Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions.

Transcription factors (TFs) are major trans-acting factors in transcriptional regulation. Therefore, elucidating TF-target interactions is a key step toward understanding the regulatory circuitry underlying complex traits such as human diseases. We previously published a reference TF-target interaction database for humans-TRRUST (Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining)-which was constructed using sentence-based text mining, followed by manual curation. Here, we present TRRUST v2 (www.grnpedia.org/trrust) with a significant improvement from the previous version, including a significantly increased size of the database consisting of 8444 regulatory interactions for 800 TFs in humans. More importantly, TRRUST v2 also contains a database for TF-target interactions in mice, including 6552 TF-target interactions for 828 mouse TFs. TRRUST v2 is also substantially more comprehensive and less biased than other TF-target interaction databases. We also improved the web interface, which now enables prioritization of key TFs for a physiological condition depicted by a set of user-input transcriptional responsive genes. With the significant expansion in the database size and inclusion of the new web tool for TF prioritization, we believe that TRRUST v2 will be a versatile database for the study of the transcriptional regulation involved in human diseases.

Development and validation of the quality care questionnaire -palliative care (QCQ-PC): patient-reported assessment of quality of palliative care.

BACKGROUND: In this study, we aimed to develop and validate an instrument that could be used by patients with cancer to evaluate their quality of palliative care. METHODS: Development of the questionnaire followed the four-phase process: item generation and reduction, construction, pilot testing, and field testing. Based on the literature, we constructed a list of items for the quality of palliative care from 104 quality care issues divided into 14 subscales. We constructed scales of 43 items that only the cancer patients were asked to answer. Using relevance and feasibility criteria and pilot testing, we developed a 44-item questionnaire. To assess the sensitivity and validity of the questionnaire, we recruited 220 patients over 18 years of age from three Korean hospitals. RESULTS: Factor analysis of the data and fit statistics process resulted in the 4-factor, 32-item Quality Care Questionnaire-Palliative Care (QCQ-PC), which covers appropriate communication with health care professionals (ten items), discussing value of life and goals of care (nine items), support and counseling for needs of holistic care (seven items), and accessibility and sustainability of care (six items). All subscales and total scores showed a high internal consistency (Cronbach alpha range, 0.89 to 0.97). Multi-trait scaling analysis showed good convergent (0.568-0.995) and discriminant (0.472-0.869) validity. The correlation between the total and subscale scores of QCQ-PC and those of EORTC QLQ-C15-PAL, MQOL, SAT-SF, and DCS was obtained. CONCLUSION: This study demonstrates that the QCQ-PC can be adopted to assess the quality of care in patients with cancer.

Korean red ginseng alleviates benign prostatic hyperplasia by dysregulating androgen receptor signaling and inhibiting DRP1-mediated mitochondrial fission.

Panax ginseng (C.A. Mey.) has been traditionally employed in Korea and China to alleviate fatigue and digestive disorders. In particular, Korean red ginseng (KRG), derived from streamed and dried P. ginseng, is known for its anti-aging and anti-inflammatory properties. However, its effects on benign prostatic hyperplasia (BPH), a representative aging-related disease, and the underlying mechanisms remain unclear. This study aims to elucidate the therapeutic effects of KRG on BPH, with a particular focus on mitochondrial dynamics, including fission and fusion processes. The effects of KRG on cell proliferation, apoptosis, and mitochondrial dynamics and morphology were evaluated in a rat model of testosterone propionate (TP)-induced BPH and TP-treated LNCaP cells, with mdivi-1 as a control. The results revealed that KRG treatment reduced the levels of androgen receptors (AR) and prostate-specific antigens in the BPH group. KRG inhibited cell proliferation by downregulating cyclin D and proliferating cell nuclear antigen (PCNA) levels, and it promoted apoptosis by increasing the ratio of B-cell lymphoma protein 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 expression. Notably, KRG treatment enhanced the phosphorylation of dynamin-related protein 1 (DRP-1, serine 637) compared with that in the BPH group, which inhibited mitochondrial fission and led to mitochondrial elongation. This modulation of mitochondrial dynamics was associated with decreased cell proliferation and increased apoptosis. By dysregulating AR signaling and inhibiting mitochondrial fission through enhanced DRP-1 (ser637) phosphorylation, KRG effectively reduced cell proliferation and induced apoptosis. These findings suggest that KRG's regulation of mitochondrial dynamics offers a promising clinical approach for the treatment of BPH.

Atomistic Simulation of HF Etching Process of Amorphous Si3N4 Using Machine Learning Potential.

An atomistic understanding of dry-etching processes with reactive molecules is crucial for achieving geometric integrity in highly scaled semiconductor devices. Molecular dynamics (MD) simulations are instrumental, but the lack of reliable force fields hinders the widespread use of MD in etching simulations. In this work, we develop an accurate neural network potential (NNP) for simulating the etching process of amorphous Si3N4 with HF molecules. The surface reactions in diverse local environments are considered by incorporating several types of training sets: baseline structures, reaction-specific data, and general-purpose training sets. Furthermore, the NNP is refined through iterative comparisons with the density functional theory results. Using the trained NNP, we carry out etching simulations, which allow for detailed observation and analysis of key processes such as preferential sputtering, surface modification, etching yield, threshold energy, and the distribution of etching products. Additionally, we develop a simple continuum model, built from the MD simulation results, which effectively reproduces the surface composition obtained with MD simulations. By establishing a computational framework for atomistic etching simulation and scale bridging, this work will pave the way for more accurate and efficient design of etching processes in the semiconductor industry, enhancing device performance and manufacturing precision.

Efficacy of Hepatitis B Vaccine in Adults with Chronic Liver Disease.

Background & Aims: Although HBV vaccine has a 95% seroconversion rate in the general population, patients with chronic liver disease have reduced seroconversion rates (16-79%). The aim of the study was to describe seroconversion rates with HBV vaccines in patients with chronic liver disease. Approach & Results: Retrospective chart review was performed among 652 patients who received a complete HBV vaccine series in the hepatology clinic. Of those, 126 patients that were included, 111 received a single dose series, and 15 patients received a double dose series. The seroconversion rate was overall low at 35%, and stayed the same at 35% with double dose and at 33% with single dose. Patients who received a single dose series were further analyzed to review risk factors for seroconversion. Overall, 65% of patients had cirrhosis. Patients were more likely to seroconvert if no cirrhosis (51% vs 72%, P=.04), higher aminotransferase levels, intermediate anti-HBs (2.5-11.9 mIU/mL) at baseline (87.5% vs 14%). Conclusion: Patients with chronic liver disease had a low rate (35%) of response to HBV vaccination. The response rates did not improve in patients that received double dose series. Patients with cirrhosis, lower aminotransferase levels and with a lower baseline anti-HBs had decreased response rates.

Fulvestrant alleviates cisplatin-induced acute kidney injury via repression of BNIP3-mediated apoptosis and autophagy.

Cisplatin-induced acute kidney injury (AKI) is a clinical disease characterized by a sudden loss of renal function within a few hours or days, due to cisplatin uptake. Fulvestrant is an oestrogen receptor alpha (ERα) antagonist used for endocrine therapy. However, the role of fulvestrant in cisplatin-induced AKI remains unclear. In this study, we investigated the effects of fulvestrant on the regulation of apoptotic cell death and autophagic response in cisplatin-induced AKI. The human kidney proximal tubule epithelial cell line (HK-2) was co-treated with fulvestrant and cisplatin. C57BL/6 mice were subcutaneously injected with fulvestrant and cisplatin was administered via intraperitoneal injection. First, cisplatin treatment increased ERα expression, apoptosis, and autophagy in HK-2 cells. Fulvestrant treatment decreased apoptosis and autophagy, which were accompanied by cisplatin treatment in HK-2 cells. Consistent with in vitro results, cisplatin treatment significantly increased ERα expression in vivo. Additionally, cisplatin treatment increased renal injury, apoptosis, and autophagy. Surprisingly, compared to that in the cisplatin-treated mice group, reduced cisplatin-induced renal injury, apoptosis, and autophagy was observed in the cisplatin+fulvestrant-treated mice group. In summary, these results suggest that fulvestrant plays an important role in cisplatin-induced AKI by decreasing apoptosis and autophagy.

Silencing of LLGL2 Suppresses the Estradiol-Induced BPH-1 Cell Proliferation through the Regulation of Autophagy.

Lethal giant larvae (Lgl) is an apical-basal polarity gene first identified in Drosophila. LLGL2 is one of the mammalian homologs of Lgl. However, little is known about its function in the prostate. In this study, to explore the new role of LLGL2 in the prostate, we examined the proliferative activity of a BPH-1 cell line, a well-established model for the human prostate biology of benign prostatic hyperplasia (BPH). The expression of LLGL2 was dose-dependently increased in BPH-1 cells after treatment with 17ß-estradiol (E2). Additionally, E2 treatment increased the proliferation of the BPH-1 cells. However, the knockdown of LLGL2 with siRNA significantly suppressed the proliferation of the E2-treated BPH-1 cells. Moreover, si-llgl2 treatment up-regulated the expression of LC-3B, ATG7, and p-beclin, which are known to play a pivotal role in autophagosome formation in E2-treated BPH-1 cells. Overexpression of LLGL2 was able to further prove these findings by showing the opposite results from the knockdown of LLGL2 in E2-treated BPH-1 cells. Collectively, our results suggest that LLGL2 is closely involved in the proliferation of prostate cells by regulating autophagosome formation. These results provide a better understanding of the mechanism involved in the effect of LLGL2 on prostate cell proliferation. LLGL2 might serve as a potential target in the diagnosis and/or treatment of human BPH.

Stauntonia hexaphylla Extract Ameliorates Androgenic Alopecia by Inhibiting Androgen Signaling in Testosterone-induced Alopecia Mice.

Background: Stauntonia hexaphylla has been a traditional folk remedy for alleviating fever and providing anti-inflammatory properties. Androgenetic alopecia (AGA) is the most common form mediated by the presence of the dihydrotestosterone (DHT). Objectives: In this study, we evaluated the effects of an extract of S. hexaphylla on AGA models and its mechanisms of action. Methods: We studied S. hexaphylla extract to evaluate 5α-reductase and androgen receptor (AR) levels, apoptosis, and cell proliferation in vitro and in vivo. In addition, paracrine factors for androgenic alopecia, such as transforming growth factor beta-1 (TGF-ß1) and dickkopf-a (DKK-1), were examined. Apoptosis was investigated, and the evaluation of proliferation was examined with cytokeratin 14 (CK-14) and proliferating cell nuclear antigen (PCNA). Results: In human follicular dermal papilla cells, the 5α-reductase and AR were decreased following S. hexaphylla treatment, which reduced the Bax/Bcl-2 ratio. Histologically, the dermal thickness and follicle number were higher in the S. hexaphylla groups compared with the AGA group. In addition, the DHT concentration, 5α-reductase, and AR were decreased, thereby downregulating TGF-ß1 and DKK-1 expression and upregulating cyclin D in S. hexaphylla groups. The numbers of keratinocyte-positive and PCNA-positive cells were increased compared to those in the AGA group. Conclusions: The present study demonstrated that the S. hexaphylla extract ameliorated AGA by inhibiting 5α-reductase and androgen signaling, reducing AGA paracrine factors that induce keratinocyte (KC) proliferation, and inhibition apoptosis and catagen prematuration.

The extract of Celtis choseniana Nakai alleviates testosterone-induced benign prostatic hyperplasia through inhibiting 5α reductase type 2 and the Akt/NF-κB/AR pathway.

Benign prostatic hyperplasia (BPH) is a chronic male disease characterized by the enlarged prostate. Celtis chosenianaNakai (C. choseniana) is medicinally used to alleviate pain, gastric disease, and lung abscess. In this study, the effect of C. choseniana extract on BPH was investigated using testosterone-induced rats. Sprague Dawley rats were divided into five groups: control, BPH (testosterone 5 mg·kg-1), Fina (finasteride 2 mg·kg-1), and C. choseniana (50 and 100 mg·kg-1). After four weeks of TP treatment with finasteride or C. choseniana, prostate weights and DHT levels were measured. In addition, the prostates were histopathologically examined and measured for protein kinase B (Akt)/nuclear factor-κB (NF-κB)/AR signaling, proliferation, apoptosis, and autophagy. Prostate weight and epithelial thickness were reduced in the C. choseniana groups compared with that in the BPH group. The extract of C. choseniana acted as a 5α reductase inhibitor, reducing DHT levels in the prostate. Furthermore, the extract of C. choseniana blocked the activation of p-Akt, nuclear NF-κB activation and reduced the expression of AR and PSA compared with BPH. Moreover, the expression of Bax, PARP-1, and p53 increased, while the expression of bcl-2 decreased. The present study demonstrated that C. choseniana extract alleviated testosterone-induced BPH by suppressing 5α reductase and Akt/NF-κB activation, reducing AR signaling and inducing apoptosis and autophagy in the prostate. These results suggested that C. choseniana probably contain potential herbal agents to alleviate BPH.

Decreased mitophagy aggravates benign prostatic hyperplasia in aged mice through DRP1 and estrogen receptor α.

Benign prostatic hyperplasia (BPH) is an age-related disease, whose etiology largely remains unclear. The regulation of mitophagy plays a key role in aging and associated diseases, however, its function in BPH has not been studied. Although the expression of the androgen receptor is primarily implicated in BPH, the estrogen receptor (ER) has been reported to be involved in the development of BPH by mediating the proliferation of prostate cells. Here, we studied the involvement of mitophagy and ERs in spontaneous BPH in aging mice and investigated their functions. To identify the activation of mitophagy and expression of ERs, 8-week, 12-month, and 24-month-old mice were used. Mice were treated with mitochondrial division inhibitor mdivi-1, a dynamin-related protein 1 (Drp1) inhibitor, to examine the expression of mitophagy-related proteins and the development of BPH. In addition, prostate stromal cells were treated with an ER antagonist to investigate the regulation of mitophagy following the expression of ERs. With aging, the Drp1 and phosphorylation of parkin reduce. Electron microscopy revealed reduced mitochondrial fission and mitophagy. In addition, the expression of androgen receptor was decreased and that of ERα was increased in aged mice with BPH. Treatment with mdivi-1 exacerbated BPH and increased cell proliferation. In addition, blockade of ERα increased mitophagy and decreased cell proliferation. In conclusion, mitophagy is reduced with aging during the development of BPH. We speculate that spontaneous BPH progresses through the reduction in the expression of ERα in aged mice by downregulating mitophagy.

Menstrual Cycle Patterns and the Prevalence of Premenstrual Syndrome and Polycystic Ovary Syndrome in Korean Young Adult Women.

Menstruation is one of the important indicators of reproductive health. Therefore, in order to improve the reproductive health of women in puberty and early adulthood, it is necessary to investigate menstrual health and symptoms. This cross-sectional descriptive correlational study was conducted to identify young women's menstrual cycle patterns, prevalence of Premenstrual Syndrome (PMS), Polycystic Ovary Syndrome (PCOS) and the relationships of health-related factors according to menstrual regularity and PCOS. 462 women participated in the first phase of the study and completed the menstrual health and health-related behaviors questionnaire. In the second phase, 88 women with irregular menstruation in phase one had blood tests taken and body composition measured. As a result, Menarche was slightly later in irregular menstruation group. Women with regular menstruation had a mean number of 11.7 menstrual cycles over the past year, 93.0% of them reported a normal menstruation cycle frequency (21-35 days), 95.2% reported a normal duration (2-7 days) and 55.9% of participants had heavy menstrual bleeding. In the irregular menstrual group, there were higher percentages of underweight and obese women as well as more women experiences weight and diet changes. The estimated prevalence rates of PMS and PCOS were 25.5%, 5.2% respectively. This study provides updated basic data about menstrual health among Korean young women but more extensive and sophisticated studies are needed in the future.

Consumers' consciousness of health-friendly products and services and its association with sociodemographic characteristics and health status: a cross-sectional survey of the South Korean population.

OBJECTIVES: To identify consumers' consciousness of health-friendly products and services (consumer reaction, purchase intention and willingness to pay more) and its association with sociodemographic characteristics and multidimensional health status. METHODS: From March to May 2018, we administered questionnaires to 1200 individuals from the general Korean population asking about their perception of health-friendly labels, and if they would purchase such labelled products (foods, pharmaceuticals, etc) and services (purifying water, preventing air pollution, etc) at extra cost. RESULTS: The participants placed a high value on the importance of mental, social, spiritual and physical health factors in terms of the company's products and services with a score of about 8 out of 10 (range, 7.74-8.33). Most respondents (72.4%) said that they were interested in adopting health-friendly labels. When a health-friendly label is introduced (such as one by the Business for Social Responsiveness), 65.1% of the respondents said that they intended to purchase the product or service, while 6.8% said that they did not and 75.0% said that they were willing to pay extra for the health-friendly product or service. Multivariate logistic regression models showed urban residence, high education level and good social health to be significantly associated with positive attitudes towards health-friendly labels. People with high income, no religion or normal weight were more likely to say that they intend to purchase products and services with health-friendly labels. They also had a more positive attitude towards paying more for such products and services, as did people with good spiritual health. CONCLUSION: This study provides data that illustrate the importance of health-friendly products and services to the general population and companies.

Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer

Purpose Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. Methods PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. Results In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. Conclusion Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Development and Validity Testing of the School Health Score Card.

BACKGROUND: The objective of this study was to develop the School Health Score Card (SHSC) and validate its psychometric properties. METHODS: The development of the SHSC questionnaire included 3 phases: item generation, construction of domains and items, and field testing with validation. To assess the instrument's reliability and validity, we recruited 15 middle schools and 15 high schools in the Republic of Korea. RESULTS: We developed the SHSC questionnaire of 158 items categorized into 5 domains: (1) Governance and Infrastructure, (2) Need Assessment, (3) Planning, (4) Health Prevention and Promotion Program, and (5) Monitoring and Feedback. All SHSC domains and subdomains demonstrated acceptable reliability with good internal consistency. Each domain and subdomain except for "Planning" was associated significantly with students' health status. Most subdomains, including school health philosophy, school policy, communication, the evaluation system, and monitoring, were significantly and negatively associated with student absence. CONCLUSIONS: The SHSC shows significant association with the overall student health and can be useful in assessing comprehensive school health programs.