• Molecules and Cells
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• v.41 no.4
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• pp.282-289
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• 2018

Interleukin-17A (IL-17A) is a pro-inflammatory cytokine mainly derived from T helper 17 cells and is known to be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke (CS) has been considered as a primary risk factor of COPD. However, the interaction between CS and IL-17A and the underlying molecular mechanisms have not been clarified. In the current study, we investigated the effects of cigarette smoke extract (CSE) on IL-17A-induced IL-8 production in human bronchial epithelial cells, and sought to identify the underlying molecular mechanisms. IL-8 production was significantly enhanced following treatment with both IL-17A and CSE, while treatment with either IL-17A or CSE alone caused only a slight increase in IL-8 production. CSE increased the transcription of IL-17RA/RC and surface membrane expression of IL-17R, which was suppressed by an inhibitor of the phosphoinositide 3-kinase (PI3K)/Akt pathway (LY294002). CSE caused inactivation of glycogen synthase $kinase-3{\beta}$ ($GSK-3{\beta}$) via the PI3K/Akt pathway. Blockade of $GSK-3{\beta}$ inactivation by overexpression of constitutively active $GSK-3{\beta}$ (S9A) completely suppressed the CSE-induced up-regulation of IL-17R expression and the CSE-induced enhancement of IL-8 secretion. In conclusion, inactivation of $GSK-3{\beta}$ via the PI3K/Akt pathway mediates CSE-induced up-regulation of IL-17R, which contributes to the enhancement of IL-17A-induced IL-8 production.

• Toxicological Research
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• v.34 no.2
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• pp.103-110
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• 2018

Environmental stimuli can lead to the excessive accumulation of reactive oxygen species (ROS), which is one of the risk factors for premature skin aging. Here, we investigated the protective effects of $7-MEGA^{TM}$ 500 (50% palmitoleic acid, 7-MEGA) against oxidative stress-induced cellular damage and its underlying therapeutic mechanisms in the HaCaT human skin keratinocyte cell line (HaCaT cells). Our results showed that treatment with 7-MEGA prior to hydrogen peroxide ($H_2O_2$)-induced damage significantly increased the viability of HaCaT cells. 7-MEGA effectively attenuated generation of $H_2O_2$-induced reactive oxygen species (ROS), and inhibited $H_2O_2$-induced inflammatory factors, such as prostaglandin $E_2$ ($PGE_2$), tumor necrosis $factor-{\alpha}$ ($TNF-{\alpha}$), and $interleukin-1{\beta}$ ($IL-1{\beta}$). In addition, cells treated with 7-MEGA exhibited significantly decreased expression of matrix metalloproteinase-1 (MMP-1) and increased expression of procollagen type 1 (PCOL1) and Elastin against oxidative stress by $H_2O_2$. Interestingly, these protective activities of 7-MEGA were similar in scope and of a higher magnitude than those seen with 98.5% palmitoleic acid (PA) obtained from Sigma when given at the same concentration (100 nL/mL). According to our data, 7-MEGA is able to protect HaCaT cells from $H_2O_2$-induced damage through inhibiting cellular oxidative stress and inflammation. Moreover, 7-MEGA may affect skin elasticity maintenance and improve skin wrinkles. These findings indicate that 7-MEGA may be useful as a food supplement for skin health.

• The Korean Journal of Physiology and Pharmacology
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• v.9 no.5
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• pp.299-304
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• 2005

Cardiac hypertrophy contributes an increased risk to major cerebrovascular events. However, the molecular mechanisms underlying cerebrovascular dysfunction during cardiac hypertrophy have not yet been characterized. In the present study, we examined the molecular mechanism of isoproterenol (ISO)-evoked activation of Ras/Raf/MAPK pathways as well as PKA activity in cerebral artery of rabbits, and we also studied whether the activations of these signaling pathways were altered in cerebral artery, during ISO-induced cardiac hypertrophy compared to heart itself. The results show that the mRNA level of c-fos (not c-jun and c-myc) in heart and these genes in cerebral artery were considerably increased during cardiac hypertrophy. These results that the PKA activity and activations of Ras/Raf/ERK cascade as well as c-fos expression in rabbit heart during cardiac hypertrophy were consistent with previous reports. Interestingly, however, we also showed a novel finding that the decreased PKA activity might have differential effects on Ras and Raf expression in cerebral artery during cardiac hypertrophy. In conclusion, there are differences in molecular mechanisms between heart and cerebral artery during cardiac hypertrophy when stimulated with β2 adrenoreceptor (AR), suggesting a possible mechanism underlying cerebrovascular dysfunction during cardiac hypertrophy.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.1
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• pp.495-499
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• 2014

Estrogens are considered the major breast cancer risk factor, and the carcinogenic potential of estrogens might be attributed to DNA modification caused by derivatives formed during metabolism. $17{\beta}$-estradiol ($E_2$), the main steroidal estrogen present in women, is metabolized via two major pathways: formation of 2-hydroxyestradiol (2-OH $E_2$) and 4-hydroxyestradiol ($4-OH\;E_2$) through the action of cytochrome P450 (CYP) 1A1 and 1B1, respectively. Previous reports suggested that $2-OH\;E_2$ has putative protective effects, while $4-OH\;E_2$ is genotoxic and has potent carcinogenic activity. Thus, the ratio of $2-OH\;E_2/4-OH\;E_2$ is a critical determinant of the toxicity of $E_2$ in mammary cells. In the present study, we investigated the effects of berberine on the expression profile of the estrogen metabolizing enzymes CYP1A1 and CYP1B1 in breast cancer MCF-7 cells. Berberine treatment produced significant induction of both forms at the level of mRNA expression, but with increased doses produced 16~ to 52~fold greater induction of CYP1A1 mRNA over CYP1B1 mRNA. Furthermore, berberine dramatically increased CYP1A1 protein levels but did not influence CYP1B1 protein levels in MCF-7 cells. In conclusion, we present the first report to show that berberine may provide protection against breast cancer by altering the ratio of CYP1A1/CYP1B1, could redirect $E_2$ metabolism in a more protective pathway in breast cancer MCF-7 cells.

• Journal of Plant Biotechnology
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• v.40 no.4
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• pp.192-197
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• 2013

This study examined the phenotypic and molecular characteristics of the $2^{nd}$ clone ($T_0V_2$) plants of LeLs-antisense gene-transgenic chrysanthemum line (LeLs80) that exhibited non-branching, proving the relevance of these characteristics as a factor for use in environmental risk assessment. Results of the Southern blot analysis showed that three copies of the LeLs-antisense gene were introduced into the transgenic line, and northern analysis showed that the transcripted gene was normally expressed in the transgenic line. A flanking T-DNA sequencing method was used to determine that sequences of 184 and 464 bps flanked the LeLs-antisense gene in the transgenic line. These sequences, respectively, matched the 35S promoter for expression of the npt II gene and the NOS terminator for expression of the LeLs-antisense gene within the pCAMBIA 2300 vector.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.12
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• pp.5043-5047
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• 2015

Background: Relatively little is known with certainty about the status and role of p53 or MDM2 in predicting prognosis and survival of renal cell carcinoma. The present study aimed to determine the value of P53 and MDM2 over-expression, alone and simultaneously, to predict five-year survival of patients with kidney cancer in Iran. Materials and Methods: Patients with kidney cancer referred to Hasheminejad Kidney Center between 2007 and 2009, underwent radical nephrectomy and had pathology reports of clear cell, papillary or chromophobe renal cell carcinoma were included in our cohort study. Other histological types of renal cell carcinoma were not included. The patients with missed, incomplete or poor quality paraffin blocks were also excluded. Overall ninety one patients met the inclusion and exclusion criteria. To assess the histopathological features of the tumor, immunohistochemical (IHC) staining of formalin fixed, paraffin-embedded tumor samples were performed. The five-year survival was determined by the patients' medical files and telephone following-up. Results: In total, 1.1% of all samples were revealed to be positive for P53. Also, 20.8% of all samples were revealed to be positive for MDM2.The patients were all followed for 5 years. In this regard, 5-year mortality was 30.5% and thus 5-year survival was 85.3%. According to the Cox proportional hazard analysis, positive P53 marker was only predictor for patients' 5-year survival that the presence of positive p53 increased the risk for long-term mortality up to 2.8 times (HR=2.798, 95%CI: 1.176-6.660, P=0.020). However, the presence of MDM2 could not predict long-term mortality. In this regard, analysis by the ROC curve showed a limited role for predicting long-term survival by confirming P53 positivity (AUC=0.610, 95%CI: 0.471-.750, P=0.106). The best cutoff point for P53 to predict mortality was 0.5 yielding a low sensitivity (32.0%) but a high specificity (97.9%). In similar analysis, measurement of MDM2 positivity could not predict mortality (AUC=0.449, 95%CI: 0.316-.583, P=0.455). Conclusions: The simultaneous presence of both P53 and MDM2 markers in our population is a rare phenomenon and the presence of these markers may not predict long-term survival in patients who undergoing radical nephrectomy.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.8
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• pp.4751-4758
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• 2013

Background: To investigate the predictive and prognostic effects of clinicopathologic and immunohistochemical (IHC) features in patients with gastrointestinal stromal tumours (GISTs). Materials and Methods: Fifty-six patients who were diagnosed with GIST between 2002 and 2012 were retrospectively evaluated. Relationships between clinicopathologic/immunohistochemical factors and prognosis were investigated. Results: Median overall survival (OS) of the whole study group was 74.9 months (42.8-107.1 months), while it was 95.2 months in resectable and 44.7 months in metastatic patients respectively (p=0.007). Epitheliolid tumor morphology was significantly associated with shortened OS as compared to other histologies (p=0.001). SMA(+) tumours were significantly correlated with low (<10/50HPF) mitotic activity (p=0.034). Moreover, SMA(+) patients tended to survive longer and had significantly longer disease-free survival (DFS) times than SMA (-) patients (37.7 months vs 15.9 months; p=0.002). High Ki-67 level (${\geq}30%$) was significantly associated with shorter OS (34 vs 95.2 months; 95%CI; p=0.001). CD34 (-) tumours were significantly associated with low proliferative tumours (Ki-67<%10) (p=0.026). Median PFS (progression-free survival) of the patients who received imatinib was 36 months (27.7-44.2 months). CD34 (-) patients had significantly longer PFS times than that of negative tumours; (50.8 vs 29.8 months; p=0.045). S100 and desmin expression did not play any role in predicting the prognosis of GISTs. Multivariate analysis demonstrated that ${\geq}10/50HPF$ mitotic activity/HPF was the only independent factor for risk of death in GIST patients. Conclusions: Despite the negative prognostic and predictive effect of high Ki-67 and CD34 expression, mitotic activity remains the strongest prognostic factor in GIST patients. SMA positivity seems to affect GIST prognosis positively. However, large-scale, multicenter studies are required to provide supportive data for these findings.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3319-3322
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• 2013

Background: Helicobacter pylori (H. pylori) is one of the risk factors for gastric cancer (GC). Any prognostic effect of HER-2 status in gastric lymph node metastasis in H. pylori positive cases is unknown. Materials and Methods: A total of 74 patients, 47 (64%) male, and 27 (34%) female, who had subtotal or total gastrectomy and also positive lymph nodes, were included in the study. Age range was 29-87 years, and median age was 58 years. HER-2 expression was assessed in both gastric resection samples and lymph node material with carcinoma metastasis of the same patient by immunohistochemistry (IHC) and silver in situ hybridization (SISH) methods. H. pylori status was examined in gastric materials of all patients. Relationships between HER-2 status in gastric cancers and lymph nodes and H. pylori status were investigated. Results: H. pylori was positive in 40 cases (54%), and negative in 34 (46%). While in the primary tissues of H. pylori positive cases, SISH positivity for HER-2 was observed in 13 cases (86%), SISH negativity was observed in 2 (14%), in metastatic lymph nodes 21 cases (72%) were SISH positive and 8 cases (28%) were SISH negative (P=0.005 and P=0.019, respectively). Initial CEA values were high in 18 cases (78%) with positive H. pylori and in 5 cases (22%) with negative H. pylori (P=0.009). While SISH data of patients were negative in 59 cases (80%) and positive in 15 cases (20%) in primary tissues, they were negative in 56 cases (75%) and positive in 18 cases (25%) in lymph nodes. Discrepancy between primary tissue and lymph node results was detected in 3 cases, in which SISH was negative in the primary tissue and HER-2 expression was positive in the lymph nodes. Conclusions: Clinical progression was poor in H. pylori positive cases with HER-2 negativity in primary gastric tissue, but HER-2 positivity in the lymph nodes. SISH positivity can be expected in H. pylori positive cases, and it may be predicted that these cases can benefit from trastuzumab treatment.

• Journal of the Korean Society of Food Science and Nutrition
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• v.41 no.8
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• pp.1106-1111
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• 2012

It is shown that the risk of chronic disease is increased not only by the concentration of fat in the diet but also by the composition of dietary fatty acids. We investigated the anti-oxidant effects of vitamin E on dietary polyunsaturated fatty acid-fed mice. Ninety male Sprague-Dawley rats were randomly divided into 9 groups: a normal diet group (C), 4 dietary polyunsaturated fatty acid diet groups (OA, LA, LNA, DHA), and 4 dietary polyunsaturated fatty acid diet with 0.05% vitamin E groups (OAE, LAE, LNAE, DHAE). The food efficiency in the dietary polyunsaturated fatty acid diet groups was higher than in the normal diet groups. The concentration of malondialdehyde (MDA) was significantly increased by LA and DHA fatty acids. Vitamin E significantly decreased LA and LHA-induced lipid peroxidation. The activity of superoxide dismutase and glutathione peroxidase was increased in the dietary polyunsaturated fatty acid diet groups compared to the control group, while these were decreased by supplements with vitamin E, except in the OAE group. Also, the protein expression of CYP2E1 was significantly increased in only the LNA group, while these were decreased by supplements with vitamin E. These results taken together indicate that vitamin E may have positive effects on a dietary polyunsaturated fatty acid diet-induced oxidative stress in brain tissue.

• Journal of Life Science
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• v.21 no.11
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• pp.1636-1640
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• 2011

Alzheimer's disease (AD) is a progressive neurodegenerative disease, resulting in the loss of cognitive function. Mitochondrial aldehyde dehydrogenase (ALDH2) has been proposed to be a risk factor for the development of AD, but there is still controversy about that. In this study, we demonstrated the role of ALDH2 enzyme activity on amyloid-beta (A${\beta}$) and nuclear factor kappa B (NF-${\kappa}B$) expression in mice brain following ethanol exposure for 8 weeks. Five male Aldh2 (+/+) and Aldh2 (-/-) mice, 8 weeks-old of age (C57BL/6J strain), in each group were exposed to ethanol for 8 weeks (2 g/kg wt./day) using gavage. Those in the control groups received 0.9% saline alone. Results showed a difference in expression level of A${\beta}$ in the hippocampus after ethanol exposure according to the ALDH2 enzyme activity (p<0.05), but not in the level of NF-${\kappa}B$). Our results suggest a possibility that ALDH2 enzyme activity may be an important role in the development of AD.