Polyphyllin D Shows Anticancer Effect through a Selective Inhibition of Src Homology Region 2-Containing Protein Tyrosine Phosphatase-2 (SHP2).

Natural products have continued to offer tremendous opportunities for drug development, as they have long been used in traditional medicinal systems. SHP2 has served as an anticancer target. To identify novel SHP2 inhibitors with potential anticancer activity, we screened a library containing 658 natural products. Polyphyllin D was found to selectively inhibit SHP2 over SHP1, whereas two other identified compounds (echinocystic acid and oleanolic acid) demonstrated dual SHP1 and SHP2 inhibition. In a cell-based assay, polyphyllin D exhibited cytotoxicity in Jurkat cells, an acute lymphoma leukemia cell line, whereas the other two compounds were ineffective. Polyphyllin D also decreased the level of phosphorylated extracellular signal-regulated kinase (p-ERK), a proliferation marker in Jurkat cells. Furthermore, knockdown of protein tyrosine phosphatase (PTP)N6 (SHP1) or PTPN11 (SHP2) decreased p-ERK levels. However, concurrent knockdown of PTPN6 and PTPN11 in Jurkat cells recovered p-ERK levels. These results demonstrated that polyphyllin D has potential anticancer activity, which can be attributed to its selective inhibition of SHP2 over SHP1.

Identification of chebulinic acid as a dual targeting inhibitor of protein tyrosine phosphatases relevant to insulin resistance.

Natural products as antidiabetic agents have been shown to stimulate insulin signaling via the inhibition of the protein tyrosine phosphatases relevant to insulin resistance. Previously, we have identified PTPN9 and DUSP9 as potential antidiabetic targets and a multi-targeting natural product thereof. In this study, knockdown of PTPN11 increased AMPK phosphorylation in differentiated C2C12 muscle cells by 3.8 fold, indicating that PTPN11 could be an antidiabetic target. Screening of a library of 658 natural products against PTPN9, DUSP9, or PTPN11 identified chebulinic acid (CA) as a strong allosteric inhibitor with a slow cooperative binding to PTPN9 (IC50 = 34 nM) and PTPN11 (IC50 = 37 nM), suggesting that it would be a potential antidiabetic candidate. Furthermore, CA stimulated glucose uptake and resulted in increased AMP-activated protein kinase (AMPK) phosphorylation. Taken together, we demonstrated that CA increased glucose uptake as a dual inhibitor of PTPN9 and PTPN11 through activation of the AMPK signaling pathway. These results strongly suggest that CA could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

Label-Free Detection of Protein Tyrosine Phosphatase 1B (PTP1B) by Using a Rationally Designed Förster Resonance Energy Transfer (FRET) Probe.

A highly selective detection method of native protein tyrosine phosphatase 1B (PTP1B) is described using a target specific probe equipped with 1-naphthylamine (λex =330 nm, λem =445 nm). Irradiation of a mixture of PTP1B and Probe 1 with ultraviolet light of 280 nm (corresponding to PTP1B excitation maximum) resulted in significant fluorescence increase at 445 nm, following FRET characteristics. This phenomenon does not occur with other closely related phosphatases or cellular abundant alkaline phosphatase (APP). Probe 1, the most potent and selective probe, was found to competitively inhibit PTP1B (Ki ≈42 nm), whereas APP inhibition was found to be in the low micromolar range. Furthermore, Probe 1 discriminates between PTP1B and several other phosphatases. Here, we report real-time label-free FRET detection of pure PTP1B as well as induced human PTP1B in Escherichia coli cell lysate. In contrast to 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP), a representative fluorescence turn-on PTP substrate, our FRET probe successfully differentiated human cervical carcinoma cell lysate, SiHa, which has a high expression level of PTP1B, from PTP1B-knockdown SiHa cell lysate (that is, siRNA was used for PTP1B knockdown).

Ginkgolic acid as a dual-targeting inhibitor for protein tyrosine phosphatases relevant to insulin resistance.

Several protein tyrosine phosphatases (PTPs) that disrupt the insulin-signaling pathway were investigated by siRNAs to identify potential antidiabetic targets. Individual knockdown of PTPN9 and DUSP9 in 3T3-L1 preadipocytes increased AMPK phosphorylation, respectively, and furthermore, concurrent knockdown of both PTPN9 and DUSP9 synergistically increased AMPK phosphorylation. Next, 658 natural products were screened to identify dual inhibitors of both PTPN9 and DUSP9. Based on the selectivity and inhibition potency of the compounds, ginkgolic acid (GA) was selected for further study as a potential antidiabetic drug candidate. GA inhibited the enzymatic activity of PTPN9 (Ki = 53 µM) and DUSP9 (Ki = 2.5 µM) in vitro and resulted in a significant increase of glucose-uptake in differentiated C2C12 muscle cells and 3T3-L1 adipocytes. In addition, GA increased phosphorylation of AMPK in 3T3L1 adipocytes. In this study, GA as a dual targeting inhibitor of PTPN9 and DUSP9 increased glucose uptake in 3T3L1 and C2C12 cells by activating the AMPK signaling pathway. These results strongly suggest GA could be used as a therapeutic candidate for type 2 diabetes.

A study on macronutrient self-selection after acute aerobic exercise in college females.

[Purpose] This study was conducted to determine whether acute aerobic exercise (climbing) is associated with changes in the dietary intake pattern. [Subjects and Methods] Food intake and physical activity data for 15 female college students were sampled for 3 days and categorized according to routine activity or high-intensity activity such as hiking. Nutrient intake based on the data was analyzed using a nutrition program. [Results] Carbohydrate and protein intake was significantly decreased after exercise compared to before acute aerobic exercise, but lipid intake showed no significant difference. Calorie intake was significantly decreased after exercise compared to before exercise; however, calorie consumption was significantly increased after exercise. [Conclusion] Aerobic exercise causes a decrease in total calories by inducing reduction in carbohydrate and protein intake. Therefore, aerobic exercise is very important for weight (body fat) control since it causes positive changes in the food intake pattern in female students.

Electromyography comparison of normal chair-desk system and assistant chair-desk system on fatigue.

[Purpose] This study was designed to test the effects of the Assistant Chair-Desk System (ACDS), which can reduce the forward tilt of the neck and trunk and the level of fatigue during long lasting study in the sitting position. [Subjects] Fourteen middle school students and 14 college students of mixed gender participated in this study. [Methods] Fatigue level, the trapezius muscle, and the forward tilt angle of the head and trunk as well as distance factors were assessed before after using a normal chair-desk system (NCDS) and the ACDS for 120 minutes. [Results] There was an interaction effect in the angle and length of the neck from the sitting posture changes after 2 hours of studying using the NCDS and ACDS. There were also significant differences in the fatigue levels, hip joint angles and the lengths from the head according to the main effects of the chair-systems. [Conclusion] The studying position while using the ACDS was determined to prevent significant fatigue levels of the muscle and body, provide support to the head, by limiting the forward movement of the neck, and prevent forward tilt of the neck and trunk, by enabling the target point and gaze to be closer to the horizontal direction.

Site-Selective Antibody-Drug Conjugation by a Proximity-Driven S to N Acyl Transfer Reaction on a Therapeutic Antibody.

Immunoglobulin Gs (IgGs) contain many Lys and Cys residues, which results in an unwanted complex product mixture with conventional drug conjugation methods. We selectively acylated the ε-NH2 of K248 on trastuzumab using an IgG Fc-binding peptide (FcBP) equipped with a 5-norbornene-2-carboxylic acid thioester (AbClick-1). AbClick-1 locates its thioester close to the ε-NH2 of K248 while binding to trastuzumab. Consequently, the thioester underwent proximity-driven selective acylation of ε-NH2 through an S to N acyl transfer reaction. Furthermore, N-tert-butyl maleimide accelerated the cross-linking reaction with an approximately 95% yield of the desired product by scavenging the byproduct (FcBP-SH). Only K248 was modified selectively with the 5-norbornene-2-carbonyl group, which was further modified by click reaction to afford an antibody-drug conjugate (ADC) with two drugs per antibody. The resulting ADCs showed remarkable in vitro and in vivo anticancer activity. Our results demonstrate that a thioester is a promising chemical entity for proximity-driven site-selective conjugation of antibodies.

Photoconjugation of an Fc-Specific Peptide Enables Efficient DAR 2 Antibody-Drug Conjugate Formation.

Antibody-drug conjugates (ADCs) in current clinical usage have been constructed via the nonspecific conjugation of drugs to antibodies, rendering the manufacturing processes difficult. In this study, a high-affinity IgG Fc-binding peptide equipped with a photoreactive amino acid was developed and successfully conjugated to Glu-382 of trastuzumab in a site-specific manner. The resulting conjugate was employed to generate a DAR 2 ADC product using click chemistry.

A relationship between personality and empathy in teenagers' school sports club participation.

This study aims to identify the relation between students' participation in sports club activities and personality and sympathy based on the findings obtained from personalty and sympathy study and understand what the interrelational characteristics are. This study investigated a total of 408 individuals (male, 58.3%; female, 41.7%) who have continuously participated in sports club activity in middle schools located at Seoul and Gyeonggi province, Korea. To look at the type of event that they selected, 127 individuals (31.1%) reported that "School sports club event is already defined in school." and 281 (68.9%) reported that "We can select among several school sports club events." The events that they participated in are that 79 individuals participated in basket ball, 47 in line dancing, 96 in badminton, 2 in yoga, 31 in football, 129 in pingpong, and 20 in floorball. In conclusion adolescence is a period that adolescents are physically and mentally developed in terms of personality, morality, creativity, and sociality. During this period, learning and experience are very important for lifetime. Therefore, teenagers' school sports club activity can contribute to fostering positive and desirable personality and stabilizing emotional empathy among student participants. This study identified the relation between personality and empathy in adolescents, which was not studied before. As presented in previous researches, it can be found that positive personality can be cultivated by teenagers' communal activities in school life. The link to connect this with empathy factor is considered to be the very communal activity, sports.

Association between Cigarette Smoking Frequency and Health Factors among Korean Adults.

BACKGROUND: Recently, there has been a trend that cigarette smoking rate in Asian and Africa adults has increased while the age group to start smoking has decreased gradually. This study aimed to investigate the relationships between lifetime smoking and hypertension, diabetes, obesity, waist measure, fasting blood pressure and food consumption, in order to look into health status depending on smoking status in Koreans. METHODS: Totally, 1075 men and 697 women with no disease participated in this study, in which one-way ANOVA was conducted by using SPSS version 18.0 for statistical process. The level of statistical significance was 0.05. RESULTS: As a result of analysis on relationship between lifetime smoking and hypertension, obesity and diabetes, statistically significant differences were revealed.Lifetime smoking was found to be significantly associated with increased waist measure, higher level of fasting blood sugar, and more ingestion of nutrients (carbohydrate, fat, and protein). CONCLUSION: Increased amount of lifetime cigarette smoking was shown to negatively influence various health factors, which might become to be a drive to cause diseases. Therefore, method to improve health factors must be sought for via education and campaign to control an amount of cigarette smoking in Korean adults.

On school violence in Korean middle school, prevention and reaction measures.

This study is aiming to explore the practical and realistic measure in more variable way, which enables us to manage the problems about school violence we are currently facing as well as to overcome limitations in the current situation where we react only with punishments, mainly in the form of the law enforcement, supported by the police. This study was conducted on male and female students (n= 424) and teachers (n= 136) attending at the seven middle schools located in Seoul. The frequency analysis, one way ANOVA F-test, t -test, the multiple regression analysis were applied. Students recognize' harmful environmental cleanup' as an important variable or factor to reduce school violence. Also, both teachers and students are aware that 'regular survey on school violence' could reduce school violence. In conclusion, it is considered that as an effective and viable prevention measure against school violence, more attention and affection efforts need to be activated and addressed, on the part of home, school, and government, which will enable our young generations of students to be brought up, and take up the future of our country.