Exploring Disparities for Obesity in Korea Using Hierarchical Age-Period-Cohort Analysis With Cross-Classified Random Effect Models.

BACKGROUND: This research article investigates the age, period, and birth cohort effects on prevalence of obesity in the Korean population, with the goal of identifying key factors to inform effective public health strategies. METHODS: We analyzed data from the Korea National Health and Nutrition Examination Survey, spanning 2007-2021, including 35,736 men and 46,756 women. Using the hierarchical age-period-cohort (APC) analysis with cross-classified random effects modeling, we applied multivariable mixed logistic regression to estimate the marginal prevalence of obesity across age, period, and birth cohort, while assessing the interaction between APC and lifestyle and socioeconomic factors. RESULTS: Our findings reveal an inverted U-shaped age effect on obesity, influenced by smoking history (P for interaction = 0.020) and physical activity (I for interaction < 0.001). The period effect was positive in 2020 and 2021, while negative in 2014 (P for period effect < 0.001). A declining trend in obesity prevalence was observed in birth cohorts from 1980s onward. Notably, disparities in obesity rates among recent birth cohorts have increased in relation to smoking history (P for interaction = 0.020), physical activity (P for interaction < 0.001), and residence (P for interaction = 0.005). Particularly, those born after 1960 were more likely to be obese if they were ex-smokers, physical inactive, or lived in rural areas. CONCLUSION: These findings highlight growing disparities in obesity within birth cohorts, underscoring the need for targeted health policies that promote smoking cessation and physical activity, especially in rural areas.

Factors associated with academic performance among medical students at a medical school in South Korea: A retrospective cohort study.

Longitudinal research has provided systematic empirical data on the short- and long-term outcomes of admissions policies, curricular innovations, and complex decisions on students' academic progress. This study aimed to investigate the academic performance of medical students and related factors using cohort database collected from a medical school. The study participants included 134 medical students who graduated from Chonnam National University Medical School in 2022. The medical school's cohort database was used to collect data on demographics, admission, academic performance, extracurricular activities, and performance on the National Korean Medical Licensing Examination (KMLE). Participating in club activities had a significant association with medical students' academic advancement delay or leave of absence during the entire course of medical school (P = 0.007). Logistic regression analysis indicated that the nationwide clinical knowledge mock examination during the fourth year of medical school was significantly associated with passing the KMLE (adjusted odds ratio 1.12, 95% confidence interval 1.02-1.22; P = 0.014). Extracurricular school activities (a non-cognitive student attribute) and a wide range of cognitive student attributes captured from the cohort database were associated with medical students' academic performance. In conclusion, this study can reinforce a strong emphasis on the inclusion of cognitive and non-cognitive information in medical school curricula and assessments in order to improve medical education programs and future postgraduate performance.

Effect Modification of Kidney Function on the Non-linear Association Between Serum Calcium Levels and Cardiovascular Mortality in Korean Adults.

OBJECTIVES: This study aimed to evaluate the potential interaction between kidney function and the non-linear association between serum calcium levels and cardiovascular disease (CVD) mortality. METHODS: This study included 8927 participants enrolled in the Dong-gu Study. Albumin-corrected calcium levels were used and categorized into 6 percentile categories: <2.5th, 2.5-25.0th, 25.0-50.0th, 50.0-75.0th, 75.0-97.5th, and >97.5th. Restricted cubic spline analysis was used to examine the non-linear association between calcium levels and CVD mortality. Cox proportional hazard regression was used to estimate hazard ratios (HRs) for CVD mortality according to serum calcium categories. All survival analyses were stratified by the estimated glomerular filtration rate. RESULTS: Over a follow-up period of 11.9±2.8 years, 1757 participants died, of whom 219 died from CVD. A U-shaped association between serum calcium and CVD mortality was found, and the association was more evident in the low kidney function group. Compared to the 25.0-50.0th percentile group for serum calcium levels, both low and high serum calcium tended to be associated with CVD mortality (<2.5th: HR, 6.23; 95% confidence interval [CI], 1.16 to 33.56; >97.5th: HR, 2.56; 95% CI, 0.76 to 8.66) in the low kidney function group. In the normal kidney function group, a similar association was found between serum calcium levels and CVD mortality (<2.5th: HR, 1.37; 95% CI, 0.58 to 3.27; >97.5th: HR, 1.65; 95% CI, 0.70 to 3.93). CONCLUSIONS: We found a non-linear association between serum calcium levels and CVD mortality, suggesting that calcium dyshomeostasis may contribute to CVD mortality, and kidney function may modify the association.

Association Between Serum Bilirubin and Atrial Fibrillation: A Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: The association between bilirubin and atrial fibrillation (AF) has been evaluated previously in observational studies but with contradictory results. This study evaluated the causal association between serum bilirubin level and AF using Mendelian randomization (MR) analysis. METHODS: This cross-sectional study includes 8,977 participants from the Dong-gu Study. In the observational analysis, multivariate logistic regression was performed to evaluate the association between bilirubin and prevalent AF. To evaluate the causal association between bilirubin and AF, MR analysis was conducted by using the UGT1A1 rs11891311 and rs4148323 polymorphisms as instrumental variables. RESULTS: Elevated serum bilirubin levels were associated with an increased risk for AF in observational analysis (total bilirubin: odds ratio [OR], 1.31; 95% confidence interval [95% CI], 1.15-1.48 per 1 standard deviation [SD]; direct bilirubin: OR, 1.31; 95% CI, 1.18-1.46 per 1 SD), whereas the genetically predicted serum bilirubin levels in MR analysis did not show this association (total bilirubin: OR, 1.02; 95% CI, 0.67-1.53 per 1 SD; direct bilirubin: OR, 1.03; 95% CI, 0.61-1.73 per 1 SD). CONCLUSIONS: Genetically predicted bilirubin levels were not associated with prevalent AF. Thus, the observational association between serum bilirubin levels and AF may be non-causal and affected by reverse causality or unmeasured confounding.

No association between genetically predicted C-reactive protein levels and colorectal cancer survival in Korean: two-sample Mendelian randomization analysis.

OBJECTIVES: Elevated C-reactive protein (CRP) levels are associated with an increased risk for colorectal cancer (CRC), as well as a poor prognosis, but it remains unclear whether these associations are causal. This study examined the potential causality between CRP levels and CRC survival using 2-sample Mendelian randomization (MR). METHODS: From the Korean Genome and Epidemiology Study, a genome-wide association study (n=59,605), 7 single-nucleotide polymorphisms (SNPs) related to log2-transformed CRP levels were extracted as instrumental variables for CRP levels. The associations between the genetically predicted CRP and CRC-specific and overall mortality among CRC patients (n=6,460) were evaluated by Aalen's additive hazard model. The sensitivity analysis excluded a SNP related to the blood lipid profile. RESULTS: During a median of 8.5 years of follow-up, among 6,460 CRC patients, 2,676 (41.4%) CRC patients died from all causes and 1,622 (25.1%) died from CRC. Genetically predicted CRP levels were not significantly associated with overall or CRC-specific mortality in CRC patients. The hazard difference per 1,000 person-years for overall and CRC-specific mortality per 2-fold increase in CRP levels was -2.92 (95% confidence interval [CI], -14.05 to 8.21) and -0.76 (95% CI, -9.61 to 8.08), respectively. These associations were consistent in a subgroup analysis according to metastasis and a sensitivity analysis excluding possible pleiotropic SNPs. CONCLUSIONS: Our findings do not support a causal role for genetically predisposed CRP levels in CRC survival.

Association Between Regional Levels of Particulate Matter and Recurrent Falls in Korea.

BACKGROUND: We investigated the extent of regional disparity of recurrent falls. In addition, we examined the association between particulate matter (PM) and recurrent falls and the association between regional disparity of recurrent falls and regional PM levels. METHOD: We used data from Korea Community Health Survey 2019 that included 204,395 participants from 237 municipal districts. The independent variables were the annual average PM10 and PM2.5 concentrations measured at the air quality measuring stations in each municipal district. The outcome variable was the experience of falls more than twice in the previous year. Multilevel analyses were conducted to estimate the association between regional PM10 and PM2.5 levels and recurrent falls. RESULTS: The regional variation was greater in the young people than that in the older people. PM10 and PM2.5 levels were positively associated with recurrent falls after adjusting for individual and regional covariates. These associations were more evident in the older group than in the young. PM10 and PM2.5 explained 2.82% and 3.33% of the remaining regional variance in models with individual and regional confounders, respectively. These proportions were greater in the older group (PM10 and PM2.5; 4.73% and 5.27%) than those in the younger age group (PM10 and PM2.5, 0.80% and 1.39%). CONCLUSION: PM concentration was associated with recurrent falls even after accounting for other regional variables and individual-level differences. Moreover, there were regional differences in the occurrence of falls, and the PM concentration explained a part of the gap, but the gap was explained more in the older group than in the young.

Effects of Diabetes Quality Assessment on Diabetes Management Behaviors Based on a Nationwide Survey.

Improved diabetes management in primary care is essential for reducing the public health burden of diabetes, and various programs are being implemented in Korea for this purpose. Although the Health Insurance Review and Assessment (HIRA) evaluates the quality of type 2 diabetes management in primary care clinics and hospitals, it is unclear whether the implementation of these evaluations is related to the adequate management of complications in diabetic patients. We evaluated the association between the proportion of clinics managing diabetes well and lifestyles and uptake of screening for complications in 24,620 diabetic participants of the 2019 Korean Community Health Survey (KCHS). Multivariate multilevel logistic regression was performed to evaluate the fixed effect of the district-level variable and the heterogeneity among districts. The proportion of clinics with good diabetes management per 10,000 inhabitants was positively related to screening for diabetes complications. Furthermore, this district variable was significantly related to engaging in walking activity (Odds ratio: 1.39, 95% CI: 1.10-1.76) and sufficiently explained the heterogeneity among districts. However, current smoking and weight control were not associated with the proportion of clinics with good diabetes management. The financial incentives to primary care clinics would improve the primary prevention of diabetic complications.

Design and evaluation of additive manufactured highly efficient inclined-wing type continuous mixer.

We develop a novel milli-scale mixer (tilted-wings mixing unit, TWM unit) based on the design for additive manufacturing (DfAM). The proposed tilted-wings mixer has basically designed to have three separate wings that split and combine fluids in order to mix together effectively. Its structure is simple for easy fabrication: two major design parameters of angle among three wings and connecting angle between tilted-unit, which are optimized using the computational fluid dynamics (CFD) analysis. From the CFD analysis, we obtain the best-combined mixing module from analyses of various combinations of TWM units for a highly effective mixing ratio. The mixing ratio of three combined units reaches near 100%, which is validated by the experiment and analysis. We believe that the proposed milli-scale mixer can be utilized in diverse chemical continuous mixers and reactors for minimizing of use of chemicals that can pollute the environment.

Causal Association Between Alcohol Consumption and Atrial Fibrillation: A Mendelian Randomization Study.

BACKGROUND AND OBJECTIVES: Previous observational studies presented a positive association between alcohol and atrial fibrillation (AF). However, previous studies using genetic polymorphisms on the causal relationship between alcohol consumption and AF have reported conflicting results. This study aimed to evaluate the causality between alcohol consumption and AF using the aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphism, which is the genetic variant with the most potent effect on drinking behavior. METHODS: A total of 8,964 participants from the Dong-gu Study were included in the present study. The causal association between alcohol consumption and AF was evaluated through a Mendelian randomization (MR) analysis using the ALDH2 rs671 polymorphism as an instrumental variable. RESULTS: No significant relationship between alcohol consumption and AF was found in the observational analysis. However, the genetic analysis using the ALDH2 polymorphism showed a significant association in men. In the MR analysis, genetically predicted daily alcohol consumption was positively related to AF. CONCLUSIONS: MR analysis revealed a significant association between the amount of alcohol consumption and AF, which suggests that the association may be causal.

Associations of regional-level perceived stress and depression with health-related quality of life in Korean adults: a multilevel analysis of 2017 Korea Community Health Survey data.

OBJECTIVES: We examined the associations of individual and regional-level perceived stress and depression with health-related quality of life (HRQOL) in Korean adults. METHODS: We used data from the 2017 Korea Community Health Survey, which included 216,713 adults living within 254 municipal districts. As individual-level independent variables, perceived stress (higher vs. lower) and depression (Patient Health Questionnaire-9 ≥10) were defined. Regional-level age-adjusted rates of perceived stress (%) and depression (%) were created for 254 municipal districts and categorized into quartiles to generate regional levels of stress and depression. HRQOL was defined as the individual-level EuroQol 5-dimensional index×100. A multilevel analysis was performed to identify the relationship between individual or regional-level independent variables and individual HRQOL. RESULTS: In the null model, the proportions of individual variation in the HRQOL explained by region were 1.7% and 2.7% for men and women, respectively. When adjusted with all individual-level variables, regional stress and depression, as well as individual-level perceived stress and depression, were significantly related to HRQOL for both genders. In the full model including all variables, the decrease in HRQOL from the first to the fourth quartile group of regional stress was greater in women (-1.09; 95% confidence interval [CI], -1.87 to -0.31) than in men (-0.65; 95% CI, -1.04 to -0.26). CONCLUSIONS: Our results suggest that regional-level perceived stress and depression, as well as individual-level perceived stress and depression, are inversely associated with individual HRQOL.

Association between ALDH2 polymorphism and esophageal cancer risk in South Koreans: a case-control study.

BACKGROUND: Alcohol consumption is a major risk factor for esophageal cancer; however, a high incidence of esophageal cancer is observed particularly among Eastern Asians, although they consume relatively less alcohol, presumably due to the high frequency of aldehyde dehydrogenase 2 (ALDH2) rs671 polymorphisms. Nevertheless, the association between ALDH2 polymorphisms and esophageal cancer remains under debate. In the present study, we evaluated the association between ALDH2 rs671 polymorphisms and the risk of esophageal cancer in the South Korean population. METHODS: This study included 783 hospital based-cases and 8732 population-based controls. Information on smoking history and alcohol consumption was obtained from the medical records or interview questionnaires. Age-adjusted logistic regression analysis was performed to assess the association between ALDH2 rs671 polymorphisms and esophageal cancer. RESULTS: Odds ratios (ORs) for esophageal cancer in men with GA and AA genotypes were 2.75 (95% confidence interval [CI]: 2.34-3.23) and 0.08 (95% CI: 0.00-0.35), respectively; whereas, in women, these ratios were 2.99 (95% CI: 1.43-6.34) and 6.18 (95% CI: 1.40-19.62), respectively, taking subjects with the ALDH2 GG genotype as a reference. In men, the association between ALDH2 polymorphisms and esophageal cancer was modified by alcohol consumption. CONCLUSION: In Eastern Asians, ALDH2 rs671 polymorphisms are associated with esophageal cancer, which may be linked to acetaldehyde accumulation.

Long-term outcomes of endoscopic papillectomy for early-stage cancer in duodenal ampullary adenoma: Comparison to surgical treatment.

BACKGROUND AND AIM: While recent evidences support endoscopic resection as curative in ampullary tumors with high-grade intraepithelial neoplasia, only small case series have reported endoscopic management of early-stage ampullary cancer; thus, radical surgery remains the only accepted treatment modality. We evaluated the long-term outcomes of early ampullary adenocarcinoma administered endoscopic management. METHODS: We retrospectively reviewed electronic medical records of 715 patients undergoing endoscopic papillectomy (EP) in a single tertiary medical center in Korea in 2004-2016. We included patients incidentally diagnosed with early-stage adenocarcinoma (Tis and T1a, American Joint Committee on Cancer 8th edition) after EP and with >2 years of follow-up data and analyzed their demographics, histopathologic data, and clinical outcomes. RESULTS: Among 70 total patients in the EP-alone (n = 42) and subsequent surgery (n = 28) groups, we observed no significant differences in demographics or tumor size (2.0 ± 0.6 vs 1.9 ± 0.5 cm, P = 0.532), histologic grade (P = 0.077), tumor extent (P = 1.000), lymphovascular invasion (2.4% vs 10.7%, P = 0.344), or complete resection rates (57.1% vs 57.1%, P = 1.000) between groups. Adenocarcinoma lesions were larger in the subsequent surgery group (0.7 ± 0.5 vs 1.1 ± 0.7 cm, P = 0.002). The EP-alone group received more additional ablative treatment (42.9% vs 14.3%, P = 0.024). The 5-year disease-free and cancer-free survival rates were 79.1% vs 87.4% (P = 0.111) and 93.5% versus 87.4% (P = 0.726), respectively, and did not differ significantly between groups. CONCLUSIONS: Endoscopic papillectomy followed by endoscopic surveillance showed long-term outcomes comparable with surgical resection for early ampullary cancer and maybe curable alternative to surgery for incidentally found early-stage ampullary cancer, especially in patients unfit for or refusing radical surgery.

A New Histone Deacetylase Inhibitor, MHY4381, Induces Apoptosis via Generation of Reactive Oxygen Species in Human Prostate Cancer Cells.

Histone deacetylase (HDAC) inhibitors represent a novel class of anticancer agents, which can be used to inhibit cell proliferation and induce apoptosis in several types of cancer cells. In this study, we investigated the anticancer activity of MHY4381, a newly synthesized HDAC inhibitor, against human prostate cancer cell lines and compared its efficacy with that of suberoylanilide hydroxamic acid (SAHA), a well-known HDAC inhibitor. We assessed cell viability, apoptosis, cell cycle regulation, and other biological effects in the prostate cancer cells. We also evaluated a possible mechanism of MHY4381 on the apoptotic cell death pathway. The IC50 value of MHY4381 was lower in DU145 cells (IC50=0.31 µM) than in LNCaP (IC50=0.85 µM) and PC-3 cells (IC50=5.23 µM). In addition, the IC50 values of MHY4381 measured in this assay were significantly lower than those of SAHA against prostate cancer cell lines. MHY4381 increased the levels of acetylated histones H3 and H4 and reduced the expression of HDAC proteins in the prostate cancer cell lines. MHY4381 increased G2/M phase arrest in DU145 cells, and G1 arrest in LNCaP cells. It also activated reactive oxygen species (ROS) generation, which induced apoptosis in the DU145 and LNCaP cells by increasing the ratio of Bax/Bcl-2 and releasing cytochrome c into the cytoplasm. Our results indicated that MHY4381 preferentially results in antitumor effects in DU145 and LNCaP cells via mitochondria-mediated apoptosis and ROS-facilitated cell death pathway, and therefore can be used as a promising prostate cancer therapeutic.

Inhibitory effects of N-(acryloyl)benzamide derivatives on tyrosinase and melanogenesis.

Targeting of tyrosinase has proven to be the best means of identifying safe, efficacious, and potent tyrosinase inhibitors for whitening skin. We designed and synthesized ten NAB (N-(acryloyl)benzamide) derivatives (1a-1j) using the Horner-Wadsworth-Emmons olefination of diethyl (2-benzamido-2-oxoethyl)phosphonate and appropriate benzaldehydes. A mushroom tyrosinase inhibitory assay showed compounds 1a (36.71 ±â€¯2.14% inhibition) and 1j (25.99 ±â€¯2.77% inhibition) inhibited tyrosinase more than the other eight NAB derivatives and kojic acid (21.56 ±â€¯2.93% inhibition), and docking studies indicated 1a (-6.9 kcal/mole) and 1j (-7.5 kcal/mole) had stronger binding affinities for tyrosinase than kojic acid (-5.7 kcal/mole). At a concentration of 25 µM, 1a and 1j were nontoxic in B16F10 melanoma cells and exhibited stronger tyrosinase inhibition (59.70% and 76.77%, respectively) than kojic acid (50.30% inhibition) or arbutin (41.78% inhibition at 400 µM). Similarly, in B16F10 melanoma cells, compounds 1a and 1j at 25 µM decreased total melanin content by 47.97% and 61.77%, respectively (kojic acid; 38.98%). Similarities between inhibitions of tyrosinase activity and melanin contents suggested the anti-melanogenic effects of 1a and 1j were due to tyrosinase inhibition. The excellent DPPH scavenging activity of 1j suggests it might enhance in vivo effect on melanin contents. The study suggests compound 1j offers a potential starting point for the development of safe, potent tyrosinase inhibitors.

Antioxidant, anti-tyrosinase and anti-melanogenic effects of (E)-2,3-diphenylacrylic acid derivatives.

During our continued search for strong skin whitening agents over the past ten years, we have investigated the efficacies of many tyrosinase inhibitors containing a common (E)-ß-phenyl-α,ß-unsaturated carbonyl scaffold, which we found to be essential for the effective inhibition of mushroom and mammalian tyrosinases. In this study, we explored the tyrosinase inhibitory effects of 2,3-diphenylacrylic acid (2,3-DPA) derivatives, which also possess the (E)-ß-phenyl-α,ß-unsaturated carbonyl motif. We synthesized fourteen (E)-2,3-DPA derivatives 1a-1n and one (Z)-2,3-DPA-derivative 1l' using a Perkin reaction with phenylacetic acid and appropriate substituted benzaldehydes. In our mushroom tyrosinase assay, 1c showed higher tyrosinase inhibitory activity (76.43 ±â€¯3.53%, IC50 = 20.04 ±â€¯1.91 µM) with than the other 2,3-DPA derivatives or kojic acid (21.56 ±â€¯2.93%, IC50 = 30.64 ±â€¯1.27 µM). Our mushroom tyrosinase inhibitory results were supported by our docking study, which showed compound 1c (-7.2 kcal/mole) exhibited stronger binding affinity for mushroom tyrosinase than kojic acid (-5.7 kcal/mole). In B16F10 melanoma cells (a murine cell-line), 1c showed no cytotoxic effect up to a concentration of 25 µM and exhibited greater tyrosinase inhibitory activity (68.83%) than kojic acid (49.39%). In these cells, arbutin (a well-known tyrosinase inhibitor used as the positive control) only inhibited tyrosinase by 42.67% even at a concentration of 400 µM. Furthermore, at 25 µM, 1c reduced melanin contents in B16F10 melanoma cells by 24.3% more than kojic acid (62.77% vs. 38.52%). These results indicate 1c is a promising candidate treatment for pigmentation-related diseases and potential skin whitening agents.

Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues.

Abnormal melanogenesis results in excessive production of melanin, leading to pigmentation disorders. As a key and rate-limiting enzyme for melanogenesis, tyrosinase has been considered an important target for developing therapeutic agents of pigment disorders. Despite having an (E)-ß-phenyl-α,ß-unsaturated carbonyl scaffold, which plays an important role in the potent inhibition of tyrosinase activity, cinnamic acids have not attracted attention as potential tyrosinase inhibitors, due to their low tyrosinase inhibitory activity and relatively high hydrophilicity. Given that cinnamic acids' structure intrinsically features this (E)-scaffold and following our experience that minute changes in the chemical structure can powerfully affect tyrosinase activity, twenty less hydrophilic cinnamamide derivatives were designed as potential tyrosinase inhibitors and synthesised using a Horner-Wadsworth-Emmons reaction. Four of these cinnmamides (4, 9, 14, and 19) exhibited much stronger mushroom tyrosinase inhibition (over 90% inhibition) at 25 µM compared to kojic acid (20.57% inhibition); crucially, all four have a 2,4-dihydroxy group on the ß-phenyl ring of the scaffold. A docking simulation using tyrosinase indicated that the four cinnamamides exceeded the binding affinity of kojic acid, and bound more strongly to the active site of tyrosinase. Based on the strength of their tyrosinase inhibition, these four cinnamamides were further evaluated in B16F10 melanoma cells. All four cinnamamides, without cytotoxicity, exhibited higher tyrosinase inhibitory activity (67.33 - 79.67% inhibition) at 25 µM than kojic acid (38.11% inhibition), with the following increasing inhibitory order: morpholino (9) = cyclopentylamino (14) < cyclohexylamino (19) < N-methylpiperazino (4) cinnamamides. Analysis of tyrosinase activity and melanin content in B16F10 cells showed that the four cinnamamides dose-dependently inhibited both cellular tyrosinase activity and melanin content and that their inhibitory activity at 25 µM was much better than that of kojic acid. The results of melanin content analysis well matched those of the cellular tyrosinase activity analysis, indicating that tyrosinase inhibition by the four cinnamamides is a major factor in the reduction of melanin production. These results imply that these four cinnamamides with a 2,4-dihydroxyphenyl group can act as excellent anti-melanogenic agents in the treatment of pigmentation disorders.

In vitro and in vivo evidence of tyrosinase inhibitory activity of a synthesized (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5-HMT).

Tyrosinase is a key enzyme that catalyses the initial rate-limiting steps of melanin synthesis. Due to its critical role in melanogenesis, various attempts were made to find potent tyrosinase inhibitors although many were not safe and effective in vivo. We evaluated tyrosinase inhibitory activity of six compounds. Among them, (Z)-5-(3-hydroxy-4-methoxybenzylidene)-2-thioxothiazolidin-4-one (5-HMT) had the greatest inhibitory effect and potency as the IC50 value of 5-HMT was lower than that of kojic acid, widely-known tyrosinase inhibitor. Based on in silico docking simulation, 5-HMT had a greater binding affinity than kojic acid with a different binding conformation in the tyrosinase catalytic site. Furthermore, its skin depigmentation effect was confirmed in vivo as 5-HMT topical treatment significantly reduced UVB-induced melanogenesis in HRM2 hairless mice. In conclusion, our study demonstrated that 5-HMT has a greater binding affinity and inhibitory effect on tyrosinase and may be a potential candidate for a therapeutic agent for preventing melanogenesis.

Design, synthesis and anti-melanogenic effect of cinnamamide derivatives.

Pigmentation disorders are attributed to excessive melanin which can be produced by tyrosinase. Therefore, tyrosinase is supposed to be a vital target for the treatment of disorders associated with overpigmentation. Based on our previous findings that an (E)-ß-phenyl-α,ß-unsaturated carbonyl scaffold can play a key role in the inhibition of tyrosinase activity, and the fact that cinnamic acid is a safe natural substance with a scaffolded structure, it was speculated that appropriate cinnamic acid derivatives may exhibit potent tyrosinase inhibitory activity. Thus, ten cinnamamides were designed, and synthesized by using a Horner-Emmons olefination as the key step. Cinnamamides 4 (93.72% inhibition), 9 (78.97% inhibition), and 10 (59.09% inhibition) with either a 2,4-dihydroxyphenyl, or 4-hydroxy-3-methoxyphenyl substituent showed much higher mushroom tyrosinase inhibition at 25 µM than kojic acid (18.81% inhibition), used as a positive control. Especially, the two cinnamamides 4 and 9 having a 2,4-dihydroxyphenyl group showed the strongest inhibition. Docking simulation with tyrosinase revealed that these three cinnamamides, 4, 9, and 10, bind to the active site of tyrosinase more strongly than kojic acid. Cell-based experiments carried out using B16F10 murine skin melanoma cells demonstrated that all three cinnamamides effectively inhibited cellular tyrosinase activity and melanin production in the cells without cytotoxicity. There was a close correlation between cellular tyrosinase activity and melanin content, indicating that the inhibitory effect of the three cinnamamides on melanin production is mainly attributed to their capability for cellular tyrosinase inhibition. These results imply that cinnamamides having the (E)-ß-phenyl-α,ß-unsaturated carbonyl scaffolds are promising candidates for skin-lighting agents.

High TNFRSF12A level associated with MMP-9 overexpression is linked to poor prognosis in breast cancer: Gene set enrichment analysis and validation in large-scale cohorts.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is associated with remodelling of the extracellular matrix and invasion in various cancers. Identifying proteins connected to high MMP-9 expression is important in explaining its mechanisms. Our study aims to shed light on genes associated with high MMP-9 expression and to discuss their clinical impact in breast cancer. METHODS: We evaluated 173 breast cancer cases from the Kangbuk Samsung Hospital, with 1964 cases from the Molecular Taxonomy of Breast Cancer International Consortium database serving as a validation cohort. We investigated relationships between MMP-9 expression and clinicopathological characteristics. We then used gene set enrichment analyses to detect the association of genes with MMP-9 overexpression, and performed survival analyses to determine the significance of the gene in three independent cohorts. RESULTS: High MMP-9 expression correlated with poor prognosis in univariate and multivariate analyses. Using gene set enrichment analysis, we found that tumour necrosis factor receptor superfamily member 12A (TNFRSF12A) was linked to high MMP-9 expression. In the survival analysis of three published data sets (METABRIC, GSE1456, GSE20685), high TNFRSF12A was relevant to a poor survival rate. CONCLUSIONS: High levels of TNFRSF12A associated with MMP-9 overexpression may be important to explain the progression of breast cancer, and survival could be improved using therapy targeting TNFRSF12A.

The tyrosinase inhibitory effects of isoxazolone derivatives with a (Z)-ß-phenyl-α, ß-unsaturated carbonyl scaffold.

Thirteen (Z)-4-(substituted benzylidene)-3-phenylisoxazol-5(4H)-ones were designed to confirm the geometric effect of the double bond of the ß-phenyl-α, ß-unsaturated carbonyl scaffold on tyrosinase inhibitory activity. Compounds 1a-1m, which all possessed the (Z)-ß-phenyl-α, ß-unsaturated carbonyl scaffold, were synthesized using a tandem reaction consisting of an isoxazolone ring formation and a Knoevenagel condensation, and three starting materials, ethyl benzoylacetate, hydroxylamine and benzaldehydes. Some of the compounds showed inhibitory activity against mushroom tyrosinase as potent as compounds containing the "(E)"-ß-phenyl-α, ß-unsaturated carbonyl scaffold. Compounds 1c and 1m showed greater inhibitory activity than kojic acid: IC50 = 32.08 ±â€¯2.25 µM for 1c; IC50 = 14.62 ±â€¯1.38 µM for 1m; and IC50 = 37.86 ±â€¯2.21 µM for kojic acid. A kinetic study indicated that 1m inhibited tyrosinase in a competitive manner and that it probably binds to the enzyme's active site. In silico docking simulation supported binding of 1m (-7.6 kcal/mol) to the active site of tyrosinase with stronger affinity than kojic acid (-5.7 kcal/mol). Similar results were obtained using cell-based assays, and in B16F10 cells, compound 1m dose-dependently inhibited tyrosinase activity and melanogenesis. These results indicate the anti-melanogenic effect of compound 1m is due to the inhibition of tyrosinase and (Z)-isomer of the ß-phenyl-α, ß-unsaturated carbonyl scaffold can, like its congener the (E)-isomer, act as an excellent scaffold for tyrosinase inhibition.