• Biomolecules & Therapeutics
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• v.23 no.4
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• pp.320-326
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• 2015

The clinical benefits of oncogenic BRAF inhibitor therapies are limited by the emergence of drug resistance. In this study, we investigated the role of a negative regulator of the MAPK pathway, Spry2, in acquired resistance using BRAF inhibitor-resistant derivatives of the BRAF-V600E melanoma (A375P/Mdr). Real-time RT-PCR analysis indicated that the expression of Spry2 was higher in A375P cells harboring the BRAF V600E mutation compared with wild-type BRAF-bearing cells (SK-MEL-2) that are resistant to BRAF inhibitors. This result suggests the ability of BRAF V600E to evade feedback suppression in cell lines with BRAF V600E mutations despite high Spry2 expression. Most interestingly, Spry2 exhibited strongly reduced expression in A375P/Mdr cells with acquired resistance to BRAF inhibitors. Furthermore, the overexpression of Spry2 partially restored sensitivity to the BRAF inhibitor PLX4720 in two BRAF inhibitor-resistant cells, indicating a positive role for Spry2 in the growth inhibition induced by BRAF inhibitors. On the other hand, long-term treatment with PLX4720 induced pERK reactivation following BRAF inhibition in A375P cells, indicating that negative feedback including Spry2 may be bypassed in BRAF mutant melanoma cells. In addition, the siRNA-mediated knockdown of Raf-1 attenuated the rebound activation of ERK stimulated by PLX4720 in A375P cells, strongly suggesting the positive role of Raf-1 kinase in ERK activation in response to BRAF inhibition. Taken together, these data suggest that RAF signaling may be released from negative feedback inhibition through interacting with Spry2, leading to ERK rebound and, consequently, the induction of acquired resistance to BRAF inhibitors.

• Biomolecules & Therapeutics
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• v.28 no.5
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• pp.389-396
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• 2020

Valproic acid is a clinically used mood stabilizer and antiepileptic drug. Valproic acid has been suggested as a teratogen associated with the manifestation of neurodevelopmental disorders, such as fetal valproate syndrome and autism spectrum disorders, when taken during specific time window of pregnancy. Previous studies proposed that prenatal exposure to valproic acid induces abnormal proliferation and differentiation of neural progenitor cells, presumably by inhibiting histone deacetylase and releasing the condensed chromatin structure. Here, we found valproic acid up-regulates the transcription of T-type calcium channels by inhibiting histone deacetylase in neural progenitor cells. The pharmacological blockade of T-type calcium channels prevented the increased proliferation of neural progenitor cells induced by valproic acid. Differentiated neural cells from neural progenitor cells treated with valproic acid displayed increased levels of calcium influx in response to potassium chloride-induced depolarization. These results suggest that prenatal exposure to valproic acid up-regulates T-type calcium channels, which may contribute to increased proliferation of neural progenitor cells by inducing an abnormal calcium response and underlie the pathogenesis of neurodevelopmental disorders.

• Korean Journal of Acupuncture
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• v.26 no.4
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• pp.39-52
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• 2009

Objectives : Cue reactivity is a key factor that modulates motivational goal-directed behavior associated with compulsive drug-taking and relapse. We investigated whether acupuncture attenuated the skin conductance response and the heart rate response to smoking-related visual cues in smokers. Methods : Twenty-nine smokers were treated with real acupuncture (RA) or sham acupuncture (SA). The stress response inventory was measured on the 5th day after quitting smoking. The skin conductance response and the heart rate were measured to evaluate the autonomic changes to the smoking related visual cues on the same day. Results : The sympathetic alterations in skin conductance and the heart rate induced by the smoking-related visual cues were significantly lower in the RA group, as compared to the SA group. The stress response inventory, such as somatization and frustration, in the RA group was significantly lower than that of the SA group. Conclusions : Acupuncture ameliorated the stress symptoms as well as the sympathetic activation to smoking cues during withdrawal. These findings indicate that acupuncture might be a useful tool in smoking cessation by inhibiting smoking cues-induced autonomic responses.

• Current Research on Agriculture and Life Sciences
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• v.31 no.3
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• pp.157-164
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• 2013

Chromatin remodelers that include histone methyl transferases (HMTases) are becoming a focal point in cancer drug development. The NSD family of three HMTases, NSD1, NSD2/MMSET/WHSC1, and NSD3/WHSC1L are bona fide oncogenes found aberrantly expressed in several cancers, suggesting their potential role for novel therapeutic strategies. Several histone modifiers including HMTase have clear roles in human carcinogenesis but the extent of their functions and regulations are not well understood, especially in pathological conditions. The extents of the NSDs biological roles in normal and pathological conditions remain unclear. In particular, the substrate specificity of the NSDs remains unsettled and discrepant data has been reported. NSD2/MMSET is a focal point for therapeutic interventions against multiple myeloma and especially for t(4;14) myeloma, which is associated with a significantly worse prognosis than other biological subgroups. Multiple myeloma is the second most common hematological malignancy in the United States, after non-Hodgkin lymphoma. Herein, as a first step before entering a pipeline for protein x-ray crystallography, we cloned, recombinantly expressed and purified the catalytic SET domain of NSD2. Next, we demonstrated the catalytic activities, in vitro, of the recombinantly expressed NSD2-SET on H3K36 and H4K20, its biological targets at the chromatin.

• Journal of Radiation Industry
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• v.3 no.1
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• pp.25-29
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• 2009

Microarrays can be used to screen thousands of binding events in a parallel and high throughput fashion and are of major importance in disease diagnosis and drug discovery. The use of radioisotope is conventionally regarded as one of the most sensitive detection methods. Atherosclerosis is a common disorder affecting arterial blood vessels. It happens when fat, cholesterol, and other substances made in the arterial blood vessels form a hard substances called plaque. Lipoprotein-associated phospholipase $A_2$ ($Lp-PLA_2$), a phospholipase $A_2$ enzyme, is used as a marker for cardiac disease. The detection of $Lp-PLA_2$ was accomplished by using radioactive [$^3H-acetyl$] PAF as a substrate and a feasibility study on RI biochip application to detection of $Lp-PLA_2$, a risk factors of atherosclerosis was performed. Inhibitive activity of a native plant extract was also determined by using the RI biochip. It was found to be applicable to a high-throughput screening of inhibitors for developing atherosclerosis therapeutic agents.

• Annals of Laboratory Medicine
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• v.38 no.6
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• pp.545-554
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• 2018

Background: The increasing morbidity and mortality rates associated with Acinetobacter baumannii are due to the emergence of drug resistance and the limited treatment options. We compared characteristics of colistin-resistant Acinetobacter baumannii (CR-AB) clinical isolates recovered from patients with and without prior colistin treatment. We assessed whether prior colistin treatment affects the resistance mechanism of CR-AB isolates, mortality rates, and clinical characteristics. Additionally, a proper method for identifying CR-AB was determined. Methods: We collected 36 non-duplicate CR-AB clinical isolates resistant to colistin. Antimicrobial susceptibility testing, Sanger sequencing analysis, molecular typing, lipid A structure analysis, and in vitro synergy testing were performed. Eleven colistin-susceptible AB isolates were used as controls. Results: Despite no differences in clinical characteristics between patients with and without prior colistin treatment, resistance-causing genetic mutations were more frequent in isolates from colistin-treated patients. Distinct mutations were overlooked via the Sanger sequencing method, perhaps because of a masking effect by the colistin-susceptible AB subpopulation of CR-AB isolates lacking genetic mutations. However, modified lipid A analysis revealed colistin resistance peaks, despite the population heterogeneity, and peak levels were significantly different between the groups. Conclusions: Although prior colistin use did not induce clinical or susceptibility differences, we demonstrated that identification of CR-AB by sequencing is insufficient. We propose that population heterogeneity has a masking effect, especially in colistin non-treated patients; therefore, accurate testing methods reflecting physiological alterations of the bacteria, such as phosphoethanolamine-modified lipid A identification by matrix-assisted laser desorption ionization-time of flight, should be employed.

• Journal of Korean Medicine Rehabilitation
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• v.29 no.4
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• pp.15-27
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• 2019

Objectives This study was performed to evaluate anti-obesity effects of Crataegus pinnatifida (CP) on high-fat-diet induced obese mice. Methods The experimental animals were divided into four groups: normal diet (NOR) group, high fat diet (HFD) group, HFD+Xenical (XEN) group, and HFD+CP (CP) group. NOR group was fed a normal diet and the other three groups were fed high fat diet during the experiment. After the first two weeks of diet, XEN group and CP group were administered with XEN or CP for seven weeks, respectively. After that, we measured body weight, liver weight, fat weight, food intake, and serum concentrations of lipids and liver enzymes. Also the liver, intestine, fat tissue was removed to estimate the obesity-related mRNA expressions and the stool sample was collected to analyze the gut microbiota. Results We found that body weight, fat weight, and triglyceride level were decreased significantly in CP group compared to HFD group. Also CP significantly suppressed gene expressions associated with lipogenesis and inflammation, and increased gene expressions of browning of white adipose tissue and mitochondrial biogenesis. Moreover, it shifted the microbial diversity closer to that of NOR group and increased Firmicutes/Bacteriodetes ratio. Conclusions These results suggest that CP decrease body weight, fat weight and serum triglyceride. Also it inhibit inflammation and adipogenesis, altering gut microbial diversity and abundance. In conclusion, CP could be used as a therapeutic drug for obesity via gut microbiota modulation.

• Journal of the Korea Convergence Society
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• v.10 no.11
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• pp.501-510
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• 2019

This study aimed to find health related lifestyle factors that influence glycemic control for diabetes mellitus (DM) management strategies. This study used nested case-control design with matching variables that were not controlled by individuals such as age, sex, insulin or oral hypoglycemic agent (OHA) use, disease duration, education level and household income. This study analyzed 983 subjects with type 2 DM who enrolled in the $7^{th}$ (2016-2017) Korean National Health and Nutrition Examination Survey (KNHANES). The target HbA1c level of controlled glucose was defined as less than 6.5%, and 289 (30%) were achieved. Conditional multivariable logistic regression analysis was performed to find self-control factors associated with HbA1c levels. The results statistically significant for variables such as duration of diabetes, insulin or OHA use in overall cohort and body mass index (BMI), smoking and fundus Examination in matched cohort. These results are expected to provide as evidence for the intensive care criteria(disease duration, drug use) and lifestyle management strategy(BMI, smoking, fundus examination).

• The Journal of Internal Korean Medicine
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• v.40 no.5
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• pp.983-989
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• 2019

Objective: Many types of delayed adverse reactions, such as long-term numbness, occur after injecting contrast medium, but few clinical studies have reported effective treatments for these reactions. We report that herbal medicine can have a positive clinical effect in patients who have experienced long-term numbness after contrast medium injection. Method: A patient who had felt numbness in her head and whole limbs presented at Semyung University Korean Medicine hospital. Her numbness had first started 2 days after injection of contrast medium, and she had felt it constantly for almost 2 years. After admission at the hospital, she took "modified Samul-tang" herbal medicine (120 cc three times per day) from 29 January 2019 to 2 February 2019. We measured her numbness using a numeric rating scale (NRS) on 29 January and 2 February and we compared both scores to determine the degree of favorable and clinical effects of herbal medicine. Result: The NRS score for numbness was 5 for her head and limbs on the first day (29 January), but after 4 days (2 February), the NRS score decreased to 0 for her head and both arms and hands, and it decreased from 5 to 2 for both her legs and feet. Conclusion: Korean herbal medicine can have positive clinical effects on treating adverse reactions due to injection of contrast medium.

• Korean Journal of Pharmacognosy
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• v.52 no.4
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• pp.242-250
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• 2021

Artemisia frigida Willd (AW, Fringed sagewort), which is widespread in Mongolia, is a well-known medicinal plant as a member of the Compositae family. This study aims to explore the gastroprotective effect of water extract of AW on 150 mM HCl/60% ethanol-induced acute gastritis in 5 week old male ICR mice. Total polyphenols, total flavonoid contents, and anti-oxidant activity in vitro in AW were evaluated. First, the gross area of gastric mucosal damage was measured. Then western blot analysis was conducted to determine the possible mechanisms of action underlying the effects of AW. AW administration decreased gastric mucosal damage. Moreover, the group with AW treatment effectively inhibited nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expression associated with oxidative stress. AW treatment enhanced an anti-oxidant effect through the increase of anti-oxidant proteins. Besides, the increased expressions of inflammatory cytokines induced by nuclear factor-kappa B (NF-κB) activation are alleviated through AW treatment. Taken together, AW exerted a gastroprotective effect against gastric mucosal damage. These results indicate that AW could have the potential used as a natural therapeutic drug for the treatment of acute gastritis.