• Journal of Life Science
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• v.30 no.9
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• pp.826-833
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• 2020

Phospholipase C gamma (PLCγ) has critical roles in receptor tyrosine kinase- and non-receptor tyrosine kinase-mediated cellular signaling relating to the hydrolysis of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P₂] to produce inositol 1,4,5 trisphosphate (IP₃) and diacylglycerol (DAG), which promote protein kinase C (PKC) and Ca²⁺ signaling to their downstream cellular targets. PLCγ has two isozymes called PLCγ1 and PLCγ2, which control cell growth and differentiation. In addition to catalytically active X- and Y-domains, both isotypes contain two Src homology 2 (SH2) domains and an SH3 domain for protein-protein interaction when the cells are activated by ligand stimulation. PLCγ also contains two pleckstrin homology (PH) domains for membrane-associated phosphoinositide binding and protein-protein interactions. While PLCγ1 is widely expressed and appears to regulate intracellular signaling in many tissues, PLCγ2 expression is restricted to cells of hematopoietic systems and seems to play a role in the regulation of immune response. A distinct mechanism for PLCγ activation is linked to an increase in phosphorylation of specific tyrosine residue, Y783. Recent studies have demonstrated that PLCγ mutations are closely related to cancer, immune disease, and brain disorders. Our review focused on the physiological roles of PLCγ by means of its structure and enzyme activity and the pathological functions of PLCγ via mutational analysis obtained from various human diseases and PLCγ knockout mice.

• Environmental Analysis Health and Toxicology
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• v.31
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• pp.10.1-10.8
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• 2016

Objectives Aromatase inhibitors that block estrogen synthesis are a proven first-line hormonal therapy for postmenopausal breast cancer. Although it is known that standardized extract of Ginkgo biloba (EGb761) induces anti-carcinogenic effects like the aromatase inhibitors, the effects of EGb761 on steroidogenesis have not been studied yet. Therefore, the effects of EGb761 on steroidogenesis and aromatase activity was studied using a H295R cell model, which was a good in vitro model to predict effects on human adrenal steroidogenesis. Methods Cortisol, aldosterone, testosterone, and $17{\beta}$-estradiol were evaluated in the H295R cells by competitive enzyme-linked immunospecific assay after exposure to EGb761. Real-time polymerase chain reaction were performed to evaluate effects on critical genes in steroid hormone production, specifically cytochrome P450 (CYP11/ 17/19/21) and the hydroxysteroid dehydrogenases ($3{\beta}$-HSD2 and $17{\beta}$-HSD1/4). Finally, aromatase activities were measured with a tritiated water-release assay and by western blotting analysis. Results H295R cells exposed to EGb761 (10 and $100{\mu}g/mL$) showed a significant decrease in $17{\beta}$-estradiol and testosterone, but no change in aldosterone or cortisol. Genes (CYP19 and $17{\beta}$-HSD1) related to the estrogen steroidogenesis were significantly decreased by EGb761. EGb761 treatment of H295R cells resulted in a significant decrease of aromatase activity as measured by the direct and indirect assays. The coding sequence/Exon PII of CYP19 gene transcript and protein level of CYP19 were significantly decreased by EGb761. Conclusions These results suggest that EGb761 could regulate steroidogenesis-related genes such as CYP19 and $17{\beta}$-HSD1, and lead to a decrease in $17{\beta}$-estradiol and testosterone. The present study provides good information on potential therapeutic effects of EGb761 on estrogen dependent breast cancer.

• Journal of Periodontal and Implant Science
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• v.37 no.3
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• pp.497-509
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• 2007

Bone morphogenetic proteins(BMPs) are regarded as members of the transforming growth $factor-{\beta}$ superfamily with characteristic features in their amino acid sequences. A number of studies have demonstrated the biologic activities of BMPs, which include the induction of cartilage and bone formation. Recently there was a attempt to overcome a limitation of mass production, and economical efficieny of rh-BMPs. The method producing PTD by using bacteria have advantages of acquiry a mass of proteins. Hences, a new treatment which deliver protein employed by protein transduction domain(PTD) has been tried. The purpose of this study was to evaluate the bone regenerative effect of TATBMP-2 and TAT-HA2-BMP-2 employed by PTD from HlV-1 TAT protein for protein translocation in the rat calvarial model. An 8mm calvarial, critical size osteotomy defect was created in each of 32 male Spraque-Dawley rats(weight $250{\sim}300g$). The animals were divided into 4 groups of 32 animals each (4 animals/group/healing interval). The defect was treated with TATBMP-2/ACS(Absorbable collagen sponge) (TATBMP-2 0.1mg/ml), TAT-HA2-BMP-2/ACS(TAT-HA2-BMP-2 0.1mg/ml), ACS alone or left untreated for surgical control(negative control). The rats were sacrificed at 2 or 8 weeks postsurgery, and the results were evaluated histologically. The results were as follows: New bone formation were not significantly greater in the TATBMP-2/ACS group relative to negative, and positive control groups. New bone was evident at the defect sites in TAT-HA2-BMP-2/ACS group relative to negative, positive control and TATBMP-2 groups. There were a little bone regeneration in TATBMP-2 groups. While, enhanced local bone formation were observed in TAT-HA2-BMP-2 group. But, The results was not the same in all rat defects. Therefore, further investigations are required to develop a method. which disperse homogenously, and adhere to target cells.

• Korean Journal of Clinical Pharmacy
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• v.23 no.4
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• pp.365-372
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• 2013

Background: Malnutrition of inpatients has been associated with higher morbidity, mortality, cost, and longer hospital stay. Total parenteral nutrition (TPN) therapy plays an important role in decreasing morbidity and mortality among critical inpatients in hospitals, and has been commonly used to improve clinical outcomes. However, only a few studies were conducted regarding patients' nutritional improvement by TPN. Method: This study therefore evaluated the changes in nutritional parameters by TPN therapy for early malnourished inpatients. Data from early malnourished inpatients who were treated with TPN therapy between January 2012 and June 2013 at the ${\bigcirc}{\bigcirc}$ university Hospital were studied retrospectively. Information regarding sex, age, underlying diseases, division, TPN (peripheral and central), and changes in nutritional parameters were collected by reviewing electronic medical records. The criteria for evaluation of the changes in nutritional parameters were included physical marker, body mass index (BMI), and biochemical markers, including albumin (Alb), total lymphocyte count (TLC), and cholesterol. Nutritional parameters were collected three times: pre-TPN, mid-TPN and end-TPN. A total of 149 patients (peripheral, 97; central, 52) was evaluated. Results: In all patients, the malnutrition number was significantly decreased following the complete TPN therapy (peripheral patients, pre-TPN: $3.33{\pm}0.12$, mid-TPN : $3.06{\pm}0.17$, and end-TPN: $2.85{\pm}0.21$ (p < 0.05); central patients, pre-TPN: $3.38{\pm}0.11$, mid-TPN: $3.06{\pm}0.13$, and end-TPN: $2.75{\pm}0.21$ (p < 0.05). The malnutrition number means number of nutrition parameters below normal range of malnutrition. In addition, all of the four nutritional parameters (BMI, Alb, TLC and cholesterol) were increased with duration of TPN periods for all patients, and the changes in the early stage were larger than in the late stage (p < 0.05). The nutritional parameters of non-cancer patients were increased to a greater extent compared to cancer patients with longer TPN therapy, but it was not significant. The nutritional parameters of younger patients (50-60 years) were also increased more than of older patients (70-80 years), but it was not significant. Conclusion: In conclusion, the TPN therapy decreases malnutritional status and improves nutritional parameters in malnourished patients, thereby decreasing morbidity and mortality. The combined evaluation of all four nutritional parameters is more accurate for nutritional assessment than a single one.

• The Korean Journal of Pharmacology
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• v.18 no.1
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• pp.65-72
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• 1982

It has been known that retinoids are intrinsically of critical importance for control of premalignant epithelial cell differentiation. In the absence of retinoids, normal cellular differentiation and growth does not occur in epithelia such as those of trachea and bronchi. Furthermore, it was also reported that retinoid deficiency enhanced susceptibility to chemical carcinogenesis in the respiratory system, in the bladder, and in the colon of the experimental animal. In 1974, Bollag examined the effects of synthetic retinoids in prevention of development of cancer and demonstrated synthetic retinoids to have more favorable therapeutic index than retinoic acid for causing regression of skin papilloma in mice. Therefore, it was assumed that this anticarcinogenic effect of vitamin A derivatives could be due to modification of the metabolism of the carcinogenic polycyclic hydrocarbon, which must first be activated to exert their effect. Hill and Shih reported that vitamin A compounds and analogs had inhibitory effect on drug metabolizing enzyme from liver and lung tissue of mouse and hamster. Lucy suggested that the chemoprevention effect of vitamin A derivatives is due to reaction with molecular oxygen, and it is possible that inhibition of hydroxybenzpyrene formation is a result of this property. On the other hand, butylated hydroxytoluene which is a potent antioxidant strongly inhibited the formation of mammary tumor induced by dimethylbenranthracene. Also, it was observed that this antioxidant inhibited cancer induction in rats by N-2-fluo-renylacetamide. The purpose of this experiment was to investigate the effect of vitamin A derivatives such as retinoic acid and retinoid on drug-metabolizing enzyme and to determine whether riboflavin tetrabutylate or vitamin E could prevent of modify any changes induced by vitamin A delivatives in the rats. The results obtained were as followings. 1) Body weight was significantly reduced by retinoic acid, but not by retinoid. 2) Retinoic acid markedly increased liver weight while retincid showed no effect on liver weight. Treatment of riboflavin tetrabutylate did not affect retinoic acid-induced change in both body weight and liver weight. 3) Both retinoic acid and retinoid remarkably decreased the activity of aminopyrine demethylase. Pretreatment of riboflavin tetrabutylate, however, prevented inhibitory effect of retinoic acid on the enzyme activity. 4) No significant effect of vitamin E on aminopyrine demethylase was observed in both groups treated with retinoic acid and retinoid.

• Korean Journal of Clinical Laboratory Science
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• v.50 no.1
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• pp.11-19
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• 2018

The gut microbiome has been studied extensively over the past decade with most scientific reports focused on the adverse role of the gut microbiome on gastrointestinal diseases. For example, the altered gut microbiome exacerbates the development of immune system-mediated damage in many diseases. The most studied pathologies include irritable bowel syndrome, inflammatory bowel diseases, and colitis-associated cancer. On the other hand, intestinal microflora is also beneficial and contributes to the intestinal physiology by the synthesis of vitamins, production of short chain fatty acids and bile acid metabolism, thereby maintaining gut homeostasis. Therefore, the balance between commensal and pathogenic bacteria populations influences mainly the maintenance of intestinal health. Changes in the intestinal microflora have been suspected to be the underlying causes of multiple diseases. Despite the immense amount of published data, the optimal gut microbiome composition is still controversial. This review briefly outlines the connection between the gut microbiome and critical gastrointestinal diseases focusing on three prominent intestinal disorders: irritable bowel syndrome, inflammatory bowel diseases, and colitis-associated cancer disorders. Finally, intervention strategies using natural products for the alleviation of these diseases and the maintenance of a health gut microbiome are suggested.

• Korean Journal of Head & Neck Oncology
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• v.17 no.2
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• pp.169-173
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• 2001

Objectives: The p53 tumor suppressor gene encodes a nuclear transcription factor that is critical regulator of cell growth and proliferation through its action in cell-cycle checkpoint control. The wide variety of stressful stmuli which include DNA damage, hypoxia, heat shock, metabolic changes activate the p53 protein, which in turn drives a series of events that culminate either in cell cycle arrest or apoptosis. Mutations of the p53 gene is the most common genetic alteration in human cancer. This gene is altered in approximately 40-60% of head and neck cancers. Whereas the wild-type form of the p53 protein plays a central role in cell-cycle control in response to DNA damage, most of the mutant forms are unable to do so. The high levels of p53 protein expression in tissues are related to the increased cellular proliferative activity and may be associated with the poor clinical outcome. To determine whether the expression of the p53 protein has prognostic significance and is associated with patterns of treatment failure in head and neck squamous cell carcinoma (HNSCC), We analyzed p53 overexpression in 40 cases of HNSCC. Materials and Methods: Immunohistochemical analysis with a monoclonal antibody (DO7) specific for p53 protein was used to detect expression of the protein in formalin-fixed, paraffin-embedded tumor samples from 40 HNSCC. We evaluated p53 protein expression and analyzed the relationship between the p53 overexpression and age, sex, primary tumor site, stage, survival rate, recurrence. All reported P values resulted from two-sided statistical tests. Results: Overexpression of p53 was detected in 20 cases(50%) among 40 cases of HNSCC. The p53 overexpression was not associated with age, sex, primary tumor site, stage, recurrence and survival rate. Conclusions: In our results, p53 was not significant prognostic factor in HNSCC. Based on many previous studies, It is evident that p53 has a certain role in tumorigenesis of HNSCC. So, the further study is needed to evaluate the prognostic significance of p53 in HNSCC.

• Clinical and Experimental Pediatrics
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• v.48 no.5
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• pp.495-499
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• 2005

Purpose : Interleukin-4(IL-4) is a critical component of the Th2 cytokine pathway and contributes to severity of respiratory syncytial virus(RSV) bronchiolitis. Previous studies observed an association between severe RSV bronchiolitis in Korean children with a common haplotype of the IL4 promoter. This study was performed to investigate functional differences of the variant IL4 promoter haplotypes. Methods : Genomic DNA was obtained from 20 children from 6 to 48 months of age in the Department of Pediatrics, Seoul National University Bundang Hospital. The IL4 promoter spanning an 1.2 kb region was amplified and haplotype was determined by cloning and the PHASE reconstruction. Transcriptional activity of Jurkat T cells which were transfected with each IL4 haplotype were analyzed by use of luciferase assay. Results : Three haplotypes of the IL4 promoter have been identified with the frequency of GCC(7 percent), TCC(17 percent), and TTT(76 percent). The TTT haplotype demonstrated the highest luciferase values in both unstimulated and PMA-stimulated Jurkat T cells. Increases in transcriptional activity compared to GCC have been shown in TTT(5.3 fold higher) followed by TCC(4.2 fold higher) in unstimulated Jurkat T cells. Conclusion : We provided evidence that increased transcriptional activity of the TTT haplotype of the IL4 promoter, which has previously been over-represented in Korean children with severe RSV bronchiolitis. Therefore, IL-4 could play a potential role in the pathogenesis of RSV infection, possibly via an altered transcriptional activity of the different IL4 haplotypes.

• Journal of Life Science
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• v.28 no.4
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• pp.488-495
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• 2018

The p53 gene plays a critical role in the transcriptional regulation of cellular response to stress, DNA damage, hypoxia, and tumor development. Keeping in mind the recently discovered manifold physiological functions of p53, its involvement in the regulation of cancer is not surprising. In about 50% of all human cancers, inactivation of p53's protein function occurs either through mutations in the gene itself or defects in the mechanisms that activate it. This disorder plays a crucial role in tumor evolution by allowing the evasion of a p53-dependent response. Many recent studies have focused on directly targeting p53 mutants by identifying selective, small molecular compounds to deplete them or to restore their tumor-suppressive function. These small molecules should effectively regulate various interactions while maintaining good drug-like properties. Among them, the discovery of the key p53-negative regulator, MDM2, has led to the design of new small molecule inhibitors that block the interaction between p53 and MDM2. Some of these small molecule compounds have now moved from proof-of-concept studies into clinical trials, with prospects for further, more personalized anti-carcinogenic medicines. Here, we review the structural and functional consequences of wild type and mutant p53 as well as the development of therapeutic agents that directly target this gene, and compounds that inhibit the interaction between it and MDM2.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.17
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• pp.7547-7554
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• 2015

Background: The use of smokeless tobacco (SLT) among women is increasing in India, especially among those with limited education and resources. Preventing the initiation of SLT among women is critical since it has known negative consequences for oral and reproductive health. Most research on tobacco initiation in India focuses on adolescents. This paper addresses the unrecognized issues of post marital initiation among women of reproductive age, highlighting the importance of reproductive stages in women's tobacco initiation. The objective is to examine the correlates of SLT initiation among low income women in Mumbai from pre-marriage through early marriage, first pregnancy and beyond, using case examples to illustrate initiation during each of these stages. Materials and Methods: In 2011-2012, cross-sectional community level survey data were collected from a representative sample of 409 daily SLT-using married women aged 18-40 years in a low income community in Mumbai. Information on socio-demographics, initiation by reproductive stage, types of tobacco use, childhood exposure to tobacco, learning to use, and initiation influences and reasons were collected through a researcher-administered survey. Univariate and bivariate analysis assessed factors influencing initiation of SLT use by reproductive stage. In addition 42 narratives of tobacco use were collected from a purposive sample of pregnant and non-pregnant married women addressing the same questions in detail. Narratives were transcribed, translated, and coded for key concepts including initiation of tobacco use. Results: Thirty-two percent of women initiated SLT use before marriage, 44% initiated after marriage but before pregnancy, 18.1% initiated during their first pregnancy and the remainder started after their first pregnancy. Mean age of marriage among women in this study was 16 years. Younger women (i.e. age at time of the interview of less than 30 years) were 0.47 [95% CI (0.32, 0.87)] percent less likely to initiate after marriage than women aged more than 30 years. Women who got married before 18 years of age were 2.34 [95% CI (1.40, 3.93)] times more likely to initiate after marriage than their counterparts. Childhood exposure was a predictor for initiating SLT use prior to marriage but not after. Women reporting tooth and gum pain were 1.85 times more likely to initiate after marriage than their counterparts. Husband and neighbours were the most significant influences on post-marital initiation. Narratives highlighted differences in processes of initiation pre and post marriage and during pregnancy. Conclusions: Most tobacco prevention interventions are directed to adolescents in school. This study suggests that especially for low literate or illiterate women, school based interventions are ineffective. To be effective strategies to prevent SLT initiation must reach women in urban areas at or immediately after marriage and during their first pregnancy. Messages must negate culturally rooted beliefs about the health benefits of SLT in order to prevent initiation and onset of daily use.