was also down-regulated, but VEGF-C and VEGF-D expressions were not affected. These findings suggest that the overexpression of Tß4 is strongly associated with HIF-1α and HIF-2α expression and is also clinicopathologically involved with lymph node metastatic potential of breast cancer through the modulation of HIF-αactivation and induction of VEGF-A. Ultimately, these results highlight Tß4 as a potentially therapeutic target in malignant cancers.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/biosynthesis , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Hypoxia-Inducible Factor 1, alpha Subunit/biosynthesis , Thymosin/biosynthesis , Biomarkers, Tumor/analysis , Blotting, Western , Cell Hypoxia/physiology , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Humans , Immunohistochemistry , Lymphatic Metastasis , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction
14.
J Ocul Pharmacol Ther ; 27(1): 73-6, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21091278

ABSTRACT

PURPOSE: To evaluate the long-term effect of latanoprost on central corneal thickness (CCT) in patients with normal tension glaucoma (NTG). METHODS: This was a retrospective study and included 166 eyes of 166 patients [128 with NTG and 38 with glaucoma suspect, suspicious discs with normal visual fields, and an intraocular pressure (IOP) ≤21 mmHg as the control group]. Patients with newly diagnosed NTG and who had not had previous topical glaucomatous treatment were followed ≥24 months and received latanoprost 0.005% monotherapy once a day. CCT measurements were performed with an ultrasound pachymeter. CCT measurements before treatment and 24 months after treatment were analyzed. RESULTS: There were no significant differences between the latanoprost group and the control group with respect to sex, age, baseline IOP, and CCT. A statistically significant reduction in the mean CCT was observed in the latanoprost group [535.5 ± 37.9 vs. 530.1 ± 36.4 µm (n = 128), P < 0.01], but not in the control group [543.1 ± 40.2 vs. 542.6 ± 37.0 µm (n = 38), P = 0.786]. CONCLUSIONS: Long-term use of latanoprost may decrease the CCT in patients with NTG. Therefore, clinicians must be aware of longitudinal CCT variations that may arise throughout the follow-up period for proper IOP targeting and management.


Subject(s)
Antihypertensive Agents/administration & dosage , Cornea/diagnostic imaging , Low Tension Glaucoma/diagnostic imaging , Low Tension Glaucoma/drug therapy , Prostaglandins F, Synthetic/administration & dosage , Administration, Topical , Adult , Aged , Cornea/drug effects , Drug Administration Schedule , Female , Humans , Intraocular Pressure , Latanoprost , Longitudinal Studies , Low Tension Glaucoma/physiopathology , Male , Middle Aged , Ocular Hypertension/diagnostic imaging , Ocular Hypertension/drug therapy , Ocular Hypertension/physiopathology , Retrospective Studies , Ultrasonography , Visual Fields
15.
J Biol Chem ; 285(11): 7995-8002, 2010 Mar 12.
Article in English | MEDLINE | ID: mdl-20075077

ABSTRACT

The forkhead transcription factor, Foxp3, is thought to act as a master regulator that controls (suppresses) expression of the breast cancer oncogenes, SKP2 and HER-2/ErbB2. However, the mechanisms that regulate Foxp3 expression and thereby modulate tumor development remain largely unexplored. Here, we demonstrate that Foxp3 up-regulation requires p53 function, showing that Foxp3 expression is directly regulated by p53 upon DNA damage responses in human breast and colon carcinoma cells. Treatment with the genotoxic agents, doxorubicin or etoposide, induced Foxp3 expression in p53-positive carcinoma cells, but not in cells lacking p53 function. Furthermore, knock down of endogenous wild-type p53 using RNA interference abrogated Foxp3 induction by genotoxic agents, and exogenous expression of p53 in cells lacking p53 restored the responsiveness of Foxp3 to DNA-damaging stresses. In addition, Foxp3 knock down blunted the p53-mediated growth inhibitory response to DNA-damaging agents. These results suggest that induction of Foxp3 in the context of tumor suppression is regulated in a p53-dependent manner and implicate Foxp3 as a key determinant of cell fate in p53-dependent DNA damage responses.


Subject(s)
Breast Neoplasms/genetics , Colonic Neoplasms/genetics , DNA Damage/genetics , Forkhead Transcription Factors/genetics , Gene Expression Regulation, Neoplastic/genetics , Tumor Suppressor Protein p53/genetics , Antibiotics, Antineoplastic/toxicity , Antineoplastic Agents, Phytogenic/toxicity , Breast Neoplasms/pathology , Cell Death/physiology , Cell Division/physiology , Colonic Neoplasms/pathology , Doxorubicin/toxicity , Etoposide/toxicity , Female , Gene Expression Regulation, Neoplastic/drug effects , HCT116 Cells , Humans , Imidazoles/pharmacology , Phosphorylation/physiology , Piperazines/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Proto-Oncogene Proteins c-mdm2/metabolism
16.
Carcinogenesis ; 30(12): 1987-96, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19638429

ABSTRACT

Cancer cells metastasize to the other site after escaping from the immune system and CD70, CD44 and vascular endothelial growth factor (VEGF) play important roles in this process. It is recently reported that interleukin (IL)-18 is closely related with the pathogenesis of skin tumor. Therefore, we investigated the role of endogenous IL-18 from stomach cancer on the immune escape mechanism and metastasis via the regulation of CD70, CD44 and VEGF expression. IL-18 and IL-18R expressions were not only investigated on tumor tissues (n = 10), and sera (n = 20) from stomach cancer patients, but also on human stomach cancer cell lines. IL-18 and IL-18R expressions were found on stomach cancer cell lines and tumor tissues. In addition, IL-18 levels were elevated in sera from cancer patients (P < 0.05), compared with sera from normal individuals. Changes in CD70, CD44 and VEGF expression by flow cytometry, immunoblotting and enzyme-linked immunosorbent assay and immune susceptibility by (51)Cr-release assay were investigated, after silencing or neutralization of endogenous IL-18. CD70 expression was increased and it increases immune susceptibility of cancer cells. In contrast, CD44 and VEGF expression was decreased and it suppresses neovascularization and the metastasis of stomach cancer. After inoculation of IL-18 small interfering RNA (siRNA)-transfected stomach cancer cells into Balb/C (nu/nu) mice, regression of tumor mass was determined by measuring of tumor size. And the number and location of metastatic lesions were investigated by hematoxylin and eosin staining. The regression of tumor mass and the suppression of metastasis were observed in the mice, which are injected with IL-18 siRNA-transfected cell lines. Our data suggest that endogenous IL-18 might facilitate stomach cancer cell immune escape by suppressing CD70 and increasing metastatic ability by upregulating CD44 and VEGF.


Subject(s)
CD27 Ligand/biosynthesis , Down-Regulation , Gene Expression Regulation, Neoplastic , Hyaluronan Receptors/biosynthesis , Interleukin-18/physiology , Stomach Neoplasms/metabolism , Vascular Endothelial Growth Factor A/metabolism , Animals , Cell Line, Tumor , Female , Humans , Immune System , Interleukin-18/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Metastasis , RNA, Small Interfering/metabolism
17.
Aesthetic Plast Surg ; 33(5): 722-9, 2009 Sep.
Article in English | MEDLINE | ID: mdl-19626359

ABSTRACT

BACKGROUND: Recently, many plastic surgeons have been using adipogenic-differentiated cell implantation for remodeling scars in patients. However, this technique is not a long-term solution because implanted cells disappear gradually. Therefore, we investigated a method to increase the grafted cell preservation rate by using an effective adjuvant, botulinum toxin. METHODS: The adipogenic-differentiated cells were subcutaneously injected in the dorsal area of C57/BL6 mice with or without botulinum toxin. Two and six weeks later we analyzed the residual volume and confirmed the characteristics of the implanted cells by real-time RT-PCR and immunohistochemistry. RESULTS: Two and six weeks after transplantation we found that the residual volume of the transplantation site was higher in the botulinum toxin-treated group than in the untreated group. We also confirmed that the residual transplanted area has characteristics of adipogenic tissue by histological analysis. Next, to determine the mechanism related to the enhanced preservation rate of grafted cells via treatment with botulinum toxin, we performed immunohistochemical staining for the angiogenesis-related marker CD31. We found that CD31 expression was higher in the botulinum toxin-treated group than in the untreated group. CONCLUSION: We have shown that in vivo grafted adipocyte cell preservation can be enhanced by treatment with botulinum toxin as an adjuvant. We suggest that botulinum toxin further increases this graft preservation rate by enhancing angiogenesis.


Subject(s)
Adipocytes/transplantation , Adipogenesis/drug effects , Botulinum Toxins/administration & dosage , Neovascularization, Physiologic/drug effects , Adipocytes/cytology , Adipocytes/drug effects , Adipogenesis/physiology , Animals , Cell Differentiation/physiology , Cell Survival , Cells, Cultured , Disease Models, Animal , Female , Follow-Up Studies , Graft Rejection , Graft Survival , Immunohistochemistry , Injections, Subcutaneous , Male , Mice , Mice, Inbred C57BL , Neovascularization, Physiologic/physiology , Probability , Random Allocation , Reverse Transcriptase Polymerase Chain Reaction , Tissue Engineering
18.
Immunol Lett ; 123(1): 72-6, 2009 Mar 24.
Article in English | MEDLINE | ID: mdl-19369144

ABSTRACT

Thymosin beta 4 (T beta 4), which is the major G-actin sequestering protein, has been shown to have ubiquitous distribution and multiple biological activities. However, T beta 4's functions in relation to natural killer(NK) cells are still unknown. In this study, we show that synthetic T beta 4 peptide increases NK cell cytotoxicity mediated by intercellular adhesion molecule-1 (ICAM-1) through the secretion of cytolytic granules to target cells. This suggests that T beta 4 is a key activator of NK cell cytotoxicity.


Subject(s)
Cytotoxicity, Immunologic , Intercellular Adhesion Molecule-1/immunology , Killer Cells, Natural/immunology , Thymosin/immunology , Cells, Cultured , Exocytosis , Humans , Killer Cells, Natural/drug effects , Lymphocyte Function-Associated Antigen-1/immunology , Peptides/immunology , Peptides/pharmacology , Thymosin/pharmacology , Up-Regulation
19.
Immunol Lett ; 120(1-2): 103-7, 2008 Oct 30.
Article in English | MEDLINE | ID: mdl-18706445

ABSTRACT

Expression of UL16-binding proteins (ULBPs) has been reported in various cancers, such as leukemia and melanoma, and also in some other cancer cell lines. However, the factors that modulate the expression of ULBPs are not well defined. In this study, we investigated the effects of IL-18 on the expression of NKG2D ligands in leukemia cells. IL-18 treatment increased ULBP2 expression in leukemia cells at the mRNA and protein levels. In addition, PD98059 (an ERK1/2 MAPK inhibitor) and SP600125 (a JNK inhibitor) attenuated IL-18-induced ULBP2 expression in a dose-dependent manner. We observed that ERK1/2 and JNK MAPK phosphorylation increased upon treatment with IL-18. IL-18 elevated CD107a expression in cancer cells and increased the cytotoxic activity of NK cells; therefore, we propose that IL-18 increases the susceptibility of target cells by inducing surface expression of ULBP2. Taken together, these findings suggest that IL-18 may play a critical role in regulating ULBP2 expression via the ERK1/2 and JNK MAPK pathways in leukemia cells.


Subject(s)
Gene Expression Regulation, Neoplastic/drug effects , Intercellular Signaling Peptides and Proteins/genetics , Interleukin-18/pharmacology , Leukemia/metabolism , Mitogen-Activated Protein Kinases/metabolism , Anthracenes/pharmacology , Cell Line, Tumor , Cytotoxicity, Immunologic/drug effects , Flavonoids/pharmacology , GPI-Linked Proteins , Humans , Jurkat Cells , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinases/immunology
20.
Korean J Ophthalmol ; 22(1): 6-9, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18323699

ABSTRACT

PURPOSE: To determine the normal reference range of pulsatile ocular blood flow (POBF) values in healthy Korean subjects and to find out the factors that may affect them. METHODS: A total of 280 eyes of 280 normal subjects were included in this study. Best corrected visual acuity (BCVA), intraocular pressure (IOP), axial length, POBF, systemic blood pressure, and pulse rate were measured. The mean, standard deviation, range, and the 5th and 95th percentiles of POBF were calculated, and the influences of various parameters to POBF were determined by multiple regression analyses. RESULTS: The mean POBF value was 766.0+/-221.6 microl/min in men and 1021.1+/-249.5 microl/min in women. The 5th and 95th percentiles for POBF values were 486.0 microl/min and 1140.0 microl/min in men and 672.0 microl/min and 1458.0 microl/min in women. The POBF values were significantly influenced by gender, mean blood pressure, pulse rate, and axial length. CONCLUSIONS: Even though the POBF values were influenced by gender, BP, and axial length, we could define the normal reference range of POBF in healthy Koreans.


Subject(s)
Asian People , Eye/blood supply , Pulsatile Flow/physiology , Adult , Blood Pressure/physiology , Female , Heart Rate/physiology , Humans , Intraocular Pressure/physiology , Korea , Male , Reference Values , Tonometry, Ocular/methods
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