Inhibitory effect of snake venom toxin on NF-κB activity prevents human cervical cancer cell growth via increase of death receptor 3 and 5 expression.

We previously found that snake venom toxin inhibits nuclear factor kappa B (NF-κB) activity in several cancer cells. NF-κB is implicated in cancer cell growth and chemoresistance. In our present study, we investigated whether snake venom toxin (SVT) inhibits NF-κB, thereby preventing human cervical cancer cell growth (Ca Ski and C33A). SVT (0-12 µg/ml) inhibited the growth of cervical cancer cells by the induction of apoptotic cell death. These inhibitory effects were associated with the inhibition of NF-κB activity. However, SVT dose dependently increased the expression of death receptors (DRs): DR3, DR5 and DR downstream pro-apoptotic proteins. Exploration of NF-κB inhibitor (Phenylarsine oxide, 0.1 µM) synergistically further increased SVT-induced DR3 and DR5 expressions accompanied with further inhibition of cancer cells growth. Moreover, deletion of DR3 and DR5 by small interfering RNA significantly abolished SVT-induced cell growth inhibitory effects, as well as NF-κB inactivation. Using TNF-related apoptosis-inducing ligand resistance cancer cells (A549 and MCF-7), we also found that SVT enhanced the susceptibility of chemoresistance of these cancer cells through down-regulation of NF-κB, but up-regulation of DR3 and DR5. In vivo study also showed that SVT (0.5 and 1 mg/kg) inhibited tumor growth accompanied with inactivation of NF-κB. Thus, our present study indicates that SVT could be applicable as an anticancer agent for cervical cancer, or as an adjuvant agent for chemoresistant cancer cells.

Anticancer effect of tectochrysin in colon cancer cell via suppression of NF-kappaB activity and enhancement of death receptor expression.

BACKGROUND: Flavonoids are a diverse family of natural phenolic compounds commonly found in fruits and vegetables. Epidemiologic studies showed that flavonoids also reduce the risk of colon cancer. Tectochrysin is one of the major flavonoids of Alpinia oxyphylla Miquel. However, the anti-cancer effects and the molecular mechanisms of tectochrysin in colon cancer cells have not yet been reported. We investigated whether tectochrysin could inhibit colon cancer cell growth at 1, 5, 10 µg/ml. In in vivo study, we injected a tectochrysin treatment dose of 5 mg/kg to each mouse. RESULTS: Tectochrysin suppressed the growth of SW480 and HCT116 human colon cancer cells. The expression of DR3, DR4 and Fas were significantly increased, and pro-apoptotic proteins were also increased. Tectochrysin treatment also inhibited activity of NF-κB. A docking model indicated that tectochrysin binds directly to the p50 unit. In in vivo, tumor weights and volumes in mice were reduced when treated with tectochrysin. Tectochrysin leads to apoptotic cell death in colon cancer cells through activation of death receptors expression via the inhibition of NF-κB. CONCLUSIONS: Tectochrysin can be a useful agent for the treatment of colon cancer cell growth as well as an adjuvant agent for chemo-resistant cancer cells growth.

Escin suppresses migration and invasion involving the alteration of CXCL16/CXCR6 axis in human gastric adenocarcinoma AGS cells.

Escin, a natural mixture of triterpene saponins isolated from horse chestnut, has been reported to possess anticancer activity in many human cancer cells. However, the effect of escin on the metastasis has not been studied. The present study examined the effect of escin on the migration and invasion of AGS human gastric cancer cells. To examine the effects of escin on metastatic capacities of gastric cancer cells, AGS cells were cultured in the presence of 0-4 µmol/L escin. Escin inhibited cell migration and invasion in AGS cells. However, escin did not affect the viability of these cells at these concentrations. The chemokine receptor and its ligands play an important role in cancer metastasis. Escin decreased the production of soluble C-X-C motif chemokine (CXCL)16 but increased the expression of trans-membranous CXCL16. The expression of C-X-C chemokine receptor (CXCR)6 was not affected by escin treatment. Exogenous CXCL16 reversed escin-induced migration inhibition. In addition, escin inhibited the phosphorylation of focal adhesion kinase and Akt. These results demonstrate that escin inhibited the migration and invasion of AGS cells, which is associated with altered CXCL16/CXCR6 axis. These findings suggest that escin has potential as an antimetastatic agent in gastric cancer.

Biological features of core networks that result from a high-fat diet in hepatic and pulmonary tissues in mammary tumour-bearing, obesity-resistant mice.

We previously demonstrated that the chronic consumption of a high-fat diet (HFD) promotes lung and liver metastases of 4T1 mammary carcinoma cells in obesity-resistant BALB/c mice. To examine early transcriptional responses to tumour progression in the liver and lungs of HFD-fed mice, 4-week-old female BALB/c mice were divided into four groups: sham-injected, control diet (CD)-fed; sham-injected, HFD-fed (SH); 4T1 cell-injected, CD-fed (TC); 4T1 cell-injected, HFD-fed (TH). Following 16 weeks of either a CD or HFD, 4T1 cells were injected into the mammary fat pads of mice in the TC and TH groups and all mice were continuously fed identical diets. At 14 d post-injection, RNA was isolated from hepatic and pulmonary tissues for microarray analysis of mRNA expression. Functional annotation and core network analyses were conducted for the TH/SH Unique gene set. Inflammation in hepatic tissues and cell mitosis in pulmonary tissues were the most significant biological functions in the TH/SH Unique gene set. The biological core networks of the hepatic TH/SH Unique gene set were characterised as those genes involved in the activation of acute inflammatory responses (Orm1, Lbp, Hp and Cfb), disordered lipid metabolism and deregulated cell cycle progression. Networks of the pulmonary Unique gene set displayed the deregulation of cell cycle progression (Cdc20, Cdk1 and Bub1b). These HFD-influenced alterations may have led to favourable conditions for the formation of both pro-inflammatory and pro-mitotic microenvironments in the target organs that promote immune cell infiltration and differentiation, as well as the infiltration and proliferation of metastatic tumour cells.

Effect of night shift work on the reduction of glomerular filtration rate using data from Korea Medical Institute (2016-2020).

Background: Shift work increases the risk of chronic diseases, including metabolic diseases. However, studies on the relationship between shift work and renal function are limited. The aim of this study was to investigate the association between shift work and a decreased glomerular filtration rate (GFR). Methods: Data were evaluated for 1,324,930 workers who visited the Korean Medical Institute from January 1, 2016 to December 31, 2020 and underwent a health checkup. Daytime workers were randomly extracted at a ratio of 1:4 after matching for age and sex. In total, 18,190 workers aged over 40 years were included in the analyses; these included 3,638 shift workers and 14,552 daytime workers. Participants were categorized into the shift work group when they underwent a specific health checkup for night shift work or indicated that they were shift workers in the questionnaire. The odds ratio was calculated using a conditional logistic regression to investigate the relevance of shift work for changes in GFR. Results: 35 workers in the shift group and 54 in the daytime group exhibited an estimated GFR (eGFR) value of < 60 mL/min/1.73m2 (p < 0.01). The difference in eGFR values between two checkups differed significantly depending on the type of work (p < 0.01); the difference in the shift work group (-9.64 mL/min/1.73 m2) was larger than that in the daytime work group (-7.45 mL/min/1.73 m2). The odds ratio for eGFR reduction to < 60 mL/min/1.73 m2 in the shift group versus the daytime group was 4.07 (95% confidence interval: 2.54-6.52), which was statistically significant. Conclusions: The results of this study suggest that eGFR decreases by a significantly larger value in shift workers than in daytime workers; thus, shift work could be a contributing factor for chronic kidney disease (CKD). Further prospective studies are necessary to validate this finding and identify measures to prevent CKD in shift workers.

Design Rule of Electron- and Hole-Selective Contacts for Polycrystalline Silicon-Based Passivating Contact Solar Cells.

A crystalline silicon (c-Si) solar cell with a polycrystalline silicon/SiOx (poly-Si/SiOx) structure, incorporating both electron and hole contacts, is an attractive choice for achieving ideal carrier selectivity and serving as a fundamental component in high-efficiency perovskite/Si tandem and interdigitated back-contact solar cells. However, our understanding of the carrier transport mechanism of hole contacts remains limited owing to insufficient studies dedicated to its investigation. There is also a lack of comparative studies on the poly-Si/SiOx electron and hole contacts for ideal carrier-selective solar cells. Therefore, this study aims to address these knowledge gaps by exploring the relationship among microstructural evolution, dopant in-diffusion, and the resulting carrier transport mechanism in both the electron and hole contacts of poly-Si/SiOx solar cells. Electron (n+ poly-Si/SiOx/substrate)- and hole (p+ poly-Si/SiOx/substrate)-selective passivating contacts are subjected to thermal annealing. Changes in the passivation properties and carrier transport mechanisms of these contacts are investigated during thermal annealing at various temperatures. Notably, the results demonstrate that the passivation properties and carrier transport mechanisms are strongly influenced by the microstructural evolution of the poly-Si/SiOx layer stack and dopant in-diffusion. Furthermore, electron and hole contacts exhibit common behaviors regarding microstructural evolution and dopant in-diffusion. However, the hole contacts exhibit relatively inferior electrical properties overall, mainly because both the SiOx interface and the p+ poly-Si are found to be highly defective. Moreover, boron in the hole contacts diffuses deeper than phosphorus in the electron contacts, resulting in deteriorated carrier collection. The experimental results are also supported by device simulation. Based on these findings, design rules are suggested for both electron and hole contacts, such as using thicker SiOx and/or annealing the solar cell at a temperature not exceeding the critical annealing temperature of the hole contacts.

Automated deep neural network analysis of lateral cephalogram data can aid in detecting obstructive sleep apnea.

STUDY OBJECTIVES: Information on obstructive sleep apnea (OSA) is often latently detected in diagnostic tests conducted for other purposes, providing opportunities for maximizing value. This study aimed to develop a convolutional neural network (CNN) to identify the risk of OSA using lateral cephalograms. METHODS: The lateral cephalograms of 5,648 individuals (mean age, 49.0 ± 15.8 years; men, 62.3%) with or without OSA were collected and divided into training, validation, and internal test datasets in a 5:2:3 ratio. A separate external test dataset (n = 378) was used. A densely connected CNN was trained to diagnose OSA using a cephalogram. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC). Gradient-weighted class activation mapping (Grad-CAM) was used to evaluate the region of focus, and the relationships between the model outputs, anthropometric characteristics, and OSA severity were evaluated. RESULTS: The AUROC of the model for the presence of OSA was 0.82 (95% confidence interval, 0.80-0.84) and 0.73 (95% confidence interval, 0.65-0.81) in the internal and external test datasets, respectively. Grad-CAM demonstrated that the model focused on the area of the tongue base and oropharynx in the cephalogram. Sigmoid output values were positively correlated with OSA severity, body mass index, and neck and waist circumference. CONCLUSIONS: Deep learning may help develop a model that classifies OSA using a cephalogram, which may be clinically useful in the appropriate context. The definition of ground truth was the main limitation of this study. CITATION: Jeong H-G, Kim T, Hong JE, et al. Automated deep neural network analysis of lateral cephalogram data can aid in detecting obstructive sleep apnea. J Clin Sleep Med. 2023;19(2):327-337.

Benzyl isothiocyanate inhibits basal and hepatocyte growth factor-stimulated migration of breast cancer cells.

Benzyl isothiocyanate (BITC), which is found in cruciferous vegetables, has been shown to have anti-carcinogenic properties. Hepatocyte growth factor (HGF) has the ability to stimulate dissociation, migration, and invasion in various tumor cells, and abnormally increased expressions of HGF and its transmembrane tyrosine kinase receptor, c-Met, have previously been detected in human breast cancer, and are associated with high tumor grade and poor prognosis. In this study, in order to assess the mechanisms relevant to the BITC-induced regulation of breast cancer cell migration and invasion, MDA-MB-231 human breast cancer cells and 4T1 murine mammary carcinoma cells were cultured in the presence of 0-4 µmol/l BITC with or without 10 µg/l of HGF. BITC inhibited both the basal and HGF-induced migration of MDA-MB-231 and 4T1 cells in a dose-dependent manner. In MDA-MB-231 cells, BITC reduced both basal and HGF-induced secretion and activity of urokinase-type plasminogen activator (uPA). In addition, BITC increased the protein levels of plasminogen activator inhibitor-1. HGF stimulated c-Met and Akt phosphorylation, but did not affect the phosphorylation of extracellular signal-regulated kinase-1/2 or stress-activated protein/c-jun N-terminal kinase. BITC suppressed NF-κB activity and reduced the HGF-induced phosphorylation of c-Met and Akt in a dose-dependent manner. LY294002, a specific Akt inhibitor, reduced both basal and HGF-induced uPA secretion and migration of MDA-MB-231 cells. In this study, we demonstrated that BITC profoundly inhibits the migration and invasion of MDA-MB-231 cells, which is associated with reduced uPA activity, and also that these phenomena are accompanied by the suppression of Akt signaling.

Differential diagnosis of common etiologies of left ventricular hypertrophy using a hybrid CNN-LSTM model.

Differential diagnosis of left ventricular hypertrophy (LVH) is often obscure on echocardiography and requires numerous additional tests. We aimed to develop a deep learning algorithm to aid in the differentiation of common etiologies of LVH (i.e. hypertensive heart disease [HHD], hypertrophic cardiomyopathy [HCM], and light-chain cardiac amyloidosis [ALCA]) on echocardiographic images. Echocardiograms in 5 standard views (parasternal long-axis, parasternal short-axis, apical 4-chamber, apical 2-chamber, and apical 3-chamber) were obtained from 930 subjects: 112 with HHD, 191 with HCM, 81 with ALCA and 546 normal subjects. The study population was divided into training (n = 620), validation (n = 155), and test sets (n = 155). A convolutional neural network-long short-term memory (CNN-LSTM) algorithm was constructed to independently classify the 3 diagnoses on each view, and the final diagnosis was made by an aggregate network based on the simultaneously predicted probabilities of HCM, HCM, and ALCA. Diagnostic performance of the algorithm was evaluated by the area under the receiver operating characteristic curve (AUC), and accuracy was evaluated by the confusion matrix. The deep learning algorithm was trained and verified using the training and validation sets, respectively. In the test set, the average AUC across the five standard views was 0.962, 0.982 and 0.996 for HHD, HCM and CA, respectively. The overall diagnostic accuracy was significantly higher for the deep learning algorithm (92.3%) than for echocardiography specialists (80.0% and 80.6%). In the present study, we developed a deep learning algorithm for the differential diagnosis of 3 common LVH etiologies (HHD, HCM and ALCA) by applying a hybrid CNN-LSTM model and aggregate network to standard echocardiographic images. The high diagnostic performance of our deep learning algorithm suggests that the use of deep learning can improve the diagnostic process in patients with LVH.

Dietary fat increases solid tumor growth and metastasis of 4T1 murine mammary carcinoma cells and mortality in obesity-resistant BALB/c mice.

INTRODUCTION: High-fat diets (HFDs) are known to cause obesity and are associated with breast cancer progression and metastasis. Because obesity is associated with breast cancer progression, it is important to determine whether dietary fat per se stimulates breast cancer progression in the absence of obesity. This study investigated whether an HFD increases breast cancer growth and metastasis, as well as mortality, in obesity-resistant BALB/c mice. METHODS: The 4-week-old, female BALB/c mice were fed HFD (60% kcal fat) or control diet (CD, 10% kcal fat) for 16 weeks. Subsequently, 4T1 mammary carcinoma cells were injected into the inguinal mammary fat pads of mice fed continuously on their respective diets. Cell-cycle progression, angiogenesis, and immune cells in tumor tissues, proteases and adhesion molecules in the lungs, and serum cytokine levels were analyzed with immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assay (ELISA). In vitro studies were also conducted to evaluate the effects of cytokines on 4T1 cell viability, migration, and adhesion. RESULTS: Spleen and gonadal fat-pad weights, tumor weight, the number and volume of tumor nodules in the lung and liver, and tumor-associated mortality were increased in the HFD group, with only slight increases in energy intake and body weight. HF feeding increased macrophage infiltration into adipose tissues, the number of lipid vacuoles and the expression of cyclin-dependent kinase (CDK)2, cyclin D1, cyclin A, Ki67, CD31, CD45, and CD68 in the tumor tissues, and elevated serum levels of complement fragment 5a (C5a), interleukin (IL)-16, macrophage colony-stimulating factor (M-CSF), soluble intercellular adhesion molecule (sICAM)-1, tissue inhibitors of metalloproteinase (TIMP)-1, leptin, and triggering receptor expressed on myeloid cells (TREM)-1. Protein levels of the urokinase-type plasminogen activator, ICAM-1, and vascular cell adhesion molecule-1 were increased, but plasminogen activator inhibitor-1 levels were decreased in the lungs of the HFD group. In vitro assays using 4T1 cells showed that sICAM-1 increased viability; TREM-1, TIMP-1, M-CSF, and sICAM-1 increased migration; and C5a, sICAM-1, IL-16, M-CSF, TIMP-1, and TREM-1 increased adhesion. CONCLUSIONS: Dietary fat increases mammary tumor growth and metastasis, thereby increasing mortality in obesity-resistant mice.

Oral administration of benzyl-isothiocyanate inhibits solid tumor growth and lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice.

Benzyl-isothiocyanate (BITC) is a hydrolysis product of glucotropaeolin, a compound found in cruciferous vegetables, and has also been shown to have anti-tumor properties. To evaluate the effects of BITC administration on the tumor growth and metastasis of breast cancer, 4T1 murine mammary carcinoma cells were injected into the inguinal mammary fat pads of syngeneic female BALB/c mice. One day later, the mice were subjected to gavage for 4 weeks with BITC (0, 5, or 10 mg/kg body weight/day). Oral BITC treatment induced a significant reduction in the growth of solid tumors. BITC reduced hemoglobin contents and CD31 and vascular endothelial growth factor (VEGF) expression in the tumors, as well as circulating levels of VEGF. Reduced expressions of proliferating cell nuclear antigen and cyclin-dependent kinase 4 were noted in the tumors of BITC-treated mice. BITC markedly increased the numbers of apoptotic cells with increased Bax expression, cleaved caspase-3, and PARP levels, but reduced Bcl-2 expression in tumor tissues. In addition, BITC was shown to reduce the numbers of pulmonary tumor nodules and the total pulmonary metastatic volume. BITC induced a significant reduction in the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and urokinase-type plasminogen activator in the sera and lungs of 4T1 cell-injected mice. However, the concentrations of TIMP-2 and plasminogen activator inhibitor-1 were increased in the sera and lungs of BITC-treated mice. The results of this study indicate that BITC has potential as a preventive agent for metastatic breast cancer.

Fully Bottom-Up Waste-Free Growth of Ultrathin Silicon Wafer via Self-Releasing Seed Layer.

The fabrication of ultrathin silicon wafers at low cost is crucial for advancing silicon electronics toward stretchability and flexibility. However, conventional fabrication techniques are inefficient because they sacrifice a large amount of substrate material. Thus, advanced silicon electronics that have been realized in laboratories cannot move forward to commercialization. Here, a fully bottom-up technique for producing a self-releasing ultrathin silicon wafer without sacrificing any of the substrate is presented. The key to this approach is a self-organized nanogap on the substrate fabricated by plasma-assisted epitaxial growth (plasma-epi) and subsequent hydrogen annealing. The wafer thickness can be independently controlled during the bulk growth after the formation of plasma-epi seed layer. In addition, semiconductor devices are realized using the ultrathin silicon wafer. Given the high scalability of plasma-epi and its compatibility with conventional semiconductor process, the proposed bottom-up wafer fabrication process will open a new route to developing advanced silicon electronics.

Photo-Oxidative Protection of Chlorophyll a in C-Phycocyanin Aqueous Medium.

In this study, potential protection of chlorophyll a from illumination and oxidation-induced decomposition has been examined using C-phycocyanin (C-PC) aqueous medium. Photo-oxidation resistance of chlorophyll a was monitored in various aqueous media using ultraviolet-visible spectroscopy and direct-infusion atmospheric pressure chemical ionization mass spectrometry analysis. The spectroscopy results showed that chlorophyll a in C-PC medium experienced the lowest rate of conversion to its derivatives; thus, it was demonstrated that chlorophyll a was mostly intact in the C-PC medium. Furthermore, the C-PC treated with chlorophyll a showed the lowest concentrations of malondialdehyde, and chlorophyll a in C-PC medium did not cause serious damage to human liver cells in vitro after intensive illumination. Therefore, we propose a new method of protecting chlorophyll a from photodegradation and oxidation using C-PC aqueous medium.

Efficacy and safety of So-Cheong-Ryong-Tang in patients with atopic dermatitis and respiratory disorders: Study protocol of a double-blind randomized placebo-controlled trial.

BACKGROUND: Atopic dermatitis (AD, atopic eczema) is a pruritic, inflammatory, chronic skin disease. Since there is limitation of conventional treatment of AD, traditional herbal medicine can be an attractive therapeutic option in patients having AD for a long time. So-Cheong-Ryong-Tang (SCRT) has been found to inhibit histamine release and degranulation of mast cells, differentiation of basophils, and proliferation of eosinophils. We designed this clinical trial to evaluate the efficacy and safety of SCRT as compared to placebo in patients with AD and respiratory disorders. METHODS/DESIGN: This study is a single-center, randomized, double-blind, placebo-controlled, and investigator-initiated clinical trial. A total of 60 patients between 7 and 65 years of age with AD and respiratory disorders who received a diagnosis of AD by Hanifin and Rajka criteria who scored 15 to 50 in a scoring atopic dermatitis (SCORAD) will be enrolled. Participants will be randomly assigned to the SCRT or placebo group in a ratio of 1:1 and they will have a visit schedule comprising 4 visits including a screening visit during 8 to 10 weeks. The participants will be administered SCRT or placebo 3 times a day for 4 weeks. The primary outcome will be measured by a change of the SCORAD index. The secondary outcomes will be measured by changes in the dose and frequency of usage of the AD ointment, dermatology life quality index scores, pruritus and sleep disorder in visual analog scale, skin moisture content, skin surface temperature, Hamilton anxiety rating scale scores, depression rating scale scores, stress/autonomic nervous function test, and attention deficit hyperactivity disorder survey scores at week 4 as compared to those at the baseline. DISCUSSION: To the best of our knowledge, SCRT has rarely been reported for dermatologic diseases. This will be the first clinical trial to assess the efficacy and safety of SCRT in patients with AD and respiratory disorders. We hope that the results of this trial will provide evidence for the use of SCRT as a new treatment for AD with respiratory disorders. TRIAL REGISTRATION: Korean National Clinical Trial Registry, Clinical Research Information Service. (KCT0004148) (https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=14981<ype=&rtype=).

Oral administration of 3,3'-diindolylmethane inhibits lung metastasis of 4T1 murine mammary carcinoma cells in BALB/c mice.

3,3'-diindolylmethane (DIM) is the major in vivo product of the acid-catalyzed oligomerization of indole-3-carbinol present in cruciferous vegetables, and it has been shown to exhibit anticancer properties. In this study, we assessed the effects of DIM on the metastasis of 4T1 mouse mammary carcinoma cells. In vitro culture studies showed that DIM dose-dependently inhibited the migration, invasion, and adhesion of 4T1 cells at concentrations of 0-10 micromol/L without attendant changes in cell viability. In an in vivo lung metastasis model, 4T1 cells (2 x 10(5) cells/mouse) were injected into the tail veins of syngeneic female BALB/c mice. Beginning on the second day, the mice were subjected to gavage with 0-10 mg DIM/(kg body weight x d) for 13 d. Oral DIM administration resulted in a marked reduction in the number of pulmonary tumor nodules. DIM treatment significantly reduced the levels of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, and vascular cell adhesion molecule (VCAM)-1 and increased TIMP-2 levels in the sera and lungs of mice injected with 4T1 cells. Additionally, DIM treatment reduced the serum concentrations of interleukin (IL)-1beta, IL-6 and tumor necrosis factor (TNF)alpha. We have demonstrated that DIM profoundly inhibits the lung metastasis of 4T1 cells, which was accompanied by reduced levels of MMP, adhesion molecules, and proinflammatory cytokines. These results indicate that DIM has potential as an antimetastatic agent for the treatment of breast cancer.

Synthesis and biological evaluation of 2,5-diaminobenzamide derivatives as anti-proliferating agents.

The screening of the chemical library for the anti-proliferative activity of the chemical library provided 2,5-diaminobenzamide as the initial hit. The confirmation and the optimization of hit were performed by synthesis followed by the evaluation of growth inhibitory activity against human cancer cell lines. The most active growth inhibitor showed IC(50) of 1.0 microM. The compound 7 increased not only sub-G1 population but also number of cells which are stained with Annexin V-FITC and 7-AAD, suggesting that compound 7 induced cell death is apoptosis.

Efficacy and safety of Soshiho-tang in patients with atopic dermatitis and gastrointestinal disorders: Study protocol for a double-blind, randomized, and placebo-controlled clinical trial.

BACKGROUND: Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease that affects the quality of life in patients with AD. Since there is limitation of conventional treatment of AD, complementary treatment is required to treat AD symptoms more effectively and safely Soshiho-tang (SSHT) is a traditional herbal medicine that exhibits anti-inflammatory and anti-ulcer effects and improves the immune function. In this clinical trial, we will evaluate the efficacy and safety of SSHT in patients with AD and gastrointestinal disorders in comparison with placebo. METHODS/DESIGN: This study is a single-center, randomized, double-blind, placebo-controlled, and investigator-initiated clinical trial. A total of 60 patients aged 3 to 18 years with AD and gastrointestinal disorders and who received a diagnosis of AD by Hanifin & Rajka criteria with a Scoring Atopic Dermatitis (SCORAD) index between 15 and 49 will be enrolled. Participants will be randomly assigned to the SSHT or placebo group in a ratio of 1:1. Additionally, they will have a visit schedule comprising 4 visits including a screening visit during 8 to 10 weeks. The participants will be administered SSHT or placebo 3 times a day for 4 weeks. The primary outcome will be measured by a change of the SCORAD index. The secondary outcome measures include the following: survey questionnaires for the perception of gastrointestinal disorders, amount and frequency of ointment usage for AD, dermatology quality of life index, itchiness and sleep disability score in visual analog scale, percutaneous water loss, skin surface temperature, Hamilton anxiety rating scale, and children's depression inventory. DISCUSSION: In our knowledge, this will be the first clinical trial to assess the efficacy and safety of SSHT in patients with AD and gastrointestinal disorders. The findings of this study will provide new treatment options for patients with AD and gastrointestinal disorders. TRIAL REGISTRATION: Korean National Clinical Trial Registry, Clinical Research Information Service. (KCT0003713) https://cris.nih.go.kr/cris/search/search_result_st01_en.jsp?seq=13489<ype=&rtype=.

Association of atopic dermatitis with obesity via a multi-omics approach: A protocol for a case-control study.

INTRODUCTION: Several studies have found that obesity is associated with atopic dermatitis (AD); however, the mechanisms underlying the association are largely unknown. This study aims to assess the association of AD with obesity in the Korean population and verify its mechanism via a multi-omics analysis. METHODS AND ANALYSIS: A case-control study will be conducted in the Republic of Korea. A total of 80 subjects, aged 4 to 12 years, matched for age and sex, with body mass index at or above the 85th percentile or at or below the 25th percentile, will be included. Subjects will be assigned to the following 4 groups: obese/overweight with AD, normal/underweight with AD, obese/overweight control, and normal/underweight control. Serum metabolome and immune biomarkers, as well as fecal metabolome and microbiome biomarkers, will be analyzed. Serum eosinophil cationic protein, total serum Immunoglobulin E (IgE), and specific IgE will be analyzed to assess allergic tendency. The SCORing of AD index, the children's dermatology life quality index, body composition analysis, and the Korean gastrointestinal symptom rating scale will be obtained to assess the disease status and severity of the subjects. DISCUSSION: The findings of this study are expected to provide evidence of an association between AD and obesity via a gut microbiome-metabolome-immune mechanism. Therefore, it may improve future management strategies for AD. TRIAL REGISTRATION: This study has been registered at the Korean National Clinical Trial Registry, Clinical Research Information Service (KCT0003630).

Alveolar Macrophages Treated With Bacillus subtilis Spore Protect Mice Infected With Respiratory Syncytial Virus A2.

Respiratory syncytial virus (RSV) is a major pathogen that infects lower respiratory tract and causes a common respiratory disease. Despite serious pathological consequences with this virus, effective treatments for controlling RSV infection remain unsolved, along with poor innate immune responses induced at the initial stage of RSV infection. Such a poor innate defense mechanism against RSV leads us to study the role of alveolar macrophage (AM) that is one of the primary innate immune cell types in the respiratory tract and may contribute to protective responses against RSV infection. As an effective strategy for enhancing anti-viral function of AM, this study suggests the intranasal administration of Bacillus subtilis spore which induces expansion of AM in the lung with activation and enhanced production of inflammatory cytokines along with several genes associated with M1 macrophage differentiation. Such effect by spore on AM was largely dependent on TLR-MyD88 signaling and, most importantly, resulted in a profound reduction of viral titers and pathological lung injury upon RSV infection. Taken together, our results suggest a protective role of AM in RSV infection and its functional modulation by B. subtilis spore, which may be a useful and potential therapeutic approach against RSV.

Proton Pump Inhibition Enhances the Cytotoxicity of Paclitaxel in Cervical Cancer.

PURPOSE: This study was conducted to investigate whether a proton pump inhibitor (PPI) could enhance chemosensitivity via the inhibition of vacuolar-type H+ ATPase (V-ATPase) in cervical cancer. MATERIALS AND METHODS: The expression of V-ATPase was evaluated in 351 formalin-fixed, paraffin-embedded human cervical cancer tissues using immunohistochemistry and compared with clinicopathologic risk factors for disease prognosis. The influence of cell proliferation and apoptosis following V-ATPase siRNA transfection or esomeprazole pretreatment was assessed in cervical cancer cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide and enzyme-linked immunosorbent assay, respectively. RESULTS: Immunohistochemical analysis revealed that V-ATPase was expressed in about 60% of cervical cancer tissue samples (211/351), and the expression was predominantly found in adenocarcinoma histology (p=0.016). Among patients with initially bulky cervical cancer (n=89), those with V-ATPase expression had shorter disease-free survival (p=0.005) and overall survival (p=0.023). Co-treatment with V-ATPase siRNA or esomeprazole with paclitaxel significantly decreased the cell proliferation of cervical cancer cell lines, including HeLa and INT407, compared to cell lines treated with paclitaxel alone (p < 0.01). Moreover, V-ATPase siRNA or esomeprazole followed by paclitaxel significantly increased the expression of active caspase-3 in these cells compared to cells treated with paclitaxel alone (both, p < 0.05). CONCLUSION: V-ATPase was predominantly expressed in cervical adenocarcinoma, and the expression of V-ATPases was associated with poor prognosis. The inhibition of V-ATPase via siRNA or PPI (esomeprazole) might enhance the chemosensitivity of paclitaxel in cervical cancer cells.