Distribution of volatile organic compounds by distance from industrial complexes and potential health impact on the residents.

Volatile organic compounds (VOCs) are the air pollutants emitted from the petrochemical industry known to pose adverse health effects on workers. The database based on the third phase of The Environmental Health Study in the Korean National Industrial Complexes (EHSNIC) in Ulsan conducted from 2018 to 2021 was used. Subjects were divided into the exposed and control group according to the estimated pollution level and distances from the industrial complexes. Ambient benzene, ethylbenzene, and xylene were significantly higher in the exposed group compared to the controls, as well as their metabolites. Risk of chronic disease and atopic dermatitis was higher in the exposed group which was supported by higher serum inflammatory markers and high hazard index of the exposed region. These results can draw attention to people engaged with environmental plans and used as primary data when making policies to reduce pollutant levels around industrial complexes.

Effects of noise exposure on stress hormone changes during task performance in young Korean men: quasi-experimental study.

Numerous studies have suggested that noise exposure might be associated with changes in stress hormone levels. However, quantitative evidence for these effects in humans is rare and remains controversial. This study aimed to investigate the acute effects of exposure to noise and its different levels on stress hormone changes in task performance. Quasi-experimental noise exposure environment was established for 90 male university student volunteers in their twenties, and each was exposed to different noise levels during task performance. The stress hormones tested included cortisol, adrenocorticotropic hormone (ACTH), adrenaline, and noradrenaline. A one-way ANOVA was performed to investigate differences in hormone levels measured in the three groups according to the noise exposure levels (35, 45, or 75 dB). Analysis of covariance (ANCOVA) was used to adjust for confounding factors that might affect hormone levels. After adjusting for confounders, significant exposure-dependent differences were found in hormone levels in salivary cortisol, serum cortisol, serum ACTH, and serum adrenaline. The amount of hormonal increase in 75 dB exposure group compared to 35 or 45 dB groups was detected. Similar results were also seen in the rate of change analysis. Our findings indicate that short-term noise exposure during task performance elevates stress hormone levels. Further, the extent of stress hormone alterations varies with noise exposure levels. Changes in hormone levels are an objective measure that may be used to identify health effects and stress responses in various noise environments.

Cooking oil fume exposure and Lung-RADS distribution among school cafeteria workers of South Korea.

Background: Cooking oil fumes (COFs) from cooking with hot oil may contribute to the pathogenesis of lung cancer. Since 2021, occupational lung cancer for individual cafeteria workers has been recognized in South Korea. In this study, we aimed to identify the distribution of lung-imaging reporting and data system (Lung-RADS) among cafeteria workers and to determine factors related to Lung-RADS distribution. Methods: We included 203 female participants who underwent low-dose computed tomography (LDCT) screening at a university hospital and examined the following variables: age, smoking status, second-hand smoke, height, weight, and years of service, mask use, cooking time, heat source, and ventilation. We divided all participants into culinary and non-culinary workers. Binomial logistic regression was conducted to determine the risk factors on LDCT of Category ≥ 3, separately for the overall group and the culinary group. Results: In this study, Lung-RADS-positive occurred in 17 (8.4%) individuals, all of whom were culinary workers. Binary logistic regression analyses were performed and no variables were found to have a significant impact on Lung-RADS results. In the subgroup analysis, the Lung-RADS-positive, and -negative groups differed only in ventilation. Binary logistic regression showed that the adjusted odds ratio (aOR) of the Lung-RADS-positive group for inappropriate ventilation at the workplace was 14.89 (95% confidence interval [CI]: 3.296-67.231) compared to appropriate ventilation as the reference, and the aOR for electric appliances at home was 4.59 (95% CI: 1.061-19.890) using liquid fuel as the reference. Conclusions: The rate of Lung-RADS-positive was significantly higher among culinary workers who performed actual cooking tasks than among nonculinary workers. In addition, appropriate ventilation at the workplace made the LDCT results differ. More research is needed to identify factors that might influence LDCT findings among culinary workers, including those in other occupations.

Effects of a supportive workplace environment on the success rate for smoking cessation camp.

Background: This study was conducted to identify the success rate for smoking cessation over time after participation in a therapeutic smoking cessation camp, and to identify how participant characteristics, including a supportive workplace environment for smoking cessation (SWESC), affect the success rate for smoking cessation. Methods: In all, 296 participants at smoking cessation camps in Ulsan between 2015 and 2020 were investigated. The success rates of smoking cessation after weeks 4, 6, 12, and 24 at camp were investigated. The participants were grouped as workers with an SWESC, and workers without an SWESC, and variables (age, education, household income, marital status, drinking, exercise, body mass index, morbidity, job, number of counseling sessions, cigarettes smoked per day and smoking initiation age) were investigated. Multiple logistic regression analysis was conducted at each time point. In addition, Cox regression analysis was performed to evaluate the variables affecting the success rate for smoking cessation over time. Results: The smoking cessation success rate of workers with an SWESC at week 24 (90.7%) was higher than that for workers without an SWESC (60.5%). Multiple logistic regression was performed to determine the relationship between each variable and the success rates for smoking cessation at week 6, 12, and 24. SWESC was confirmed as significant (p < 0.05) variables for increased success rate for smoking cessation at all 3 time points. After adjusting for all variables, the Cox proportional hazards survival analysis showed a hazard ratio of 6.17 for SWESC (p < 0.001,; 95% confidence interval: 3.08-12.38). Conclusions: At a professional treatment smoking cessation camp, participants with an SWESC showed a significantly higher success rate for smoking cessation. Supportive workplace environment for workers' health is expected to be an important factor for smoking cessation projects as well as other health promotion projects at workplace.

Degranulation of Mast Cells as a Target for Drug Development.

Mast cells act as key effector cells of inflammatory responses through degranulation. Mast cell degranulation is induced by the activation of cell surface receptors, such as FcεRI, MRGPRX2/B2, and P2RX7. Each receptor, except FcεRI, varies in its expression pattern depending on the tissue, which contributes to their differing involvement in inflammatory responses depending on the site of occurrence. Focusing on the mechanism of allergic inflammatory responses by mast cells, this review will describe newly identified mast cell receptors in terms of their involvement in degranulation induction and patterns of tissue-specific expression. In addition, new drugs targeting mast cell degranulation for the treatment of allergy-related diseases will be introduced.

Cannabidiol mediates epidermal terminal differentiation and redox homeostasis through aryl hydrocarbon receptor (AhR)-dependent signaling.

BACKGROUND: Cannabidiol, a non-psychoactive phytocannabinoid, has antioxidant and anti-inflammatory activity in keratinocytes. However, the signaling pathway through which cannabidiol exerts its effect on keratinocytes or whether it can modulate keratinocyte differentiation has not been fully elucidated yet. OBJECTIVE: We investigated whether cannabidiol modulates epidermal differentiation and scavenges reactive oxygen species through the aryl hydrocarbon receptor (AhR) in keratinocytes and epidermal equivalents. METHODS: We investigated the cannabidiol-induced activation of AhR using AhR luciferase reporter assay, qRT-PCR, western blot, and immunofluorescence assays. We also analyzed whether keratinocyte differentiation and antioxidant activity are regulated by cannabidiol-induced AhR activation. RESULTS: In both keratinocytes and epidermal equivalents, cannabidiol increased both the mRNA and protein expression of filaggrin, involucrin, NRF2, and NQO1 and the mRNA expression of the AhR target genes, including CYP1A1 and aryl hydrocarbon receptor repressor. Additionally, cannabidiol showed antioxidant activity that was attenuated by AhR knockdown or co-administration with an AhR antagonist. Moreover, cannabidiol increased the ratio of OVOL1/OVOL2 mRNA expression, which is a downstream regulator of AhR that mediates epidermal differentiation. In addition to increased expression of barrier-related proteins, cannabidiol-treated epidermal equivalent showed a more prominent granular layer than the control epidermis. The increased granular layer by cannabidiol was suppressed by the AhR antagonist. CONCLUSION: Cannabidiol can be a modulator of the AhR-OVOL1-filaggrin axis and AhR-NRF2-NQO1 signaling, thus indicating a potential use of cannabidiol in skin barrier enhancement and reducing oxidative stress.

Structural and Functional Validation of a Full-Thickness Self-Assembled Skin Equivalent for Disease Modeling.

Recently, various types of in vitro-reconstructed 3D skin models have been developed for drug testing and disease modeling. Herein, we structurally and functionally validated a self-assembled reconstructed skin equivalent (RSE) and developed an IL-17a-induced in vitro psoriasis-like model using a self-assembled RSE. The tissue engineering approach was used to construct the self-assembled RSE. The dermal layer was generated using fibroblasts secreting their own ECM, and the epidermal layer was reconstructed by seeding keratinocytes on the dermal layer. To generate the psoriatic model, IL-17A was added to the culture medium during the air-liquid interface culture period. Self-assembled RSE resulted in a fully differentiated epidermal layer, a well-established basement membrane, and dermal collagen deposition. In addition, self-assembled RSE was tested for 20 reference chemicals according to the Performance Standard of OECD TG439 and showed overall sensitivity, specificity, and accuracy of 100%, 90%, and 95%, respectively. The IL-17a-treated psoriatic RSE model exhibited psoriatic epidermal characteristics, such as epidermal hyperproliferation, parakeratosis, and increased expression of KRT6, KRT17, hBD2, and S100A9. Thus, our results suggest that a self-assembled RSE that structurally and functionally mimics the human skin has a great potential for testing various drugs or cosmetic ingredients and modeling inflammatory skin diseases.

2-Methoxyestradiol Inhibits Radiation-Induced Skin Injuries.

Radiation-induced skin injury (RISI) is a main side effect of radiotherapy for cancer patients, with vascular damage being a common pathogenesis of acute and chronic RISI. Despite the severity of RISI, there are few treatments for it that are in clinical use. 2-Methoxyestradiol (2-ME) has been reported to regulate the radiation-induced vascular endothelial-to-mesenchymal transition. Thus, we investigated 2-ME as a potent anti-cancer and hypoxia-inducible factor 1 alpha (HIF-1α) inhibitor drug that prevents RISI by targeting HIF-1α. 2-ME treatment prior to and post irradiation inhibited RISI on the skin of C57/BL6 mice. 2-ME also reduced radiation-induced inflammation, skin thickness, and vascular fibrosis. In particular, post-treatment with 2-ME after irradiation repaired the damaged vessels on the irradiated dermal skin, inhibiting endothelial HIF-1α expression. In addition to the increase in vascular density, post-treatment with 2-ME showed fibrotic changes in residual vessels with SMA+CD31+ on the irradiated skin. Furthermore, 2-ME significantly inhibited fibrotic changes and accumulated DNA damage in irradiated human dermal microvascular endothelial cells. Therefore, we suggest that 2-ME may be a potent therapeutic agent for RISI.

Prevention of urethral fibrosis induced by transforming growth factor beta 1 using selective Wnt/ß-catenin signaling inhibitors in a rat model.

OBJECTIVES: To determine the anti-fibrotic effects of Wnt/ß-catenin signaling inhibitors on urethral stricture. METHODS: Human fibroblasts were exposed to transforming growth factor beta 1 combined with various concentrations of Wnt/ß-catenin inhibitors (ICG-001, IWR-1, and PRI-724), and cell proliferation and migration were evaluated. Urethral fibrosis was induced in male Sprague-Dawley rats by urethral injection of transforming growth factor beta 1 and co-treatement with inhibitors. Urethral tissues were harvested 2 weeks after the injection. The messenger ribonucleic acid and protein expression was examined for fibrosis markers Axin-1, collagen type 1, alpha smooth muscle actin, and ß-catenin. Histological analysis of fibrosis and collagen deposition was also performed. RESULTS: Cell migration was ameliorated by ICG-001 and PRI-724. Protein and messenger ribonucleic acid expression of collagen type 1 and alpha smooth muscle actin in transforming growth factor beta 1-treated fibroblasts decreased in a concentration-dependent manner with the ICG-001 and PRI-724 treatments (P < 0.05). However, there were no significant changes with the IWR-1 treatment. Collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression were both significantly increased in the urethral tissues of rats with transforming growth factor beta 1-induced urethral fibrosis. Rats co-treated with ICG-001 or PRI-724 showed relatively mild fibrosis and significantly reduced collagen type I and alpha smooth muscle actin messenger ribonucleic acid and protein expression (P < 0.05). CONCLUSIONS: ICG-001 and PRI-724 significantly ameliorated urethral fibrosis induced by transforming growth factor beta 1 in rats. These results suggest that ICG-001 and PRI-724 can be developed as therapeutics for treating urethral stricture.

Nickel dust-induced occupational contact dermatitis by welding and grinding work in shipyard workers: a report of nine cases.

Background: Occupational skin diseases are skin conditions that occur or worsen in relation to work and known to be the second most common type of occupational disease affecting individuals in the United States. In Korea, epidemiological reports related to occupational skin diseases are rare. But, no cases of occupational contact dermatitis caused by welding and grinding work have been reported previously. Case presentation: Nine male workers working in the production department for liquefied natural gas (LNG) ships in Ulsan complained of erythematous papules/patches and itching in various areas of the body after welding and grinding work. The work environment monitoring report revealed that the amount of nickel dust exceeded the time weighted average (TWA) and poor local ventilation status. Based on the symptoms and the overall results of surveys, several tests, and work environment monitoring report, the 2 workers who had positive patch-test reactions to nickel were diagnosed with nickel dust-induced allergic contact dermatitis. The other 7 workers were diagnosed that there was a high probability that they had nickel dust-induced irritant contact dermatitis. The 2 workers who had nickel dust-induced allergic contact dermatitis were recommended to switch their jobs. Conclusions: Nickel is one of the most common cause of allergic contact dermatitis. In this case, the dust was assumed to be created by welding work with a high nickel content new welding rod and subsequent grinding work, and the concentration of this dust exceeded the time weighted average. Thus, it is thought that the nickel dust may have caused contact dermatitis through continuous contact with the workers' exposed skin in a poorly ventilated space. Currently, several domestic shipbuilding companies are manufacturing LNG tankers using a new construction method. Consequently, it is highly likely that similar cases will occur in the future, which makes this case report meaningful.

What Is the Role of Night-Time Noise Exposure in Childhood Allergic Disease?

The cause of the allergic disease is known to be multifactorial, and there is growing evidence of environmental factors triggering the disease. Indeed, it is essential to find modifiable environmental factors related to allergic disease. Noise is an environmental pollutant causing various health problems, especially when exposed during the night-time. This study assessed the impact of night-time noise exposure in allergic disease. Subjects were selected from a panel data survey containing questions on allergic disease and related factors. Incidence of allergic disease, covariates, and addresses was derived from survey questionnaires. By applying the Land Use Regression modeling method, each subject's night-time noise estimates were elicited based on the night-time noise level collected from the noise monitoring site. Association between night-time noise difference rate and incidence of asthma were analyzed by Cox proportional hazard regression. Incidence of allergic disease increased when night-time noise difference was positive compared to the negative difference. Additionally, the incidence of allergic disease increased by per interquartile range of night-time noise difference rate. The result showed that exposure to night-time noise tends to increase the risk of allergic disease. With further studies, the result of our study may serve as supplementary data when determining noise limits.

PFN1 Prevents Psoriasis Pathogenesis through IκBζ Regulation.

PFN1 is an actin-binding protein that regulates actin polymerization, cell proliferation, apoptosis, angiogenesis, and carcinogenesis. Its dysregulation has been reported in diverse pathologic diseases; however, the role of PFN1 in psoriasis has not yet been elucidated. In this study, we show that PFN1 expression is increased in both skin and serum of patients with psoriasis. PFN1 was markedly expressed in the epidermis of psoriatic lesions, and its expression positively correlated with psoriasis severity. IL-17A treatment of keratinocytes increased PFN1 expression, whereas TNF-α induced PFN1 expression and secretion. In addition, knockdown of PFN1 with short hairpin RNA resulted in an altered expression of psoriasis-associated inflammatory markers, HBD2, S100A7, S100A9, and Ki-67, and recombinant PFN1 suppressed the IL-17A‒induced inflammatory response in keratinocytes. Interestingly, recombinant PFN1 also suppressed IL-17A‒induced IκBζ, an important player in immune response in psoriasis. Collectively, our results show that PFN1 acts as a negative regulator of psoriatic inflammation through the suppression of IκBζ and that the balanced level of PFN1 is important for IκBζ regulation. Thus, the expression of PFN1 can be used as a biomarker for psoriasis severity, and it can be considered as a possible target for the treatment of psoriasis.

Adiponectin and 8-epi-PGF2α as intermediate influencing factors in weight reduction after legume consumption: a 12-week randomised controlled trial.

Legumes are rich sources of essential nutrients, and their potential health benefits were reported in many studies. Several studies showed a positive effect of legumes on obesity, but randomised clinical trials are limited in the Korean population. The present intervention study investigated the impact of legumes on body weight in obese Korean subjects. A total of 400 participants (BMI ≥ 25 kg/m2) were randomised into two groups. The legume-enriched diet (LD) group replaced one-third of their refined rice consumption with legumes three times per day as a carbohydrate source. In contrast, the usual diet (UD) group consumed their UD. The mean weight loss at 12 weeks was 2·87 (sem 0·21) kg and 0·17 (sem 0·11) kg in the LD and UD, respectively, which was significantly different between the groups (P < 0·001). HDL-cholesterol and adiponectin levels were increased, and levels of glucose, insulin, TAG, and 8-epi-PGF2α and the homoeostasis model assessment of insulin resistance (IR) index value decreased at 12 weeks compared with baseline in the LD. The consumption of legumes may accelerate weight loss accompanied by regulation of adiponectin and 8-epi-PGF2α in obese subjects. In particular, legumes seemed to induce significant changes in BMI by increasing adiponectin in females. Additionally, increases in plasma adiponectin due to greater substantial weight loss may be related to the improvement in IR.

Factors related to depressive symptoms in Korean self-employed workers.

BACKGROUND: We examined factors related to depressive symptoms in Korean self-employed workers. METHODS: This secondary analysis examined data of 14,454 self-employed individuals from the fifth Korean Working Conditions Survey (2017). Multiple logistic regression analysis was used to assess the relationship of depressive symptoms with different variables. RESULTS: Self-employed workers who had a good work-life balance, a good subjective health, and worked 40 to 48 hours or 48 to 60 hours/week were less likely to report depressive symptoms (all p < 0.05). However, those who always interacted with angry clients, had severe exposure to ergonomic risk factors, and were exposed to moderate or severe abusive behaviors were more likely to report depressive symptoms (all p < 0.05). Age, gender, weekly work days, and working at very fast speed were unrelated to depressive symptoms. CONCLUSIONS: Several factors known to be related to depressive symptoms do not lead to depression in self-employed individuals. Different interventions may therefore be needed to prevent depression in self-employed workers.

A Michael Acceptor Analogue, SKSI-0412, Down-Regulates Inflammation and Proliferation Factors through Suppressing Signal Transducer and Activator of Transcription 3 Signaling in IL-17A-Induced Human Keratinocyte.

The activation of signal transducer and activator of transcription 3 (STAT3), as well as up-regulation of cytokines and growth factors to promote STAT3 activation, have been found in the epidermis of psoriatic lesions. Recently, a series of synthetic compounds possessing the Michael acceptor have been reported as STAT3 inhibitors by covalently binding to cysteine of STAT3. We synthesized a Michael acceptor analog, SKSI-0412, and confirmed the binding affinity between STAT3 and SKSI-0412. We hypothesized that the SKSI-0412 can inhibit interleukin (IL)-17A-induced inflammation in keratinocytes. The introduction of IL-17A increased the phosphorylation of STAT3 in keratinocytes, whereas the inactivation of STAT3 by SKSI-0412 reduced IL-17A-induced STAT3 phosphorylation and IκBζ expression. In addition, human ß defensin-2 and S100A7, which are regulated by IκBζ, were significantly decreased with SKSI-0412 administration. We also confirmed that SKSI-0412 regulates cell proliferation, which is the major phenotype of psoriasis. Based on these results, we suggest targeting STAT3 with SKSI-0412 as a novel therapeutic strategy to regulate IL-17A-induced psoriatic inflammation in keratinocytes.

An antibody against L1 cell adhesion molecule inhibits cardiotoxicity by regulating persistent DNA damage.

Targeting the molecular pathways underlying the cardiotoxicity associated with thoracic irradiation and doxorubicin (Dox) could reduce the morbidity and mortality associated with these anticancer treatments. Here, we find that vascular endothelial cells (ECs) with persistent DNA damage induced by irradiation and Dox treatment exhibit a fibrotic phenotype (endothelial-mesenchymal transition, EndMT) correlating with the colocalization of L1CAM and persistent DNA damage foci. We demonstrate that treatment with the anti-L1CAM antibody Ab417 decreases L1CAM overexpression and nuclear translocation and persistent DNA damage foci. We show that in whole-heart-irradiated mice, EC-specific p53 deletion increases vascular fibrosis and the colocalization of L1CAM and DNA damage foci, while Ab417 attenuates these effects. We also demonstrate that Ab417 prevents cardiac dysfunction-related decrease in fractional shortening and prolongs survival after whole-heart irradiation or Dox treatment. We show that cardiomyopathy patient-derived cardiovascular ECs with persistent DNA damage show upregulated L1CAM and EndMT, indicating clinical applicability of Ab417. We conclude that controlling vascular DNA damage by inhibiting nuclear L1CAM translocation might effectively prevent anticancer therapy-associated cardiotoxicity.

Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model.

A chronic, local inflammatory milieu can cause tissue fibrosis that results in epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), increased abundance of fibroblasts, and further acceleration of fibrosis. In this study, we aimed to identify potential mechanisms and inhibitors of fibrosis using 3D model-based phenotypic screening. We established liver fibrosis models using multicellular tumor spheroids (MCTSs) composed of hepatocellular carcinoma (HCC) and stromal cells such as fibroblasts (WI38), hepatic stellate cells (LX2), and endothelial cells (HUVEC) seeded at constant ratios. Through high-throughput screening of FDA-approved drugs, we identified retinoic acid and forskolin as candidates to attenuate the compactness of MCTSs as well as inhibit the expression of ECM-related proteins. Additionally, retinoic acid and forskolin induced reprogramming of fibroblast and cancer stem cells in the HCC microenvironment. Of interest, retinoic acid and forskolin had anti-fibrosis effects by decreasing expression of α-SMA and F-actin in LX2 cells and HUVEC cells. Moreover, when sorafenib was added along with retinoic acid and forskolin, apoptosis was increased, suggesting that anti-fibrosis drugs may improve tissue penetration to support the efficacy of anti-cancer drugs. Collectively, these findings support the potential utility of morphometric analyses of hepatic multicellular spheroid models in the development of new drugs with novel mechanisms for the treatment of hepatic fibrosis and HCCs.

Pharmacologic Inhibition of HIF-1α Attenuates Radiation-Induced Pulmonary Fibrosis in a Preclinical Image Guided Radiation Therapy.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a long-term side effect of thoracic radiation therapy. Hypoxia-induced vascular endothelial mesenchymal transition (EndMT) can occur during the development of RIPF. Here, we examined the direct contribution of endothelial HIF-1α (EC-HIF1α) on RIPF. METHODS AND MATERIALS: An inducible Cre-lox-mediated endothelial Hif1a deletion mouse line was used to evaluate the potential of HIF-1α inhibition to suppress RIPF. To evaluate the effects of a pharmacologic HIF-1α inhibitor on RIPF after image guided radiation therapy (IGRT) for spontaneous lung adenocarcinoma, we generated conditional tdTomato; K-RasG12D; and p53 flox/flox mice to facilitate tracking of tumor cells expressing tdTomato. RESULTS: We found that vascular endothelial-specific HIF-1α deletion shortly before radiation therapy inhibited the progression of RIPF along with reduced EndMT, whereas prolonged deletion of endothelial HIF-1α before irradiation did not. Moreover, we revealed that postirradiation treatment with the novel HIF-1α inhibitor, 2-methoxyestradiol (2-ME) could efficiently inhibit RIPF and EndMT. In addition, IGRT using primary mouse models of non-small cell lung cancer showed that combined treatment of 2-ME with ablative high-dose radiation therapy efficiently inhibited RIPF and the growth of both multifocal and single tumors, concomitantly reducing radiation-induced EndMT of normal as well as tumor regions. CONCLUSION: These results suggest that a negative regulator of HIF-1α-mediated EndMT, such as 2-ME, may serve as a promising inhibitor of RIPF in radiation therapy.

Concise Synthesis of Catechin Metabolites 5-(3',4'-Dihydroxyphenyl)-γ-valerolactones (DHPV) in Optically Pure Form and Their Stereochemical Effects on Skin Wrinkle-Reducing Activities.

A concise and scalable synthetic route for optically pure (4S) and (4R)-5-(3',4'-dihydroxyphenyl)-γ-valerolactones (DHPVs), catechin metabolites, has been developed via the efficient construction of a γ-valerolactone moiety from hexenol. Noticeably, the different skin wrinkle-reducing activities of each metabolite were revealed via our unique syntheses of DHPVs in an enantiomerically pure form.

Inhibitors of Na+/K+ ATPase exhibit antitumor effects on multicellular tumor spheroids of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), one of the most common malignant cancers worldwide, is associated with substantial mortality. Because HCCs have strong resistance to conventional chemotherapeutic agents, novel therapeutic strategies are needed to improve survival in patients with HCC. The multicellular tumor spheroid (MCTS) model is a powerful method for anticancer research because of its ability to mimic the complexity and heterogeneity of tumor tissue, the three-dimensional cellular context of tumor tissue, and the pathophysiological gradients of in vivo tumors. However, it is difficult to obtain meaningful results from the MCTS model without considering the conditions of clinical tumors. We, therefore, provided a proof of concept to determine whether spheroid models simulate in vivo tumor microenvironments. Through a high-throughput screening for HCC therapy using the MCTS model, we selected inhibitors of Na+/K+-ATPase (ouabain and digoxin) that could suppress cell growth and migration via inhibition of the epithelial-mesenchymal transition of HCC in vivo and in vitro. The results showed that this model provides a new paradigm for high-throughput drug screening and will significantly improve the efficiency of identifying new drugs for HCC treatment. Through utilization of MCTS models, here we found that inhibitors of Na+/K+-ATPase may be feasible as a novel target to sensitize HCC cells.