Effect of pentacyclic triterpenes found in Perilla frutescens alone or in combination with resveratrol on skin tumor promotion by 12-o-tetra-decanoylphorbol-13-acetate

textA series of pentacyclic triterpenes found in P. frutescens, including ursolic acid (UA), oleanolic acid (OA), augustic acid (AA), corosolic acid (CA), 3-epi-corosolic acid (3-epiCA), maslinic acid (MA), and 3-epi-maslinic acid (3-epiMA) were evaluated for their effects on skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate (TPA). UA was also evaluated in a combination with resveratrol (Res) for possible combinatorial chemopreventive activity. All triterpene compounds significantly inhibited skin tumor promotion by TPA. MA and 3-epiCA, were significantly more effective than UA at inhibiting tumor development. Topical pretreatment with all of these compounds significantly inhibited epidermal proliferation induced by TPA, however, CA, 3-epiCA and MA were more effective than UA. All compounds reduced skin inflammation and inflammatory gene expression induced by TPA, however, 3-epiCA and MA were identified to be more effective than UA. Finally, the ability of these compounds to alter epidermal signaling pathways associated with skin tumor promotion by TPA was also evaluated. The greater ability of 3-epiCA and MA to inhibit skin tumor promotion was associated with greater reduction of Cox-2 and Twist1 proteins and inhibition of activation of IGF-1R, Stat3 and Src. The effect of combining UA + Res for combinatorial inhibitory effects on skin tumor promotion were also examined. The combination of UA + Res produced a greater inhibition of TPA-induced epidermal hyperproliferation, epidermal inflammatory signaling, and inflammatory gene expression when compared to UA or Res alone. Furthermore, NF-kB, Egr-1, and AP-1 DNA binding activities following TPA treatment were dramatically decreased by the combination of UA + Res. Treatment with UA + Res during skin tumor promotion by TPA produced greater inhibition of tumor multiplicity and tumor size than with either agent alone. Collectively, the current data demonstrate that UA and related triterpenes as well as the combination of UA + Res inhibited skin tumor promotion by TPA via effects on multiple cellular and biochemical/molecular mechanisms associated with this process similar to calorie restriction. Of the tritperpenes tested, 3-epiCA and MA were the most active. Furthermore, the favorable anti-tumor promoting effects of combining UA + Res suggest that phytochemical combination therapy may be a more efficacious strategy for cancer chemoprevention.Pharmaceutical Science

Role of AMPK and PPARα in the anti-skin cancer effects of ursolic acid

The phytonutrient ursolic acid (UA), present in apples, rosemary, and other plant sources, has anti-cancer properties in a number of systems, including skin cancers. However, few reports have examined upstream mechanisms by which UA may prevent or treat cancer. Recent reports have indicated UA induces death of cancer cell lines via AMP-activated protein kinase (AMPK), an energy-sensing kinase which possesses both pro-metabolic and anti-cancer effects. Other studies have shown UA activates peroxisome proliferator activated receptor α (PPARα) and the glucocorticoid receptor (GR). Here, we found the cytotoxic effect of UA in skin carcinoma cells required AMPK activation. In addition, two inhibitors of PPARα partially reversed the cytotoxic effects of UA, suggesting its effects are at least partially mediated through this receptor. Finally, inhibition of the GR did not reverse the effects of UA nor did this compound bind the GR under the conditions of experiments performed. Overall, studies elucidating the anti-cancer effects of UA may allow for the development of more potent analogues utilizing similar mechanisms. These studies may also reveal the mediators of any possible side effects or resistance mechanisms to UA therapy

Intramembrane proteolysis of an extracellular serine protease, epithin/PRSS14, enables its intracellular nuclear function

Background Epithin/PRSS14, a type II transmembrane serine protease, is an emerging target of cancer therapy because of its critical roles in tumor progression and metastasis. In many circumstances, the protease, through its ectodomain shedding, exists as a soluble form and performs its proteolytic functions in extracellular environments increasing cellular invasiveness. The seemingly functional integrity of the soluble form raises the question of why the protease is initially made as a membrane-associated protein. Results In this report, we show that the epithin/PRSS14 intracellular domain (EICD) can be released from the membrane by the action of signal peptide peptidase-like 2b (SPPL2b) after ectodomain shedding. The EICD preferentially localizes in the nucleus and can enhance migration, invasion, and metastasis of epithelial cancer when heterologously expressed. Unbiased RNA-seq analysis and subsequent antibody arrays showed that EICD could control the gene expression of chemokines involved in cell motility, by increasing their promoter activities. Finally, bioinformatics analysis provided evidence for the clinical significance of the intramembrane proteolysis of epithin/PRSS14 by revealing that the poor survival of estrogen receptor (ER)-negative breast cancer patients with high epithin/PRSS14 expression is further worsened by high levels of SPPL2b. Conclusions These results show that ectodomain shedding of epithin/PRSS14 can initiate a unique and synchronized bidirectional signal for cancer metastasis: extracellularly broadening proteolytic modification of the surrounding environment and intracellularly reprogramming the transcriptome for metastatic conversion. Clinically, this study also suggests that the intracellular function of epithin/PRSS14 should be considered for targeting this protease for anti-cancer treatment.This work was supported in part by the National Research Foundation of Korea (NRF) grants (NRF-2017R1A2B4008109 to M.G.K. and NRF2019R1A2C2008067 to C.K.) and a Korea University grant (to C.K.)

Mitochondrial uncoupling links lipid catabolism to Akt inhibition and resistance to tumorigenesis

To support growth, tumour cells reprogramme their metabolism to simultaneously upregulate macromolecular biosynthesis while maintaining energy production. Uncoupling proteins (UCPs) oppose this phenotype by inducing futile mitochondrial respiration that is uncoupled from ATP synthesis, resulting in nutrient wasting. Here using a UCP3 transgene targeted to the basal epidermis, we show that forced mitochondrial uncoupling inhibits skin carcinogenesis by blocking Akt activation. Similarly, Akt activation is markedly inhibited in UCP3 overexpressing primary human keratinocytes. Mechanistic studies reveal that uncoupling increases fatty acid oxidation and membrane phospholipid catabolism, and impairs recruitment of Akt to the plasma membrane. Overexpression of Akt overcomes metabolic regulation by UCP3, rescuing carcinogenesis. These findings demonstrate that mitochondrial uncoupling is an effective strategy to limit proliferation and tumorigenesis through inhibition of Akt, and illuminate a novel mechanism of crosstalk between mitochondrial metabolism and growth signalling

Self-assembled adipose-derived mesenchymal stem cells as an extracellular matrix component- and growth factor-enriched filler

The clinical application of mesenchymal stem cells (MSCs) is attracting attention due to their excellent safety, convenient acquisition, multipotency, and trophic activity. The clinical effectiveness of transplanted MSCs is well-known in regenerative and immunomodulatory medicine, but there is a demand for their improved viability and regenerative function after transplantation. In this study, we isolated MSCs from adipose tissue from three human donors and generated uniformly sized MSC spheroids (∼100 µm in diameter) called microblocks (MiBs) for dermal reconstitution. The viability and MSC marker expression of MSCs in MiBs were similar to those of monolayer MSCs. Compared with monolayer MSCs, MiBs produced more extracellular matrix (ECM) components, including type I collagen, fibronectin, and hyaluronic acid, and growth factors such as vascular endothelial growth factor and hepatocyte growth factor. Subcutaneously injected MiBs showed skin volume retaining capacity in mice. These results indicate that MiBs could be applied as regenerative medicine for skin conditions such as atrophic scar by having high ECM and bioactive factor expression

Psychometric properties and factor structure of the Korean version of the screen for child anxiety related emotional disorders (SCARED)

The aim of this study was to examine the psychometric properties of the Korean version of Screen for Child Anxiety Related Emotional Disorders (SCARED) on a sample of Korean youths and to examine the cross-cultural differences in adolescents anxiety. Our study included 147 adolescents (ages 12–17, 92 girls), 93 with major depressive disorder and 54 as controls. Participants were evaluated using the Kiddie-Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL), SCARED, Child Behavior Checklist (CBCL), Disruptive Behavioral Disorder Scale (DBD) and Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS). Pearsons r and Cronbachs α values of the SCARED were calculated, and exploratory factor analysis was conducted. The Korean SCARED scores were correlated with the total anxiety scores of K-SADS-PL (r = 0.74) and the CBCL anxious/depressed subscale scores (r = 0.35). Results showed a five-factor structure with good internal consistency, in which some items were loaded on different factors compared to previous studies. The Korean SCARED demonstrated promising psychometric properties, and could be a valid scale for screening anxiety symptoms in primary care. The fact that different items comprised the factors may reflect the cultural difference between United States and Korea in experiencing anxiety.This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (NRF-2015R1A2A2A01004501) and was supported by Promising-Pioneering Research Program through Seoul National University (SNU) in 2015. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Low Frequency and Variability of FLT3 Mutations in Korean Patients with Acute Myeloid Leukemia

FLT3 mutations are common genetic changes, and are reported to have prognostic significance in acute myeloid leukemia (AML). The FLT3 internal tandem duplication (ITD) and the D835 activating mutation in the tyrosine kinase domain (TKD) were analyzed by polymerase chain reaction (PCR) in the genomic DNA of Korean patients with AML at diagnosis and during follow-up. There were 226 patients with AML enrolled between March 1996 and August 2005. The incidence of ITD and TKD at diagnosis was 13% (29/226) and 3% (6/226). When compared to Western and other Asian patients with AML, Korean patients had a lower frequency by about two-thirds of ITD and TKD. Among the non-M3 cases (N=203), the patients with an ITD had a significantly shorter event-free survival when compared with those without an ITD (p=0.0079). Among 54 relapsed patients, 9 patients had the FLT3 ITD at diagnosis. Six patients demonstrated a reappearance of the ITD and 3 patients remained negative at relapse. One patient, among 45 patients who relapsed, had a negative baseline ITD but acquired a de novo ITD at relapse. There were 101 samples from 93 patients in remission; they were all negative for an ITD. Among 34 patients who failed to achieve a remission, five patients had a persistent ITD and one patient had a de novo ITD. These results support the concept of resistance of FLT3 ITD leukemic clones to chemotherapy. Therefore, effective therapy with FLT3 targeting agents may improve the prognosis of non-M3 AML patients with the FLT3 mutation

Object-based Suppression in Target Search but not in Distractor Inhibition

Data acquired for the project "Object-based Suppression in Target Search but not in Distractor Inhibition

Retail regulation in South Korea: The NoBrand case

This study examines how NoBrand has faced legal regulations in Korea, and NoBrand's transition to the franchise system to respond to regulatory changes (examined with a case analysis). In 2015, Emart, a Korean retail giant, launched its private brand (PB), NoBrand, to address stagnant sales. With advantages in price and quality due to supply chain management (SCM), NoBrand not only established a successful foothold, but also gained success in the market. Despite the rapid growth of NoBrand, it has faced government regulations that restrict its operations. To respond to these regulations, NoBrand changed its direct operating system to a franchise system that allows an individual owner to run his or her own NoBrand store. However, the transition triggered conflicts with both local stakeholders and other branches of its parent firm, Emart. By analyzing these conflicts, this study finds that Korean retail policy did not effectively protect small business owners as primarily aimed