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This article discusses the potential therapeutic target MKK3 in blister formation in pemphigus, a condition characterized by autoantibody-mediated disruption of keratinocyte adhesion. The study aims to understand the roles of MKK3 and MKK6 in pemphigus and evaluate their inhibition as a treatment approach. Immunohistochemical analysis of skin specimens from pemphigus patients showed pronounced expression of phosphorylated MKK3 and p38 MAPK, indicating their involvement in pemphigus pathogenesis. In vitro studies using an MKK3 inhibitor demonstrated improved cell-cell adhesion and reduced blister formation. Targeting MKK3 may offer a promising alternative treatment option for pemphigus and other autoimmune and inflammatory conditions. [Extracted from the article]

Inhibiting the functional role of negative regulators in immune cells is an effective approach for developing immunotherapies. The serine/threonine kinase hematopoietic progenitor kinase 1 (HPK1) involved in the T-cell receptor signaling pathway attenuates T-cell activation by inducing the degradation of SLP-76 through its phosphorylation at Ser-376, reducing the immune response. Interestingly, several studies have shown that the genetic ablation or pharmacological inhibition of HPK1 kinase activity improves the immune response to cancers by enhancing T-cell activation and cytokine production; therefore, HPK1 could be a promising druggable target for T-cell-based cancer immunotherapy. To increase the immune response against cancer cells, we designed and synthesized KHK-6 and evaluated its cellular activity to inhibit HPK1 and enhance T-cell activation. KHK-6 inhibited HPK1 kinase activity with an IC50 value of 20 nM and CD3/CD28-induced phosphorylation of SLP-76 at Ser-376 Moreover, KHK-6 significantly enhanced CD3/CD28-induced production of cytokines; proportion of CD4+ and CD8+ T cells that expressed CD69, CD25, and HLA-DR markers; and T-cell-mediated killing activity of SKOV3 and A549 cells. In conclusion, KHK-6 is a novel ATP-competitive HPK1 inhibitor that blocks the phosphorylation of HPK1 downstream of SLP-76, enhancing the functional activation of T cells. In summary, our study showed the usefulness of KHK-6 in the drug discovery for the HPK1-inhibiting immunotherapy. [ABSTRACT FROM AUTHOR]

The human microbiome contains genetic information that regulates metabolic processes in response to host health and disease. While acidic vaginal pH is maintained in normal conditions, the pH level increases in infectious vaginitis. We propose that this change in the vaginal environment triggers the biosynthesis of anti-vaginitis metabolites. Gene expression levels of Chryseobacterium gleum, a vaginal symbiotic bacterium, were found to be affected by pH changes. The distinctive difference in the metabolic profiles between two C. gleum cultures incubated under acidic and neutral pH conditions was suggested to be an anti-vaginitis molecule, which was identified as phenylacetic acid (PAA) by spectroscopic data analysis. The antimicrobial activity of PAA was evaluated in vitro, showing greater toxicity toward Gardnerella vaginalis and Candida albicans, two major vaginal pathogens, relative to commensal Lactobacillus spp. The activation of myeloperoxidase, prostaglandin E2, and nuclear factor-κB, and the expression of cyclooxygenase-2 were reduced by an intravaginal administration of PAA in the vaginitis mouse model. In addition, PAA displayed the downregulation of mast cell activation. Therefore, PAA was suggested to be a messenger molecule that mediates interactions between the human microbiome and vaginal health. [ABSTRACT FROM AUTHOR]

A central nervous system (CNS)‐oriented compound collection was screened to find hit compounds for human glioblastoma T98G cell growth inhibition. A series of quinoxaline‐based derivatives were identified as hit compounds having one‐ to two‐digit micromolar GI50 values. Anti‐glioblastoma activity was improved in structure–activity relationship studies varying the substituents on the quinoxaline ring system, resulting in the discovery of four compounds exhibiting sub‐micromolar GI50 values. The potentials of the four compounds to induce apoptosis were confirmed by annexin V staining assay. The development potential of the four compounds as CNS drug leads was evaluated by in vitro MDR‐MDCK cell permeability and in vivo brain disposition in mice. The mouse pharmacokinetic and kinome profiling studies for compound 10g, which showed high brain‐penetrating ability, revealed that the compound is orally bioavailable and inhibits the kinase activities of anaplastic lymphoma kinase (ALK) and Erb‐B2 receptor tyrosine kinase (ERBB3). [ABSTRACT FROM AUTHOR]

Introduction: Digital healthcare systems based on augmented reality (AR) show promise for postoperative rehabilitation. We compared the effectiveness of AR-based rehabilitation and conventional rehabilitation after total knee arthroplasty (TKA). Materials and methods: We randomly allocated 56 participants to digital healthcare rehabilitation group (DR group) and conventional rehabilitation group (CR group). Participants in the CR group performed brochure-based home exercises for 12 weeks, whereas those in the DR group performed AR-based home exercises that showed each motion on a monitor and provided real-time feedback. The primary outcome was change in 4-m gait speed. The secondary outcomes were the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, health-related quality of life [assessed by the EuroQoL 5-Dimension 5-Level (EQ5D5L) questionnaire], pain [measured using a numeric rating scale (NRS)], Berg Balance Scale (BBS), range of motion (ROM), and muscle strength. Outcomes were measured at baseline (T0) and 3 (T1), 12 (T2), and 24 (T3) weeks after randomization. Results: There was no significant difference in baseline characteristics of participants between two groups, except age and body mass index. No group difference was observed in 4-m gait speed (0.37 ± 0.19 and 0.42 ± 0.28 for the DR and CR groups, respectively; p = 0.438). The generalized estimating equation model revealed no significant group by time interaction regarding for 4-m gait speed, WOMAC, EQ5D5L, NRS, BBS, ROM, and muscle strength score. All outcomes were significantly improved in both groups (p < 0.001). Conclusion: The use of a digital healthcare system based on AR improved the functional outcomes, pain, and quality of life of patients after TKA. AR-based rehabilitation may be useful treatment as an alternative to conventional rehabilitation. Trial registration: ClinicalTrials.gov (identifier: NCT04513353). Registered on August 9, 2020. http://clinicaltrials.gov/ct2/show/NCT04513353. [ABSTRACT FROM AUTHOR]

Aim: To identify the predictors of mental health nurses' person‐centred care, including moral sensitivity. Background: Person‐centred care meets patients' ethical needs by protecting their autonomy and dignity and respecting their choices; it is essential to enhance patient outcomes. Therefore, it is important to identify the predictors of the practice of advocating patients' rights and dignity and providing person‐centred care among mental health nurses to foster competency and ensure the highest quality of care. Methods: This cross‐sectional study included 220 mental health nurses in South Korea. It measured their general and work‐related characteristics, moral sensitivity, and person‐centred care. Multiple regression analysis was conducted to identify the person‐centred care predictors. Results: The most potent person‐centred care predictor was moral sensitivity (β =.35, p <.001). Other predictors included prior biomedical ethics education (β =.15, p =.013) and marital status (β =.14, p =.025). The regression model had 28.0% explanatory power. Conclusions: Mental health nurses' moral sensitivity must be increased to improve their person‐centred care. Implications for Nursing Management: Nurses should receive continuous education to remain aware of and maintain a high level of moral sensitivity and be encouraged to continue the person‐centred practice. Organizational and policy support is needed to promote the practice of person‐centred care in the workplace. [ABSTRACT FROM AUTHOR]

Upregulation of oncogenic miRNA21 (miR-21) plays a pivotal role in proliferation, migration and invasion of cancer cells. In addition to cancer cells, tumor-associated macrophages (TAMs) also have high abundance of miR-21, which accelerates malignant progression of tumors in the late stages of carcinogenesis. Despite of the pro-tumorigenic functions of miR-21 in TAMs and cancer cells, reliable therapeutic strategies to simultaneously inhibit miR-21 activity in both types of cell have not yet been developed. In this study, we designed a dual-targeting drug delivery system of miR-21 inhibitors that could bind to both tumor cells and macrophages with overexpressed PD-L1 receptors. This peptide-oligonucleotide conjugate (Pep-21) consists of a PDL1-binding peptide covalently linked with an anti-miR-21 inhibitor via click chemistry. Pep-21 was preferentially internalized in both cell types, consequently depleting endogenous miR-21. Our studies found that Pep-21 treatment reduced tumor cell migration, reprogrammed immunosuppressive M2-type TAMs into M1-type macrophages, and restrained tumor progression. Collectively, neutralization of miR-21 activity in both cancer cells and TAMs can be a promising strategy for effective antitumor responses. [Display omitted] • PDL1-binding peptide-anti-miR-21 conjugates (Pep-21) were prepared by click reaction. • Pep-21 could simultaneously target PD-L1high tumors and TAMs. • Pep-21 normalized miR-21 levels in TME, inducing antitumor activity. • Dual targeting ability of Pep-21 elicited effective antitumor response. [ABSTRACT FROM AUTHOR]

Isothiazolinone (IT) biocides are potent antibacterial substances used as preservatives and disinfectants. These biocides exert differing biocidal effects and display environmental stability based upon chemical structure. In agreement with our recent study reporting that 2-n-octyl-4-isothiazolin-3-one (OIT) induced dysfunction of the blood-brain barrier (BBB), the potential adverse health effects of two IT biocides 1,2-benzisothiazolin-3-one (BIT) and 4,5-dichloro-2-n-octyl-isothiazolin-3-one (DCOIT) were compared using brain endothelial cells (ECs) derived from murine brain endothelial cell line (bEND.3). BIT possesses an unchlorinated IT ring structure and used as a preservative in cleaning products. DCOIT contains a chlorinated IT ring structure and employed as an antifouling agent in paints. Data demonstrated that DCOIT altered cellular metabolism at a lower concentration than BIT. Both BIT and DCOIT increased reactive oxygen species (ROS) generation at the mitochondrial and cellular levels. However, the effect of DCOIT on glutathione (GSH) levels appeared to be greater than BIT. While mitochondrial membrane potential (MMP) was decreased in both BIT- and DCOIT-exposed cells, direct disturbance in mitochondrial bioenergetic flux was only observed in BIT-treated ECs. Taken together, IT biocides produced toxicity in brain EC and barrier dysfunction, but at different concentration ranges suggesting distinct differing mechanisms related to chemical structure. [ABSTRACT FROM AUTHOR]

Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue‐specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor‐targeting peptides into the LNPs; the programmed death ligand 1 (PD‐L1) binding peptides are conjugated to PEGylated lipids via a copper‐free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD‐L1 proteins, which leads to the uptake of LNPs into PD‐L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN‐deficient triple‐negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy‐mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor‐targeted LNPs for mRNA‐based cancer therapy. [ABSTRACT FROM AUTHOR]

Background: The comparative efficacy of various anti-ulcer medications after gastric endoscopic submucosal dissection (ESD) has not been fully evaluated. Recently, vonoprazan, a novel potassium-competitive acid blocker, has also been used in ulcer treatment after ESD.Methods: We searched for all relevant randomized controlled trials examining the efficacy of anti-ulcer medications after gastric ESD, published through October 2017. Healing of iatrogenic ulcers was investigated at 4-8 weeks after ESD. A network meta-analysis was performed to calculate the network estimates.Results: Twenty-one studies with 2005 patients were included. Concerning the comparative efficacy for ulcer healing at 4 weeks after ESD, no network inconsistency was identified (Cochran's Q-test, df = 10, P = 0.13; I2 = 34%). A combination therapy of proton-pump inhibitor (PPI) and muco-protective agent was superior to PPI alone [risk ratio (RR) (95% confidence interval, CI) 1.69 (1.20-2.39)]. The combination therapy of PPI and muco-protective agents tended to be superior to vonoprazan [RR (95% CI) 1.98 (0.99-3.94)]. There was no difference of ulcer healing effect between PPI and vonoprazan [RR (95% CI) PPI vs. vonoprazan, 1.17 (0.64-2.12)]. Concerning the ulcer healing rate at 8 weeks after ESD, however, vonoprazan was superior to PPI [RR (95% CI) 1.27 (1.03-1.56)]. Additionally, vonoprazan tended to be superior to the combination therapy of PPI and muco-protective agent [RR (95% CI) 1.20 (0.96-1.51)].Conclusions: A combination therapy of PPI and muco-protective agent was superior to PPI alone for ulcer healing at 4 weeks after ESD. In the ulcer healing effect at 8 weeks after ESD, vonoprazan was superior to PPI. [ABSTRACT FROM AUTHOR]

Abstract Glutathione peroxidase 4 (GPX4) is a regulator of ferroptosis (iron-dependent, non-apoptotic cell death); its inhibition can render therapy-resistant cancer cells susceptible to ferroptosis. However, some cancer cells develop mechanisms protective against ferroptosis; understanding these mechanisms could help overcome chemoresistance. In this study, we investigated the molecular mechanisms underlying resistance to ferroptosis induced by GPX4 inhibition in head and neck cancer (HNC). The effects of two GPX4 inhibitors, (1 S , 3 R)-RSL3 and ML-162, and of trigonelline were tested in HNC cell lines, including cisplatin-resistant (HN3R) and acquired RSL3-resistant (HN3-rslR) cells. The effects of the inhibitors and trigonelline, as well as of inhibition of the p62, Keap1, or Nrf2 genes, were assessed by cell viability, cell death, lipid ROS production, and protein expression, and in mouse tumor xenograft models. Treatment with RSL3 or ML-162 induced the ferroptosis of HNC cells to varying degrees. RSL3 or ML-162 treatment increased the expression of p62 and Nrf2 in chemoresistant HN3R and HN3-rslR cells, inactivated Keap1, and increased expression of the phospho-PERK–ATF4–SESN2 pathway. Transcriptional activation of Nrf2 was associated with resistance to ferroptosis. Overexpression of Nrf2 by inhibiting Keap1 or Nrf2 gene transfection rendered chemosensitive HN3 cells resistant to RSL3. However, Nrf2 inhibition or p62 silencing sensitized HN3R cells to RSL3. Trigonelline sensitized chemoresistant HNC cells to RSL3 treatment in a mouse model transplanted with HN3R. Thus, activation of the Nrf2–ARE pathway contributed to the resistance of HNC cells to GPX4 inhibition, and inhibition of this pathway reversed the resistance to ferroptosis in HNC. Graphical abstract A proposed model of Nrf2-induced resistance to GPX4 inhibition-induced ferroptosis in cancer cells. The GPX4 inhibitors RSL3 and ML-162 induce endoplasmic reticulum stress and subsequently p62 expression via the PERK–ATF4–SESN2 pathways. Nrf2 is activated by p62–Keap1 interaction and antioxidant response elements (ARE) related to iron and antioxidant systems is increased, resulting in a decreased labile iron pool, thus contributing to the resistance to ferroptosis. fx1 Highlights • RSL3 and ML-162 inhibited GPX4, inducing the ferroptotic death of head and neck cancer (HNC) cells to varying degrees. • Resistance to GPX4 inhibition is related to the increased expression of p62. • The p62–Keap1–Nrf2 antioxidant system is also involved in the RSL3 resistance mechanism. • Nrf2 inhibition sensitized chemoresistant HNC cells to RSL3 treatment. • Trigonelline reversed RSL3-induced resistance to ferroptosis in HNC via inhibition of the Nrf2 system, both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Abstract Recently, many of studies have been attempted to determine how to decrease adhesion. To effectively prevent adhesion, decrease in unnecessary surgical procedures, prevention of contact with other tissue, and drug treatment for inflammation are required. However, current anti-adhesion materials have disadvantages. To solve current problems, we prepared a biocompatible drug-loaded anti-adhesion barrier using a visible-light curable furfuryl gelatin derivative. We used riboflavin as a photo-initiator in the photo-curing process. The biocompatibility of riboflavin was estimated compared with that of Rose Bengal. In addition, the curing ratio was measured to determine whether riboflavin initiated photo-curing. We also evaluated the curing ratio of riboflavin according to the concentration of F-gelatin and the photo-irradiation time. A drug used to decrease inflammation that causes adhesion should not disappear from the surgical site and should also be released consistently. For this, we observed the release profiles of photo-immobilized ibuprofen with different concentrations of F-gelatin. Because an anti-adhesion barrier should protect from bacterial infection we evaluated the protective ability of a barrier formed by F-gelatin. In conclusion, a drug-loaded anti-adhesion barrier was prepared using a visible-light curable furfuryl gelatin derivative, with riboflavin as a photo-initiator. We expect that this drug-loaded anti-adhesion barrier effectively decrease adhesion formation. Highlights • Riboflavin showed the better photo-curable property and biocompatibility as photo-initiator than Rose Bengal. • As concentration of furfuryl gelatin and photo-irradiation time increase, the photo-curing ratio increase. • Release profile of photo-immobilized ibuprofen can be controlled by changing the concentration of furfuryl gelatin. • Surgical site can be protected from bacterial infection by furfuryl gelatin barrier and adhesion also can be decreased. • Drug-loaded anti-adhesion barrier can protect surgical site and prevent inflammation. [ABSTRACT FROM AUTHOR]

Parabens are widely used as preservatives, added to products commonly used by humans, and to which individuals are exposed orally or dermally. Once absorbed into the body, parabens move into the bloodstream and travel through the systemic circulation. We investigated the potential impact of parabens on the enhanced generation of thrombin by red blood cells (RBCs), which are the principal cellular components of blood. We tested the effects of methylparaben (MeP), ethylparaben (EtP), propylparaben (PrP), butylparaben (BuP), and p -hydroxybenzoic acid on freshly isolated human RBCs. BuP and simultaneous exposure to BuP and PrP significantly increased phosphatidylserine (PS) externalization to the outer membranes of RBCs. PS externalization by BuP was found to be mediated by increasing intracellular Ca2+ levels in RBCs. The morphological changes in BuP-treated RBCs were observed under an electron microscope. The BuP-exposed RBCs showed increased thrombin generation and adhesion to endothelial cells. Additionally, the externalization of PS exposure and thrombin generation in BuP-treated RBCs were more susceptible to high shear stress, which mimics blood turbulence under pathological conditions. Collectively, we observed that BuP induced morphological and functional changes in RBCs, especially under high shear stress, suggesting that BuP may contribute to the thrombotic risk via procoagulant activity in RBCs. [Display omitted] • BuP enhanced PS externalization by increasing intracellular Ca2+ levels in isolated human RBCs. • Morphological changes, procoagulant activity, and adhesion to endothelial cells were increased in BuP-treated RBCs. • High shear stress amplified the susceptibility of BuP-treated RBCs in PS exposure and thrombin generation. • Combined exposure to BuP and PrP enhanced RBC damage at lower concentrations than individual exposure. [ABSTRACT FROM AUTHOR]

Periodontitis is an infectious disease that is associated with microorganisms that colonize the tooth surface. Clinically, periodontal condition stability reflects dynamic equilibrium between bacterial challenge and host response. Therefore, periodontal pathogen assessment can assist in the early detection of periodontitis. Here we developed a grading system called the periodontal pathogen index (PPI) by analyzing the copy numbers of multiple pathogens both in healthy and chronic periodontitis patients. We collected 170 mouthwash samples (64 periodontally healthy controls and 106 chronic periodontitis patients) and analyzed the salivary 16S rRNA levels of nine pathogens using multiplex, quantitative real-time polymerase chain reaction. Except for Aggregatibacter actinomycetemcomitans, copy numbers of all pathogens were significantly higher in chronic periodontitis patients. We classified the samples based on optimal cut-off values with maximum sensitivity and specificity from receiver operating characteristic curve analyses (AUC = 0.91, 95% CI: 0.87–0.96) into four categories of PPI: Healthy (1–40), Moderate (41–60), At Risk (61–80), and Severe (81–100). PPI scores were significantly higher in all chronic periodontitis patients than in the controls (odds ratio: 31.7, 95% CI: 13.41–61.61) and were associated with age, scaling as well as clinical characteristics including clinical attachment level and plaque index. Our PPI grading system can be clinically useful for the early assessment of pathogenic bacterial burden and follow-up monitoring after periodontitis treatment. [ABSTRACT FROM AUTHOR]

Sulfasalazine has been repurposed to induce ferroptotic cancer cell death via inhibition of xc--cystine/glutamate antiporter (xCT). However, cancer cells are capable of developing mechanisms to evade cell death. Therefore, we sought to determine the molecular mechanisms underlying resistance to sulfasalazine-induced ferroptosis in head and neck cancer (HNC). The effects of sulfasalazine and pioglitazone were tested in various HNC cell lines. The effects of these drugs and inhibition and overexpression of CISD2 gene were determined by evaluating viability, cell death, lipid ROS production, mitochondrial iron, and mouse tumor xenograft models. SAS induced ferroptotic cell death in HNC at different levels. CISD2 expression showed an association between its expression and ferroptosis resistance. CISD2 overexpression conferred resistance to ferroptosis by sulfasalazine. Silencing CISD2 gene rendered resistant HNC cells susceptible to sulfasalazine-induced ferroptosis, with increased levels of lipid ROS and mitochondrial ferrous iron. Pioglitazone induced over-accumulation of mitochondrial iron and ROS and sensitized resistant HNC cells to sulfasalazine treatment in vitro and in a mouse tumor-xenograft model. CISD2 inhibition overcomes HNC resistance to ferroptotic cell death induced by sulfasalazine via increased accumulation of mitochondrial ferrous iron and lipid ROS. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose treatment causes severe liver injury. Adiponectin, a hormone predominantly produced by adipose tissue, exhibits protective effects against APAP-induced hepatotoxicity. However, the underlying mechanisms are not clearly understood. In the present study, we examined the protective effect of globular adiponectin (gAcrp) on APAP-induced hepatocyte death and its underlying mechanisms. We found that APAP (2 mM)-induced hepatocyte death was prevented by inhibition of the inflammasome. In addition, treatment with gAcrp (0.5 and 1 μg/ml) inhibited APAP-induced activation of the inflammasome, judged by suppression of interleukin-1β maturation, caspase-1 activation, and apoptosis-associated speck-like protein (ASC) speck formation, suggesting that protective effects of gAcrp against APAP-induced hepatocyte death is mediated via modulation of the inflammasome. APAP also induced ER stress and treatment with tauroursodeoxycholic acid (TUDCA), an ER chaperone and inhibitor of ER stress, abolished APAP-induced inflammasomes activation, implying that ER stress acts as signaling event leading to the inflammasome activation in hepatocytes stimulated with APAP. Moreover, gAcrp significantly suppressed APAP-induced expression of ER stress marker genes. Finally, the modulatory effects of gAcrp on ER stress and inflammasomes activation were abrogated by treatment with autophagy inhibitors, while an autophagy inducer (rapamycin) suppressed APAP-elicited ER stress, demonstrating that autophagy induction plays a crucial role in the suppression of APAP-induced inflammasome activation and ER stress by gAcrp. Taken together, these results indicate that gAcrp protects hepatocytes against APAP-induced cell death by modulating ER stress and the inflammasome activation, at least in part, via autophagy induction. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aim: Although propofol has been widely used for sedation during esophagogastroduodenoscopy (EGD), adverse events including hypoxia and hypotension may be a concern in the propofol‐based sedation. We aimed to analyze whether administration of midazolam would improve safety and efficacy of propofol‐based sedation in EGD. Methods: One hundred twenty patients who were scheduled to undergo diagnostic EGD were randomly assigned to either midazolam plus propofol (MP) or propofol alone groups. In the MP group, 2 mg of midazolam and 10 mg of propofol were given initially. In the propofol alone group, 40–60 mg of propofol was given initially. In both groups, 20 mg of propofol was given repeatedly to maintain moderate sedation as needed. Vital signs including oxygen saturation were monitored every 2 min. After the patients fully recovered, satisfaction score was investigated from endoscopists, nurses, and patients, respectively. Results: The baseline characteristics did not differ between the MP and propofol alone groups. The mean required doses of propofol was (mean ± standard deviation) 0.3 ± 0.3 and 0.8 ± 0.2 mg/kg in the MP and propofol alone groups, respectively (P < 0.001). In addition, sedation‐related adverse events and recovery time did not differ between the two groups. The proportion of satisfactory did not differ between the two groups (MP vs propofol alone; proportion; patient, 95.0% vs 93.3%, P > 0.999; endoscopist, 73.3% vs 80.0%, P = 0.064; nurse, 73.3% vs 76.7%, P = 0.551). Conclusion: Adding midazolam to propofol did not reduced the safety and efficacy, and sedation using propofol alone could be suitable for sedation during diagnostic EGD. [ABSTRACT FROM AUTHOR]

A new chemical space was explored based on an indolizine-chalcone hybrid, which was readily accessible by base-mediated aldol condensation of indolizine bearing a 7-acetyl group with various (hetero)aromatic aldehydes. Their anticancer effect was evaluated, revealing that indolizine-chalcone hybrids with 3,5-dimethoxyphenyl group ( 4h ) or the halogen at the meta position ( 4j and 4l ) could have the potential to induce the caspase-dependent apoptosis of human lymphoma cells. [ABSTRACT FROM AUTHOR]

Chitosan, which has many biocompatible properties, is used widely in medical field like wound healing, drug delivery and so on. Chitosan could be used as a biomaterial to immobilize protein-drug. There are many methods to immobilize protein-drug, but they have some drawbacks such as low efficiency and denaturation of protein. Therefore, photo-immobilization method is suggested to immobilize protein-drug. Photo-immobilization method is simple-reaction and also needs no additional crosslinking reagent. There has been some effort to modify chitosan to have an ability of photo-immobilization. Generally, visible and UV light reactive chitosan derivatives were prepared. Various types of photo-curable chitosan derivatives showed possibility for application to medical field. For example, they showed ability for protein-immobilization and some of them showed wound-healing effect, anti-adhesive effect, or property to interact directly with titanium surface. In this study, we introduce many types of photo-curable chitosan derivative and their possibility of medical application. [ABSTRACT FROM AUTHOR]

Cell sheets with pre-vascularization have recently been developed but remain relatively untested in oral wound healing. Therefore, we examined the potential utility of our newly developed pre-vascularized mucosal cell sheets in oral wound healing. Mucosal keratinocytes, fibroblasts, and endothelial progenitor cells were primarily cultured for in vitro cell expansion from mucosa and blood of Sprague-Dawley rats. Mucosal cell sheets were generated using cultured keratinocytes and plasma fibrin (K sheet) or keratinocytes and a mixture of fibrin, fibroblasts, and endothelial cells (PV sheet). Autologous sheets were transplanted on deep wounds in the buccal region of rats. The gross and histological characteristics of wound healing were compared among control wound, K sheet, and PV sheet groups. We successfully cultured and expanded keratinocytes, fibroblasts, and endothelial progenitor cells in vitro for generating mucosal cell sheets with or without pre-vascularization. In the in vivo oral wound model, compared with the control wound, the PV sheet group exhibited rapid wound closure more prominently than the K sheet group. The histological healing in the PV sheet group was similar to that in rat normal buccal mucosa without fibrosis. The pre-vascularized mucosal cell sheet exhibited in vivo efficacy in oral wound healing by promoting accelerated healing. [ABSTRACT FROM AUTHOR]

Background Although several studies have shown that second-look endoscopy does not affect the incidence of bleeding after gastric endoscopic submucosal dissection (ESD), the potential roles of second-look endoscopy have not been fully evaluated. This study aimed to determine the role of second-look endoscopy after ESD through a systematic review and meta-analysis. Methods This study conducted a systematic literature search of MEDLINE, EMBASE, and the Cochrane Library through March 2016 using the keywords 'second-look,' 'prophylactic hemostasis,' 'prophylactic haemostasis,' 'prevention,' 'prophylaxis,' and 'endoscopic submucosal dissection.' Studies were included if they evaluated the incidence of post-ESD bleeding according to second-look endoscopy or prophylactic hemostasis during second-look endoscopy. Results Four randomized controlled trials on post-ESD bleeding between second-look endoscopy and no second-look endoscopy and 12 non-randomized studies with a cohort design on post-ESD bleeding were included. On meta-analysis, second-look endoscopy did not affect delayed post-ESD bleeding (odds ratio [95% confidence interval] = 1.27 [0.80-2.00], I2 = 0%). During second-look endoscopy, patients who were considered as high-risk for post-ESD bleeding underwent prophylactic hemostasis. Delayed post-ESD bleeding was more common in patients who were treated with hemostasis during second-look endoscopy compared with those who were not (odds ratio [95% confidence interval] = 3.40 [1.87-6.18], I2 = 62%). In patients who underwent prophylactic hemostasis, the number needed to prolong a hospitalization period to avoid one additional post-ESD bleeding after discharge was 25. Conclusion Second-look endoscopy after ESD could not reduce the risk of delayed post-ESD bleeding. Delayed post-ESD bleeding was more common in patients who underwent prophylactic hemostasis than in those who did not. [ABSTRACT FROM AUTHOR]

An analytical method for the reliable screening and confirmation of 156 illegal drugs (58 erectile dysfunction drugs, 49 synthetic steroids, 26 anabolic steroids, and 23 anti-histamine drugs) in supplementary diets using ultra-high-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UHPLC-Q/TOF-MS) was developed. Various types of supplements (liquid, capsule, powder, pill and tablet) with complicated matrices were pretreated by simple liquid–liquid extraction. The wide scope of 156 target compounds was effectively determined within 15 min in the positive ion mode, detecting the compounds at a sub-ppb level. Their MS/MS spectra were preferentially investigated to find diagnostic common ions according to the structural similarity of diverse adulterants. For the rapid screening of multiple classes of the target adulterants, extracted common ion chromatograms (ECICs) based on specific fragments of similar molecular moieties were attempted. A database including the elemental compositions, retention times, and MS/MS spectra was built for the confirmation of adulterants. The established method was validated in terms of the linearity, limits of detection (LOD), precision, and accuracy. The linear correlation coefficient and limit of detection ranged from 0.9880 to 1 and from 0.02 to 16.04 ng/mL, respectively. The precision and accuracy of intra- and inter-day experiments for the spiked samples at the range of 0.2 and 16.0 ng/mL were from 0.16 to 13.50% and 0.19–11.48%, respectively, with relative standard deviation. Mean recoveries ranged from 81.6 to 124.7%, and relative standard deviation was less than 9.20%. The screening and confirmation method demonstrated the usefulness of UHPLC-Q/TOF-MS combined with ECICs as a promising approach for the analysis of multi-class adulterants. Finally, the established method was successfully applied for the monitoring of several types of dietary supplements in routine analysis. [ABSTRACT FROM AUTHOR]

The nonsteroidal anti-inflammatory drug aspirin and the multikinase inhibitor sorafenib have both shown experimental and clinical anticancer activities. The present study investigated whether aspirin and sorafenib synergize to potentiate cisplatin treatment in resistant head and neck cancer (HNC) cells. The effects of aspirin, sorafenib and cisplatin, and combinations thereof were assessed by measuring cell viability, death, glutathione (GSH) and reactive oxygen species (ROS) levels, protein and mRNA expression, genetic inhibition and overexpression of cystine–glutamate antiporter (xCT) and tumor xenograft mouse models. Even at low concentrations, aspirin plus sorafenib synergized to induce cell death of cisplatin-resistant HNC cells. The combination of aspirin and sorafenib induced xCT inhibition, GSH depletion, and ROS accumulation in cancer cells. Genetic and pharmacological inhibition of xCT potentiated the cytotoxic effects of aspirin plus sorafenib; this effect was diminished by xCT overexpression. Low-dose aspirin plus sorafenib enhanced the cytotoxicity of cisplatin in resistant HNC cells through xCT inhibition and oxidant and DNA damage. The in vivo effects of aspirin plus sorafenib on cisplatin therapy were also confirmed in resistant HNC xenograft models, in terms of growth inhibition, GSH depletion, and increased γH2AX formation and apoptosis in tumors. Aspirin and sorafenib synergize to potentiate the cytotoxicity of cisplatin in resistant HNC cells. This therapeutic strategy may help to eliminate resistant HNC. [ABSTRACT FROM AUTHOR]

We hypothesized that distinct acute right hemisphere lesions disrupt separate components of valuation and emotional response to winning and losing money and of emotional empathy in observing a partner win or lose money. We measured skin conductance response (SCR) and ratings of emotions when acute right hemisphere stroke patients or healthy controls won or lost money in roulette, or when they watched a partner win or lose. Our results showed that percentage of damage after stroke to right anterior insula and frontal operculum negatively correlated with both SCR to winning and losing and difference between rating wins versus losses. [ABSTRACT FROM AUTHOR]

The article discusses a study on the use of titanium dioxide in the photocatalysis of methylene blue (MB) on carbon nanotubes (CNTs). Topics include the enhancement of the photocatalytic properties of CNT and titanium dioxide composites, the higher photodegradation activity of titanium catalyst and the photocatalytic discoloration of MB.

Inhibition of key molecules related to ferroptosis, cystine/glutamate antiporter and glutathione peroxidase, may induce eradication of chemotherapy/radiotherapy-resistant cancer cells. The present study investigated whether ferroptosis could overcome head and neck cancer (HNC) resistance to cisplatin treatment. Three cisplatin-resistant HNC cell lines (AMC-HN3R, -HN4R, and -HN9R) and their parental lines were used. The effects of cystine and glutamate alteration and pharmacological and genetic inhibition of cystine/glutamate antiporter were assessed by measuring viability, death, reactive oxygen species production, protein expression, and preclinical mouse tumor xenograft models. Conditioned media with no cystine or glutamine excess induced ferroptosis of both cisplatin-sensitive and -resistant HNC cells without any apparent changes to necrosis and apoptosis markers. The cystine/glutamate antiporter inhibitors erastin and sulfasalazine inhibited HNC cell growth and accumulated lipid reactive oxygen species, thereby inducing ferroptosis. Genetic silencing of cystine/glutamate antiporter with siRNA or shRNA treatment also induced effective ferroptotic cell death of resistant HNC cells and enhanced the cisplatin cytotoxicity of resistant HNC cells. Pharmacological and genetic inhibition of cystine/glutamate antiporter significantly sensitized resistant HNC cells to cisplatin in vitro and in vivo. Pharmacological and genetic inhibition of cystine/glutamate antiporter overcomes the cisplatin resistance of HNC cells by inducing ferroptosis. [ABSTRACT FROM AUTHOR]

Background: Screening endoscopies in individuals 40 years or older in regions where gastric cancer is prevalent increase the diagnosis of gastric cancer at an early stage. However, the benefits of screening endoscopies in a young population (<40 years) have not been evaluated. Methods: We reviewed data from patients less than 40 years old who underwent endoscopic submucosal dissection or surgery for initial-onset gastric cancer. We also administered a questionnaire to gather information concerning periodic endoscopic inspections and the period from the penultimate endoscopy to diagnosis. Results: Of the 564 patients in this study, 101 (17.9%) patients underwent screening endoscopy within 24 months of their gastric cancer diagnosis. Lesion size was significantly smaller in the ≤24 months group than in the >24 month group (23.8 mm [standard deviation, 22.2 mm] vs. 30.5 mm [standard deviation, 23.1 mm], P = 0.008). However, the proportion of patients with early gastric cancer did not differ between the two groups (≤24 months vs. >24 months group; 67.6% vs. 65.7%, P = 0.712). On multivariable analysis, periodic endoscopies did not influence the early diagnosis of gastric cancer (with >24 months as the reference group: ≤24 months, odds ratio = 0.939, 95% confidence interval = 0.583–1.513). Conclusion: Although periodic endoscopies aided in the detection of gastric cancer when lesions were smaller in size, they seemed not to increase the proportion of patients with early gastric cancer in young patients diagnosed with resectable gastric cancer. [ABSTRACT FROM AUTHOR]

Background: Gastric cancer with undifferentiated histology has different clinicopathologic characteristics compared to differentiated type gastric cancer. We aimed to compare the risk of synchronous or metachronous tumors after curative resection of early gastric cancer (EGC) via endoscopic submucosal dissection (ESD), according to the histologic differentiation of the primary lesion. Methods: Clinicopathological data of patients with initial-onset EGC curatively resected via ESD between January 2007 and November 2014 in a single institution were reviewed. We analyzed the incidence of synchronous or metachronous tumors after ESD with special reference to the differentiation status of the primary lesion. Results: Of 1,560 patients with EGC who underwent curative resection via ESD, 1,447 had differentiated type cancers, and 113 had undifferentiated type cancers. The cumulative incidence of metachronous or synchronous tumor after ESD was higher in the differentiated cancer group than in the undifferentiated cancer group (P = 0.008). Incidence of metachronous or synchronous tumor was 4.8% and 1.2% per person-year in the differentiated and undifferentiated cancer groups, respectively. The Cox proportional hazard model revealed that undifferentiated cancers were associated with a low risk of synchronous or metachronous tumors after adjusting for confounding variables (hazard ratio [95% confidence interval] = 0.287 [0.090–0.918]). Conclusions: The rate of synchronous or metachronous tumors after curative ESD was significantly lower for undifferentiated cancers compare to differentiated cancers. These findings suggest that ESD should be actively considered as a possible treatment for undifferentiated type EGCs. [ABSTRACT FROM AUTHOR]

Most of researches on the impact of indoor air pollutants on atopic dermatitis (AD) have been based upon animal models, in vitro experiments and case-control studies. However, human data to elucidate the role of indoor air pollution on worsening symptoms of pre-existing AD from a longitudinal study are scarce. The objective of this prospective study was to evaluate the effect of indoor air pollution on AD symptoms in children. We surveyed 30 children with AD in a day-care centre, which moved to a new building during the study. These children stayed there for 8 hours a day Monday through Friday, and their daily symptom scores were recorded. Indoor and outdoor air pollutant levels were continuously measured 24 hours a day for 12 months (Period 1 to 4). Data were analyzed using a generalized linear mixed model. Compared to the period before moving (Period 1), concentrations of indoor air pollutants mostly increased after moving (Period 2) and decreased by natural ventilation and bake-out (Periods 3 and 4). The rate of positive AD symptom increased from 32.8% (Period 1) up to 43.8% (Period 2) and 50.5% (Period 3), then decreased to 35.4% in Period 4 (P < 0.0001). When the delayed effects of indoor air pollutants on AD symptoms 2 days later were evaluated, AD symptoms significantly increased by 12.7% (95% CI: -0.01 to 27.1) as toluene levels increased by 1 ppb (P = 0.05). In conclusion, indoor air pollutants increase the risk of AD aggravation in children and toluene in the indoor environment might act as an aggravating factor. [ABSTRACT FROM AUTHOR]

BACKGROUND: Activating transcription factor-3 (ATF3) is known as a suppressor of cytokine production after exposure to lipopolysaccharide or during gram-negative bacterial infection. However, the mechanism by which ATF3 regulates innate immunity against gram-positive bacterial infection, particularly Streptococcus pneumoniae, remains unknown. METHODS: The wild-type and ATF3 knock-out (KO) mice were infected intranasally (i.n) or intraperitoneally with S. pneumoniae, and bacterial colonization or survival rate was determined. Pneumococcal pneumonia was induced by i.n infection, and ATF3 level was determined by Western blot. ATF3 KO cells or ATF3 siRNA transfection were used to determine expression of ATF3 downstream genes. Enzyme-linked immunosorbent assay was used to examine cytokines levels. RESULTS: ATF3 was highly expressed in various cell lines in vitro and in many organs in vivo. Pneumolysin was a novel inducer of ATF3. Pneumococcal infection induced ATF3, which subsequently stimulated production of cytokines (tumor necrosis factor [TNF]-[alpha], interleukin [IL]-1[beta], and interferon [IFN]-[gamma]). ATF3-mediated cytokine induction protected the host from pneumococcal infection. In the pneumonia infection model, the bacterial clearance of wild-type mice was more efficient than those of ATF3 KO mice. CONCLUSIONS: Taken together, we can conclude that ATF3 regulates innate immunity positively upon pneumococcus infection by enhancing TNF-[alpha], IL-1[beta], and IFN-[gamma] expression and modulating bacterial clearance. [ABSTRACT FROM AUTHOR]

Background. Activating transcription factor–3 (ATF3) is known as a suppressor of cytokine production after exposure to lipopolysaccharide or during gram-negative bacterial infection. However, the mechanism by which ATF3 regulates innate immunity against gram-positive bacterial infection, particularly Streptococcus pneumoniae, remains unknown.Methods. The wild-type and ATF3 knock-out (KO) mice were infected intranasally (i.n) or intraperitoneally with S. pneumoniae, and bacterial colonization or survival rate was determined. Pneumococcal pneumonia was induced by i.n infection, and ATF3 level was determined by Western blot. ATF3 KO cells or ATF3 siRNA transfection were used to determine expression of ATF3 downstream genes. Enzyme-linked immunosorbent assay was used to examine cytokines levels.Results. ATF3 was highly expressed in various cell lines in vitro and in many organs in vivo. Pneumolysin was a novel inducer of ATF3. Pneumococcal infection induced ATF3, which subsequently stimulated production of cytokines (tumor necrosis factor [TNF]–α, interleukin [IL]–1β, and interferon [IFN]–γ). ATF3-mediated cytokine induction protected the host from pneumococcal infection. In the pneumonia infection model, the bacterial clearance of wild-type mice was more efficient than those of ATF3 KO mice.Conclusions. Taken together, we can conclude that ATF3 regulates innate immunity positively upon pneumococcus infection by enhancing TNF-α, IL-1β, and IFN-γ expression and modulating bacterial clearance. [ABSTRACT FROM AUTHOR]

Background: Although many case reports have described patients with proton pump inhibitor (PPI)-induced hypomagnesemia, the impact of PPI use on hypomagnesemia has not been fully clarified through comparative studies. We aimed to evaluate the association between the use of PPI and the risk of developing hypomagnesemia by conducting a systematic review with meta-analysis. Methods: We conducted a systematic search of MEDLINE, EMBASE, and the Cochrane Library using the primary keywords “proton pump,” “dexlansoprazole,” “esomeprazole,” “ilaprazole,” “lansoprazole,” “omeprazole,” “pantoprazole,” “rabeprazole,” “hypomagnesemia,” “hypomagnesaemia,” and “magnesium.” Studies were included if they evaluated the association between PPI use and hypomagnesemia and reported relative risks or odds ratios or provided data for their estimation. Pooled odds ratios with 95% confidence intervals were calculated using the random effects model. Statistical heterogeneity was assessed with Cochran’s Q test and I2 statistics. Results: Nine studies including 115,455 patients were analyzed. The median Newcastle-Ottawa quality score for the included studies was seven (range, 6–9). Among patients taking PPIs, the median proportion of patients with hypomagnesemia was 27.1% (range, 11.3–55.2%) across all included studies. Among patients not taking PPIs, the median proportion of patients with hypomagnesemia was 18.4% (range, 4.3–52.7%). On meta-analysis, pooled odds ratio for PPI use was found to be 1.775 (95% confidence interval 1.077–2.924). Significant heterogeneity was identified using Cochran’s Q test (df = 7, P<0.001, I2 = 98.0%). Conclusions: PPI use may increase the risk of hypomagnesemia. However, significant heterogeneity among the included studies prevented us from reaching a definitive conclusion. [ABSTRACT FROM AUTHOR]

Flexible organic light emitting diodes (OLEDs) have been studied actively for the potential application to OLED display and OLED lighting. One of the key materials for flexible OLED is the flexible and transparent film substrate which can substitute ITO glass in flat panel OLEDs. In this work we deposited silicon and aluminium oxide and nitride single layer thin films on different flexible substrates such as poly(polyethylene terephthalate) (PET) and poly(polyethylene naphthalate (PEN) to investigate the gas barrier properties. After selecting the polymer film substrate and thin inorganic layer material, the inorganic/organic/inorganic multiple gas barrier was formed on film substrate by using roll-to-roll sputter and their property was examined from the viewpoint of multilayer structure and gas barrier properties for application to flexible substrate of OLED devices. [ABSTRACT FROM AUTHOR]

House dust mite (HDM) is a primary allergen in allergic rhinitis (AR) and asthma. Neutrophil apoptosis is associated with allergic diseases and innate immunity to infection. The present study examined how HDM affects constitutive neutrophil apoptosis in normal and AR subjects. Total IgE increased in AR subjects when compared to normal subjects, and patients with AR were HDM-specific IgE positive (+), which is specific IgE to Dermatophagoides pteronissinus and Dermatophagoides farinae. In normal and AR subjects, neutrophil apoptosis was inhibited by extract of Dermatophagoides pteronissinus (DP), but not by extract of Dermatophagoides farina (DF). Aprotinin (serine protease inhibitor) and E64 (cysteine protease inhibitor) have no effect on neutrophil apoptosis due to DP. The anti-apoptotic effect of DP was blocked by TLR4i, an inhibitor of TLR4, rottlerin, an inhibitor of PKCδ, PD98059, an inhibitor of ERK, and BAY-11-7085, an inhibitor of NF-κB. DP induced PKCδ, ERK, and NF-κB activation in a time-dependent manner. DP inhibited the cleavage of procaspase 3 and procaspase 9. The expression of IL-6, IL-8, TNF-α, G-CSF, GM-CSF, and CCL2 increased in the supernatant collected from the normal and AR neutrophils after DP treatment and the supernatant inhibited the apoptosis of normal and AR neutrophils. In summary, DP has anti-apoptotic effects on neutrophils of normal and AR subjects through the TLR4/PKCδ/ERK/NF-κB pathway, and this finding may contribute to solution of the pathogenic mechanism of allergic diseases triggered by DP. [ABSTRACT FROM AUTHOR]

Highlights: [•] Static and dynamic life time of flexible OLED were examined. [•] Multiple gas barrier layers on PEN film are given. [•] Film encapsulation of f-OLED with OCA gasket is given. [•] Film encapsulated f-OLED withstand better under static stress than dynamic one. [ABSTRACT FROM AUTHOR]

Highlights: [•] Isoflavone diversity (44 varieties) of the soybean seeds were examined by HPLC. [•] Multivariate analyses were performed to classify genetic varieties. [•] Metabolic profiling could be used as a tool for identifying metabolic links. [ABSTRACT FROM AUTHOR]

Highlights: [•] Phenolic compounds in soybean seeds were determined using HPLC. [•] PLS-DA was performed to classify genetic varieties. [•] Cooler environment may be more suitable for the production of isoflavone in soybeans. [ABSTRACT FROM AUTHOR]

Highlights: [•] Phenolic compounds in mungbean seeds were determined using HPLC. [•] Multivariate analyses were performed to classify genetic varieties. [•] Metabolic profiling could be used as a tool for assessing the quality of food. [Copyright &y& Elsevier]

P21-activated kinase 1 (PAK1) is activated by binding to GTP-bound Rho GTPases Cdc42 and Rac via its CRIB domain. Here, we provide evidence that S79 in the CRIB domain of PAK1 is not directly involved in this binding but is crucial for PAK1 activation. S79A mutation reduces the binding affinity of PAK1 for the GTPases and inhibits autophosphorylation and kinase activity of PAK1. Thus, this mutation abrogates the ability of PAK1 to induce changes in cell morphology and motility and to promote malignant transformation of prostate epithelial cells. We also show that growth of the prostate cancer cell line PC3 is inhibited by the treatment of a PAK1-inhibiting peptide comprising 19 amino acids centered on S79, but not by the PAK1 peptide containing the S79A mutation, and that this growth inhibition is correlated with reduced autophosphorylation activity of PAK1. Together, these findings demonstrate a significant role of S79 in PAK1 activation and provide evidence for a novel mechanism of the CRIB-mediated interaction of PAK1 with Cdc42 and Rac. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Ginseng has been used as an anti-stress agent, and its active ingredient, ginsenoside, is similar in structure to estrogen. However, the effect of ginseng on the stressed brain is not completely understood. The aim of this study is to understand systematically how red ginseng (RG) affects gene expressions in the brain of immobilization (IMO) stressed mice to elucidate its underlying mechanism. Materials and methods: For in vivo experiments, mice were stressed by immobilization for 30, 45, or 60min, and gene expression in the mice brain was analyzed by microarray and system biology. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and gene expression by Western blot or qPCR. For in vitro study, the SK-N-SH neuroblastoma cells were stressed by H2O2 exposure. The resultant cytotoxicity was measured by MTT assay, and gene expression by Western blot, ELISA, or qPCR. Results: Microarray analysis of genes in IMO stressed mice brains showed that RG administration prior to IMO stress downregulated >40 genes including peptidyl arginine deiminase type 4 (PADI4). Interestingly, PADI4 was up-regulated by various stresses such as H2O2, acrylamide, and tunicamycin in neuroblastoma SK-N-SH cells but inhibited by RG. IMO stress and in vitro H2O2 stress depressed the estrogen receptor (ER)-β expression but not ERα. However, RG treatment increased ERβ expression both in vivo and in vitro. Comparative analysis regarding the networks by systems biology revealed that TNF-α plays a critical role in IMO stress, and the cell death associated network was much higher than other categories. Consistently, the IMO stress induced TNF-α and Cox-2 expressions, malondialdehyde (MDA), and cell death in the brain, whereas RG administration inhibited these inductions in vivo. siRNA and transient expression studies revealed that ERβ inhibited the PADI4 expression. Conclusion: PADI4 could be used as an oxidative stress marker. RG seems to inhibit oxidative stress-inducible PADI4 by up-regulating ERβ expression in the brain thus protecting brain cells from apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Aim of the study: Ginseng has been used as an anti-stress agent, and its active ingredient, ginsenoside, is similar in structure to estrogen. However, the effect of ginseng on the stressed brain is not completely understood. The aim of this study is to understand systematically how red ginseng (RG) affects gene expressions in the brain of immobilization (IMO) stressed mice to elucidate its underlying mechanism. Materials and methods: For in vivo experiments, mice were stressed by immobilization for 30, 45, or 60min, and gene expression in the mice brain was analyzed by microarray and system biology. Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling (TUNEL) staining, and gene expression by Western blot or qPCR. For in vitro study, the SK-N-SH neuroblastoma cells were stressed by H2O2 exposure. The resultant cytotoxicity was measured by MTT assay, and gene expression by Western blot, ELISA, or qPCR. Results: Microarray analysis of genes in IMO stressed mice brains showed that RG administration prior to IMO stress downregulated >40 genes including peptidyl arginine deiminase type 4 (PADI4). Interestingly, PADI4 was up-regulated by various stresses such as H2O2, acrylamide, and tunicamycin in neuroblastoma SK-N-SH cells but inhibited by RG. IMO stress and in vitro H2O2 stress depressed the estrogen receptor (ER)-β expression but not ERα. However, RG treatment increased ERβ expression both in vivo and in vitro. Comparative analysis regarding the networks by systems biology revealed that TNF-α plays a critical role in IMO stress, and the cell death associated network was much higher than other categories. Consistently, the IMO stress induced TNF-α and Cox-2 expressions, malondialdehyde (MDA), and cell death in the brain, whereas RG administration inhibited these inductions in vivo. siRNA and transient expression studies revealed that ERβ inhibited the PADI4 expression. Conclusion: PADI4 could be used as an oxidative stress marker. RG seems to inhibit oxidative stress-inducible PADI4 by up-regulating ERβ expression in the brain thus protecting brain cells from apoptosis. [Copyright &y& Elsevier]

Abstract: Recently, the DraR/DraK (Sco3063/Sco3062) two-component system (TCS) of Streptomyces coelicolor has been reported to be involved in the differential regulation of antibiotic biosynthesis. However, it has not been shown that under which conditions and how the DraR/DraK TCS is activated to initiate the signal transduction process. Therefore, to understand the sensing mechanism, structural study of the sensory domain of DraK is highly required. Here, we report the biochemical and biophysical properties of the extracellular sensory domain (ESD) of DraK. We observed a reversible pH-dependent conformational change of the ESD in a pH range of 2.5–10. Size-exclusion chromatography and AUC (analytical ultracentrifugation) data indicated that the ESD is predominantly monomeric in solution and exists in equilibrium between monomer and dimer states in acidic condition. Using NMR (nuclear magnetic resonance) and CD (circular dichroism) spectroscopy, our findings suggest that the structure of the ESD at low pH is more structured than that at high pH. In particular, the glutamate at position 83 is an important residue for the pH-dependent conformational change. These results suggest that this pH-dependent conformational change of ESD may be involved in signal transduction process of DraR/DraK TCS. [Copyright &y& Elsevier]

Abstract: Streptococcus pneumoniae (pneumococcus) is responsible for significant morbidity and mortality in worldwide. After introduction of current pneumococcal vaccines, a marked decrease in the incidence of pneumococcal disease was observed. Unfortunately, serotype shifts in carriage and disease, including capsular switch and presence of antimicrobial resistance, have been found. Here we report live attenuated vaccine strain which is avirulent and can protect from systemic and mucosal pneumococcal diseases. Pep27, an autolysis-inducing factor of S. pneumoniae is known to mediate LytA-dependent and -independent lysis and it was thus expected to effect virulence. The loss of Pep27 had a much larger than expected decrease in virulence and has made the Pep27 mutant strain sufficiently avirulent to be used as a live vaccine. The pep27 mutation unexpectedly had lower level of capsular polysaccharide than the wild type (type 2, D39) strain. Moreover, the pep27 mutant showed rapid clearance by 24h post intranasal infection, and was not detected in lung and blood suggesting that mutant could not invade into the tissue. Even when 2×108 CFU were injected intravenously the mutant was not detected in the blood or brain after 4h. Whereas 4h after injection of 6×106 CFU of the wild type parent D39 strain, bacteremia was readily detected. Two dose intranasal immunizations with the live pep27 mutant in the absence of adjuvant elicited IgG antibody and serotype-independent protection against lethal intranasal challenge. Thus Pep27 was essential for virulence, and intranasal immunization with the pep27 mutant could provide protective immunity. [Copyright &y& Elsevier]

The leaves of Angelica anomala Lallemant, Angelica cartilagino-marginata var. distans (Nakai) Kitag, Angelica czernevia (Fisch. et Meyer) Kitagawa, Angelica dahurica Benth. et Hooker, Angelica decursiva (Miq.) Franch. & Sav, Angelica fallax Boissieu, Angelica gigas Nakai, Angelica japonica A. gray were essential oil extracted and immunotoxicity effects were studied. The Angelica anomala, A. cartilagino-marginata var. distans, A. czernevia, A. dahurica, A. decursiva, A. fallax, A. gigas, A. japonica essential oil yield were 4.13, 4.83, 4.45, 3.25, 4.11, 4.73, 4.34 and 4.21%. The A. dahurica essential oil had a significant toxic effect against early fourth-stage larvae of Aedes aegypti L with a lethal concentration 50 (LC50) value of 43.12 ppm and an LC90 value of 65.23 ppm. The above indicates that essential oil contents may play a more important role in the toxicity of essential oil. [ABSTRACT FROM AUTHOR]

Abstract: Multidrug resistance (MDR) is a major obstacle in effective chemotherapy for cancer patients. The expression of P-glycoprotein (P-gp) in cancer cells is highly correlated with resistance to chemotherapeutic drugs. (−)-Antofine, a phenanthroindolizidine alkaloid derived from Cynanchum paniculatum, inhibits the growth of various human cancer cells. In this study, we further explored the potential of (−)-antofine to overcome the resistance induced by anti-cancer drugs. To this end, we established the paclitaxel-resistant human lung cancer cell line A549-PA by gradually exposing A549 cells to increasing concentrations of paclitaxel. As a result, the A549-PA cells acquired resistance against paclitaxel treatment and had an IC50 that was more than 200 times that of the parental A549 cells. (−)-Antofine, however, effectively suppressed the growth of both the parental and drug-resistant cells. Additional studies revealed that the anti-proliferative activity of (−)-antofine in A549-PA cells is accompanied by a down-regulation of P-gp mRNA and protein expression. The effect of reversing the multidrug resistance of A549-PA cells via (−)-antofine treatment was demonstrated an increase in intracellular rhodamine-123 accumulation, measured using FACS analysis. These findings suggest an additional chemotherapeutic value of (−)-antofine, that is, regulation of cancer cell drug resistance, in addition to its antitumor effect. [Copyright &y& Elsevier]

The rhizomes and roots of Valeriana fauriei were extracted and the major essential oil composition and immunotoxicity effects were studied. The analyses were conducted by gas chromatography--mass spectroscopy (GC-MS) revealed that the essential oils of V. fauriei. The V. fauriei essential oil (VFEO) yield was 1.93%, and GC/MS analysis revealed that its major constituents were bornyl acetate (32.83%), terpinyl acetate (3.82%), bornyl isovalerate (2.11%), ββ-sesquiphellandrene (2.21%), sesquiterpene alcohol (7.32%), and cedrol (2.45%). The essential oil had a significant toxic effect against early fourth-stage larvae of Aedes aegypti L with an LC50 value of 30.44 ppm and an LC90 value of 82.64 ppm. The results could be useful in search for newer, safer, and more effective natural immunotoxicity agents against Aedes aegypti L. [ABSTRACT FROM AUTHOR]

Abstract: The present study evaluated the antidiabetic effects from phenolic extracts of three varieties (Hwanggeumchal sorghum, Chal sorghum, and Heuin sorghum) from Korean sorghum (Sorghum bicolor L. Monech) in normal and streptozotocin-induced diabetic rats. Hwanggeumchal sorghum phenolic extracts in the streptozotocin-induced diabetic rats showed significant hypoglycemic activity for 14days and significantly decreased the serum glucose, total cholesterol, triglycerides, urea, uric acid, creatinine, aspartate amino transferase and alanine amino transferase while it increased the serum insulin in diabetic rats but not in normal rats (p <0.05) (at doses of 100 and 250mg/kg for 14days). A comparison was made between the action of Hwanggeumchal sorghum phenolic extracts and glibenclamide (600μg/kg), a known antidiabetic drug. Twenty-four of the 29 phenolic components monitored were detected by high performance liquid chromatography. The antidiabetic effect of the Hwanggeumchal sorghum phenolic extracts was similarly effective with that observed with glibenclamide. Phenolic components were analyzed using high performance liquid chromatography, and a total of 29 phenolic components were detected in the Korean sorghum studied. The relationships of antidiabetic effects and phenolic components of Hwanggeumchal sorghum phenolic extracts were significantly higher than that of Chal sorghum and Heuin sorghum phenolic extracts. [ABSTRACT FROM AUTHOR]

Abstract: We present the nucleation and growth mode of crystalline ITO (c-ITO) on polymeric substrates. Crystallinity is known to be one of the most important factors that determine the functional and structural properties of ITO coated as electrodes. We sputter–deposit ITO on polymeric substrates at low temperatures varying deposition conditions. The thermal energy supplied from a heated substrate during deposition or from thermal annealing is known to be as important as deposition parameters to make the growth of high quality c-ITO possible. However, raising temperatures of the polymeric substrates is quite limited due to low glass transition temperatures (T g). The nucleation and growth patterns of c-ITO from amorphous ITO (a-ITO) are observed using high resolution transmission electron microscopy (HR TEM) and are compared with those on Si or glass substrates that were reported by others. The sheet resistance (R s) of ITO is also measured and the relationship to the microstructures is investigated. Our results reveal that crystallites are nucleated on growing surfaces of a-ITO and grow with little interruption to be columnar grains in ITO on the polymeric substrates. This is different from the random nucleation and competitive growth mode of columnar grains from the interface with Si or glass substrates at similar deposition conditions. The lattice distortion in ITO due to mismatches in physical and chemical properties with the substrate is more severe on polymers than on Si or glasses, which seems to be one of the potential reasons that the ITO between the interface and columnar grains remains mostly amorphous. [Copyright &y& Elsevier]