Visceral Adipose Tissue Reduction Measured by Deep Neural Network Architecture Improved Reflux Esophagitis Endoscopic Grade.

INTRODUCTION: Visceral obesity is a risk factor for reflux esophagitis (RE). We investigated the risk of RE according to visceral adipose tissue (VAT) measured by deep neural network architecture using computed tomography (CT) and evaluated the longitudinal association between abdominal adipose tissue changes and the disease course of RE. METHODS: Individuals receiving health checkups who underwent esophagogastroduodenoscopy (EGD) and abdominal CT at Seoul National University Healthcare System Gangnam Center between 2015 and 2016 were included. Visceral and subcutaneous adipose tissue areas and volumes were measured using a deep neural network architecture and CT. The association between the abdominal adipose tissue area and volume and the risk of RE was evaluated. Participants who underwent follow-up EGD and abdominal CT were selected; the effects of changes in abdominal adipose tissue area and volume on RE endoscopic grade were investigated using Cox proportional hazards regression. RESULTS: We enrolled 6,570 patients who underwent EGD and abdominal CT on the same day. RE was associated with male sex, hypertension, diabetes, excessive alcohol intake, current smoking status, and levels of physical activity. The VAT area and volume increased the risk of RE dose-dependently. A decreasing VAT volume was significantly associated with improvement in RE endoscopic grade (hazard ratio: 3.22, 95% confidence interval: 1.82-5.71). Changes in subcutaneous adipose tissue volume and the disease course of RE were not significantly correlated. DISCUSSION: Visceral obesity is strongly associated with RE. VAT volume reduction was prospectively associated with improvement in RE endoscopic grade dose-dependently. Visceral obesity is a potential target for RE treatment.

Development and validation of a convolutional neural network model for diagnosing Helicobacter pylori infections with endoscopic images: a multicenter study.

BACKGROUND AND AIMS: Insufficient validation limits the generalizability of deep learning in diagnosing Helicobacter pylori infection with endoscopic images. The aim of this study was to develop a deep learning model for the diagnosis of H pylori infection using endoscopic images and validate the model with internal and external datasets. METHODS: A convolutional neural network (CNN) model was developed based on a training dataset comprising 13,403 endoscopic images from 952 patients who underwent endoscopy at Seoul National University Hospital Gangnam Center. Internal validation was performed using a separate dataset comprised of images of 411 individuals of Korean descent and 131 of non-Korean descent. External validation was performed with the images of 160 patients in Gangnam Severance Hospital. Gradient-weighted class activation mapping was performed to visually explain the model. RESULTS: In predicting H pylori ever-infected status, the sensitivity, specificity, and accuracy of internal validation for people of Korean descent were .96 (95% confidence interval [CI], .93-.98), .90 (95% CI, .85-.95), and .94 (95% CI, .91-.96), respectively. In the internal validation for people of non-Korean descent, the sensitivity, specificity, and accuracy in predicting H pylori ever-infected status were .92 (95% CI, .86-.98), .79 (95% CI, .67-.91), and .88 (95% CI, .82-.93), respectively. In the external validation cohort, sensitivity, specificity, and accuracy were .86 (95% CI, .80-.93), .88 (95% CI, .79-.96), and .87 (95% CI, .82-.92), respectively, when performing 2-group categorization. Gradient-weighted class activation mapping showed that the CNN model captured the characteristic findings of each group. CONCLUSIONS: This CNN model for diagnosing H pylori infection showed good overall performance in internal and external validation datasets, particularly in categorizing patients into the never- versus ever-infected groups.

Is spiritual well-being related to survival time of inpatients with advanced cancer? An East Asian cohort study.

OBJECTIVES: It has been suggested that psychosocial factors are related to survival time of inpatients with cancer. However, there are not many studies examining the relationship between spiritual well-being (SWB) and survival time among countries. This study investigated the relationship between SWB and survival time among three East Asian countries. METHODS: This international multicenter cohort study is a secondary analysis involving newly admitted inpatients with advanced cancer in palliative care units in Japan, South Korea, and Taiwan. SWB was measured using the Integrated Palliative Outcome Scale (IPOS) at admission. We performed multivariate analysis using the Cox proportional hazards model to identify independent prognostic factors. RESULTS: A total of 2,638 patients treated at 37 palliative care units from January 2017 to September 2018 were analyzed. The median survival time was 18.0 days (95% confidence interval [CI] 16.5-19.5) in Japan, 23.0 days (95% CI 19.9-26.1) in Korea, and 15.0 days (95% CI 13.0-17.0) in Taiwan. SWB was a significant factor correlated with survival in Taiwan (hazard ratio [HR] 1.27; 95% CI 1.01-1.59; p = 0.04), while it was insignificant in Japan (HR 1.10; 95% CI 1.00-1.22; p = 0.06), and Korea (HR 1.02; 95% CI 0.77-1.35; p = 0.89). SIGNIFICANCE OF RESULTS: SWB on admission was associated with survival in patients with advanced cancer in Taiwan but not Japan or Korea. The findings suggest the possibility of a positive relationship between spiritual care and survival time in patients with far advanced cancer.

Small sessile serrated polyps might not be at a higher risk for future advanced neoplasia than low-risk adenomas or polyp-free groups.

BACKGROUND: Polypectomy surveillance colonoscopy is recommended according to the risk stratification of initially removed polyps. This study aimed to evaluate the risk of advanced neoplasia following low-risk SSPs compared with that following LRAs and polyp-free groups. MATERIALS AND METHODS: From September 2013 to August 2017, asymptomatic Koreans aged 50-75 years who underwent surveillance colonoscopy post-baseline colonoscopy were enrolled. The 1314 participants who met the study design criteria were stratified into three groups according to the presence of LRAs or low-risk SSPs. The rate of advanced neoplasia was then compared between groups by surveillance colonoscopy. RESULTS: A total of 1314 participants were classified according to baseline colonoscopy findings: no polyp (n = 551), LRA (n = 707), and low-risk SSP (n = 56). All participants underwent surveillance colonoscopy after an average of 28.1 ± 8.7 months. The rate of advanced neoplasia at surveillance was not different between groups: no polyp group (13/551, 2.4%), LRA group (27/707, 3.8%), and low-risk SSP group (0/56, 0%). The LRA group exhibited a significantly higher rate of low- and high-risk polyps (47.5, 13.4%) than did the no polyp (35.6, 7.4%, p < .001, p = .001), but no significant differences to the low-risk SSP group (35.7, 7.1%, p = .117, p = .253), respectively. CONCLUSIONS: Patients with low-risk SSPs were not at a higher risk of advanced neoplasia than LRA patients, even in the polyp-free group. We suggest that surveillance colonoscopy after the removal of low-risk SSPs is not required more often than for LRAs.

Impact of comprehensive optical diagnosis training using Workgroup serrAted polypS and Polyposis classification on detection of adenoma and sessile serrated lesion.

OBJECTIVES: Many interventions have been attempted to improve adenoma detection rate (ADR) and sessile serrated lesion detection rate (SDR), and one of these interventions is educational training to recognize polyp characteristics. This study aimed to investigate the change in polyp detection rates of endoscopists before and after comprehensive training through the Gangnam-Real Time Optical Diagnosis (Gangnam-READI) program. METHODS: Fifteen gastroenterologists participated in a 1-year comprehensive training program that consisted of ex vivo and in vivo training that encompasses knowledge and skills in endoscopic characterization of colonic polyps using the Workgroup serrAted polypS and Polyposis (WASP) classification. We evaluated the impact of the training program by comparing the overall and individual ADR and SDR 6 months before and after the training. RESULTS: Overall, 18,280 polyps (9337 adenomas and 855 sessile serrated lesion) were collected. The optical diagnosis training had no significant impact on the difference in ADR after training compared to before training (47.7% vs. 46.5%, P = 0.608). A tendency for a decrease in ADR variance was noted among the endoscopists after training (74.9 vs. 32.7, P = 0.121). The overall pre-training period SDR was 4.5% and showed a statistically significant increase to 5.6%, 8.0%, and 7.1% in the first and second half of the training period, and post-training period, respectively (P = 0.003). The optical diagnosis training did not decrease variance in SDR (8.9 vs. 8.8, P = 0.985). CONCLUSION: Comprehensive optical diagnosis training with WASP classification has a significant impact on increasing the overall SDR of expert endoscopists.

Comparison of Objective Prognostic Score and Palliative Prognostic Score performance in inpatients with advanced cancer in Japan and Korea.

OBJECTIVE: Accurate prognostication is important for patients and their families to prepare for the end of life. Objective Prognostic Score (OPS) is an easy-to-use tool that does not require the clinicians' prediction of survival (CPS), whereas Palliative Prognostic Score (PaP) needs CPS. Thus, inexperienced clinicians may hesitate to use PaP. We aimed to evaluate the accuracy of OPS compared with PaP in inpatients in palliative care units (PCUs) in three East Asian countries. METHOD: This study was a secondary analysis of a cross-cultural, multicenter cohort study. We enrolled inpatients with far-advanced cancer in PCUs in Japan, Korea, and Taiwan from 2017 to 2018. We calculated the area under the receiver operating characteristics (AUROC) curve to compare the accuracy of OPS and PaP. RESULTS: A total of 1,628 inpatients in 33 PCUs in Japan and Korea were analyzed. OPS and PaP were calculated in 71.7% of the Japanese patients and 80.0% of the Korean patients. In Taiwan, PaP was calculated for 81.6% of the patients. The AUROC for 3-week survival was 0.74 for OPS in Japan, 0.68 for OPS in Korea, 0.80 for PaP in Japan, and 0.73 for PaP in Korea. The AUROC for 30-day survival was 0.70 for OPS in Japan, 0.71 for OPS in Korea, 0.79 for PaP in Japan, and 0.74 for PaP in Korea. SIGNIFICANCE OF RESULTS: Both OPS and PaP showed good performance in Japan and Korea. Compared with PaP, OPS could be more useful for inexperienced physicians who hesitate to estimate CPS.

Evaluation of design, mechanical properties, and torque/force generation of heat-treated NiTi glide path instruments.

BACKGROUND: Recently, various kinds of heat-treated nickel-titanium (NiTi) glide path instruments have been manufactured. This study aimed to investigate design, phase transformation behavior, mechanical properties of TruNatomy Glider (#17/02), V Taper 2H (#14/03), and HyFlex EDM (#15/03) and compare torque/force generated during simulated glide path preparation with them. METHODS: The designs and phase-transformation behaviors of the instruments were examined via scanning electron microscopy (n = 3) and differential scanning calorimetry (n = 2). Their bending (n = 15), torsional (n = 15), and cyclic fatigue resistances (n = 15) were tested. The ultimate strength and distortion angle were obtained from torsional resistance test. The number of cycles to failure (NCF) was calculated from cyclic fatigue resistance test. The preparation of the glide path was simulated using a double-curved artificial canal (n = 15), and the maximum torque and screw-in forces were measured. Data except NCF was compared between brands with one-way ANOVA with Tukey's honestly significant difference test. NCF was analyzed via Kruskal-Wallis and Mann-Whitney U tests. RESULTS: TruNatomy Glider had the greatest number of threads. TruNatomy Glider showed progressive taper, while V Taper 2H and HyFlex EDM had constant taper. The austenitic transformation-finish temperatures of all the instruments were above body temperature. V Taper 2H demonstrated significantly lower ultimate strength, higher distortion angle, and a higher number of cycles to failure compared with HyFlex EDM and TruNatomy Glider (p < 0.05). The maximum torque generated during preparing glide path was lowest for V Taper 2H, and the maximum screw-in force was lowest for HyFlex EDM (p < 0.05). TruNatomy Glider generated the highest torque and screw-in force during the apical preparation. CONCLUSIONS: V Taper 2H #14/03 showed superior cyclic fatigue resistance and lower ultimate strength. TruNatomy Glider generated greater clockwise torque and screw-in force during apical preparation. The mechanical properties, torque, and screw-force was affected by design of heat-treated glide path instruments. Cervical pre-flaring prior to glide path instrument is recommended.

Improved Accuracy in Optical Diagnosis of Colorectal Polyps Using Convolutional Neural Networks with Visual Explanations.

BACKGROUND & AIMS: Narrow-band imaging (NBI) can be used to determine whether colorectal polyps are adenomatous or hyperplastic. We investigated whether an artificial intelligence (AI) system can increase the accuracy of characterizations of polyps by endoscopists of different skill levels. METHODS: We developed convolutional neural networks (CNNs) for evaluation of diminutive colorectal polyps, based on efficient neural architecture searches via parameter sharing with augmentation using NBIs of diminutive (≤5 mm) polyps, collected from October 2015 through October 2017 at the Seoul National University Hospital, Healthcare System Gangnam Center (training set). We trained the CNN using images from 1100 adenomatous polyps and 1050 hyperplastic polyps from 1379 patients. We then tested the system using 300 images of 180 adenomatous polyps and 120 hyperplastic polyps, obtained from January 2018 to May 2019. We compared the accuracy of 22 endoscopists of different skill levels (7 novices, 4 experts, and 11 NBI-trained experts) vs the CNN in evaluation of images (adenomatous vs hyperplastic) from 180 adenomatous and 120 hyperplastic polyps. The endoscopists then evaluated the polyp images with knowledge of the CNN-processed results. We conducted mixed-effect logistic and linear regression analyses to determine the effects of AI assistance on the accuracy of analysis of diminutive colorectal polyps by endoscopists (primary outcome). RESULTS: The CNN distinguished adenomatous vs hyperplastic diminutive polyps with 86.7% accuracy, based on histologic analysis as the reference standard. Endoscopists distinguished adenomatous vs hyperplastic diminutive polyps with 82.5% overall accuracy (novices, 73.8% accuracy; experts, 83.8% accuracy; and NBI-trained experts, 87.6% accuracy). With knowledge of the CNN-processed results, the overall accuracy of the endoscopists increased to 88.5% (P < .05). With knowledge of the CNN-processed results, the accuracy of novice endoscopists increased to 85.6% (P < .05). The CNN-processed results significantly reduced endoscopist time of diagnosis (from 3.92 to 3.37 seconds per polyp, P = .042). CONCLUSIONS: We developed a CNN that significantly increases the accuracy of evaluation of diminutive colorectal polyps (as adenomatous vs hyperplastic) and reduces the time of diagnosis by endoscopists. This AI assistance system significantly increased the accuracy of analysis by novice endoscopists, who achieved near-expert levels of accuracy without extra training. The CNN assistance system can reduce the skill-level dependence of endoscopists and costs.

Longer Withdrawal Time Is More Important than Excellent Bowel Preparation in Colonoscopy of Adequate Bowel Preparation.

BACKGROUND: Adequate bowel preparation is crucial for effective screening colonoscopy. However, it is unclear whether higher bowel preparation scores correspond to beneficial effects on the adenoma and polyp detection rate (ADR and PDR) in the adequate bowel preparation group. AIMS: This study aimed to evaluate the effects of bowel preparation, according to the Boston Bowel Preparation Scale (BBPS), and colonoscopy withdrawal time (CWT) on ADR and PDR in the adequate bowel preparation group. METHODS: Healthy examinees between 50 and 75 years old who underwent colonoscopy between September 2015 and August 2016 were included. BBPS scores, CWT, ADR, and PDR were reviewed retrospectively. Predictors of ADR and PDR were analyzed with a generalized linear mixed model. RESULTS: A total of 5073 cases with adequate bowel preparation (BBPS ≥ 6) were analyzed. Examinees with good (BBPS = 6, 7) and excellent (BBPS = 8, 9) bowel preparation were 1898 (37.4%) and 3175 (62.6%), respectively. Both ADR and PDR were higher in the good bowel preparation group than in the excellent bowel preparation group (ADR 47.3% vs. 45.0%, P = 0.035; PDR 73.7% vs. 69.5%, P = 0.004, respectively). In the multivariate analysis, CWT, rather than BBPS, was significantly associated with both ADR (OR 1.04; 95% CI 1.02-1.06; P < 0.001) and PDR (OR 1.05; 95% CI 1.02-1.07; P = 0.002). CONCLUSIONS: Both ADR and PDR were lower when bowel preparation was excellent rather than good. However, CWT, not BBPS, was significantly associated with ADR and PDR in the adequate bowel preparation group. Therefore, meticulous inspection is important for high-quality colonoscopy regardless of the BBPS score in examinees with adequate bowel preparation.

Factors related to spiritual well-being in the last days of life in three East Asian countries: An international multicenter prospective cohort study.

BACKGROUND: Some factors associated with spiritual well-being in dying patients have previously been reported. However, there has been no cross-cultural study comparing factors related to spiritual well-being. The current investigation may shed light on this under-investigated area through a comparison of diverse factors. AIM: We aimed to (1) examine factors associated with spiritual well-being in the last days and (2) compare those factors across three East Asian countries. DESIGN: This is an international multicenter prospective cohort study. SETTING/PARTICIPANTS: Newly admitted inpatients with far advanced cancer in palliative care units in Japan, Korea and Taiwan were enrolled. Each patient was classified into one of two groups based on spiritual well-being score in the last days of life. Univariate and multivariate analyses were performed to identify the factors related to better spiritual well-being score in each country. RESULTS: A total of 1761 patients treated at 37 palliative care units from January 2017 to September 2018 were analyzed. Seven variables were significant in Japan, three in Korea, and five in Taiwan. "Good death scale [acceptance]," "fatigue" and "expressed wish for hastened death" were unique in Japan. "Visit from a pastoral care worker within 48 h of death" was unique in Korea. "Patient's preferences for place of death," "dyspnea" and "continuous deep sedation" were unique in Taiwan. CONCLUSIONS: This study found novel factors related to spiritual well-being in the last days of life, several of which differed according to country. Recognition of factors associated with spiritual well-being can improve the quality of palliative care.

Multidirectional Colonoscopy Quality Improvement Increases Adenoma Detection Rate: Results of the Seoul National University Hospital Healthcare System Gangnam Center Colonoscopy Quality Upgrade Project (Gangnam-CUP).

BACKGROUND: To prevent colorectal cancer, high-quality colonoscopy is advocated, undertaken by endoscopists with high adenoma detection rates (ADRs). Despite reports that various factors may impact ADRs, the significance of such factors is still unclear. AIMS: The analysis was aimed at quality-oriented interventions for boosting ADRs. METHODS: Study enrollees were adults subjected to screening colonoscopy between September 2013 and August 2016 at the Gangnam Center of Seoul National University Hospital Healthcare System. The investigation entailed six periods (P1-6) of 6 months each, during which serial multidirectional quality improvement efforts were instituted. In particular, we sought to further educate endoscopists, provide feedback on individual ADRs, and introduce a split-dose regimen, gauging results via the Boston Bowel Preparation Score. Changes in polyp detection rates (PDRs) and ADRs were then analyzed. RESULTS: A total of 13,430 colonoscopies were undertaken by 15 experienced endoscopists. Overall, the ADR increased from 45.6% (P1) to 48.2% (P6, p < 0.001). The PDR, ADR, and advanced adenoma detection rate (AdvADR) showed the greatest increases between P3 and P4 [PDR 67.8% → 71.2% (p < 0.001); ADR 44.1% → 47.7% (p = 0.001); AdvADR 2.3% → 3.3% (p = 0.028)] in keeping with the introduction of a split-dose regimen. The sessile serrated adenoma detection rate (SSADR) increased substantially from 2.1% (P1) to 7.9% (P6, p < 0.001), with the largest gain between P1 and P2, just after education (p = 0.023). CONCLUSIONS: Successful quality improvement in colonoscopy was achieved through comprehensive multidirectional efforts in education, feedback, and enhanced bowel preparation. Achieving high-level bowel preparation was paramount in ADR improvement. The SSADR was improved through education.

Improved Real-Time Optical Diagnosis of Colorectal Polyps Following a Comprehensive Training Program.

BACKGROUND & AIMS: The optimal training method for endoscopic characterization of colorectal polyps using narrow-band imaging is uncertain, and sessile serrated lesions (SSLs) optical diagnosis data are lacking. We aimed to evaluate a comprehensive training program for real-time optical diagnosis of colorectal polyps, including SSLs. METHODS: We performed a single-institution prospective study of 15 endoscopists trained with the Workgroup Serrated Polyps and Polyposis classification system. After the first phase of in vivo optical diagnosis, their performances were evaluated. After re-education for insufficient competency, they began the second phase. The learning curves and performance on 2 preservation and incorporation of valuable endoscopic innovations benchmarks were assessed. RESULTS: A total of 7294 polyps, including 486 SSLs, were diagnosed in real-time. The overall accuracy improved from 73.5% in the first phase to 77.1% in the second. The accuracy with high confidence was 79.4% and 85.1% in the first and second phases, respectively. In the first and second phases, the negative predictive values for diminutive neoplastic polyps were 82.1% and 92.5%, respectively, and concordances of the surveillance intervals were 80.7% and 89.7%, respectively. Eight endoscopists achieved the preservation and incorporation of valuable endoscopic innovations benchmarks after the second phase compared with none after the first. In contrast, the high confidence rate decreased from 74.6% to 70.2% as training progressed. CONCLUSION: A comprehensive training program for real-time optical diagnosis significantly improved performance and reduced individual variability in less-experienced endoscopists. ClinicalTrials.gov no: NCT02516748.

Chronophin coordinates cell leading edge dynamics by controlling active cofilin levels.

Cofilin, a critical player of actin dynamics, is spatially and temporally regulated to control the direction and force of membrane extension required for cell locomotion. In carcinoma cells, although the signaling pathways regulating cofilin activity to control cell direction have been established, the molecular machinery required to generate the force of the protrusion remains unclear. We show that the cofilin phosphatase chronophin (CIN) spatiotemporally regulates cofilin activity at the cell edge to generate persistent membrane extension. We show that CIN translocates to the leading edge in a PI3-kinase-, Rac1-, and cofilin-dependent manner after EGF stimulation to activate cofilin, promotes actin free barbed end formation, accelerates actin turnover, and enhances membrane protrusion. In addition, we establish that CIN is crucial for the balance of protrusion/retraction events during cell migration. Thus, CIN coordinates the leading edge dynamics by controlling active cofilin levels to promote MTLn3 cell protrusion.

Soybean-Derived Phytoalexins Improve Cognitive Function through Activation of Nrf2/HO-1 Signaling Pathway.

As soy-derived glyceollins are known to induce antioxidant enzymes in various types of cells and tissues, we hypothesized that the compounds could protect neurons from damage due to reactive oxygen species (ROS). In order to examine the neuroprotective effect of glyceollins, primary cortical neurons collected from mice and mouse hippocampal HT22 cells were challenged with glutamate. Glyceollins attenuated glutamate-induced cytotoxicity in primary cortical neuron isolated from mice carrying wild-type nuclear factor (erythroid-derived 2)-like 2 (Nrf2), but the compounds were ineffective in those isolated from Nrf2 knockout mice, suggesting the involvement of the Nrf2 signaling pathway in glyceollin-mediated neuroprotection. Furthermore, the inhibition of heme oxygenase-1 (HO-1), a major downstream enzyme of Nrf2, abolished the suppressive effect of glyceollins against glutamate-induced ROS production and cytotoxicity, confirming that activation of HO-1 by glyceollins is responsible for the neuroprotection. To examine whether glyceollins also improve cognitive ability, mice pretreated with glyceollins were challenged with scopolamine and subjected to behavioral tests. Glyceollins attenuated scopolamine-induced cognitive impairment of mice, but failed to enhance memory in Nrf2 knockout mice, suggesting that the memory-enhancing effect is also mediated by the Nrf2 signaling pathway. Overall, glyceollins showed neuroprotection against glutamate-induced damage, and attenuated scopolamine-induced memory deficits in an Nrf2-dependent manner.

Anthraquinones from Morinda longissima and their insulin mimetic activities via AMP-activated protein kinase (AMPK) activation.

AMP-activated protein kinase (AMPK) activators are known to increase energy metabolism and to reduce body weight, as well as to improve glucose uptake. During for searching AMPK activators, a new anthraquinone, modasima A (10), along with eighteen known analogues (1-9 and 11-19) were isolated from an ethanol extract of the roots of Morinda longissima Y. Z. Ruan (Rubiaceae). Using the fluorescent tagged glucose analogues, 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxy-D-glucose (2-NBDG), insulin mimetics were screened with compounds 1-19 in 3T3-L1 adipocytes. Among them, compounds 2, 8 and 10 enhanced significantly glucose uptake into adipocytes and up-regulated the phosphorylated AMPK (Thr172) whereas the glucose uptake enhancing activities of compounds 2, 8 and 10 were abrogated by treatment of compound C, an AMPK inhibitor. Taken together, these anthraquinones showed the potential action as insulin mimetic to improve glucose uptake via activation of AMPK.

Andrographolide Activates Keap1/Nrf2/ARE/HO-1 Pathway in HT22 Cells and Suppresses Microglial Activation by Aß42 through Nrf2-Related Inflammatory Response.

Therapeutic approach of Alzheimer's disease (AD) has been gradually diversified. We examined the therapeutic and preventive potential of andrographolide, which is a lactone diterpenoid from Andrographis paniculata, and focused on the Kelch-like ECH-associated protein 1 (Keap1)/nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-mediated heme oxygenase (HO)-1-inducing effects and the inhibitory activity of amyloid beta (Aß)42-induced microglial activation related to Nrf2 and nuclear factor κB (NF-κB)-mediated inflammatory responses. Andrographolide induced the expression and translocation of Nrf2 from the cytoplasm to the nucleus, thereby activating antioxidant response element (ARE) gene transcription and HO-1 expression in murine hippocampal HT22 cells. Andrographolide eliminated intracellular Aß42 in BV-2 cells and decreased the production of interleukin (IL)-6, IL-1ß, prostaglandin (PG)E2, and nitric oxide (NO) because of artificial phagocytic Aß42. It decreased pNF-κB accumulation in the nucleus and the expression of inducible nitric oxide synthase (i-NOS) and cyclooxygenase II (COX-II) in the microglial BV-2 cell line. In summary, andrographolide activates Nrf2-mediated HO-1 expression and inhibits Aß42-overexpressed microglial BV-2 cell activation. These results suggested that andrographolide might have the potential for further examination of the therapeutics of AD.

Alantolactone and Isoalantolactone Prevent Amyloid ß25-35 -induced Toxicity in Mouse Cortical Neurons and Scopolamine-induced Cognitive Impairment in Mice.

Given the evidence for detoxifying/antioxidant enzyme-inducing activities by alantolactone (AL) and isoalantolactone (IAL), the purpose of this study was to investigate the effects of AL and IAL on Aß25-35 -induced cell death in mouse cortical neuron cells and to determine their effects on scopolamine-induced amnesia in mice. Our data demonstrated that both compounds effectively attenuated the cytotoxicity of Aß25-35 (10 µM) in neuronal cells derived from the mouse cerebral cortex. It was also found that the production of intracellular reactive oxygen species, including superoxide anion induced by Aß25-35 , was inhibited. Moreover, the administration of the sesquiterpenes reversed scopolamine-induced cognitive impairments as assessed by Morris water, Y-maze, and the passive avoidance tests, and the compounds decreased acetylcholinesterase (AChE) activities in a dose-dependent manner. Interestingly, AL and IAL did not improve scopolamine-induced cognitive deficit in Nrf2-/- mice, suggesting that memory improvement by sesquiterpenes was mediated not only by the activation of the Nrf2 signaling pathway but also by their inhibitory activity against AChE. In conclusion, our results showed that AL and IAL had neuroprotective effects and reversed cognitive impairments induced by scopolamine in a mouse model. Therefore, AL and IAL deserve further study as potential therapeutic agents for reactive oxygen species-related neurodegenerative diseases. Copyright © 2017 John Wiley & Sons, Ltd.

Clinical outcomes of re-stenting in patients with stent malfunction in malignant gastric outlet obstruction.

BACKGROUND AND AIMS: Self-expanding metal stents (SEMS) have been used for the palliative treatment of malignant gastric outlet obstruction (GOO). The aim of this study was to evaluate the clinical outcomes of salvage SEMS for stent malfunction and to identify the prognostic factors for a longer patency. METHODS: A total of 108 patients who underwent a secondary salvage SEMS placement for a primary stent malfunction were retrospectively reviewed at the Seoul National University Hospital between August 2004 and May 2013. The duration of patency for salvage SEMS was defined as the time between salvage SEMS placement and the recurrence of obstructive symptoms that were confirmed either endoscopically or radiologically. RESULTS: The technical and clinical success rates for salvage SEMS were 100 and 82.4% (95% confidence interval [CI] 74.0-89.0), respectively. A salvage SEMS malfunction occurred in 29 (26.9%) of the 108 patients. The median duration of patency for salvage SEMS was 59.5 days (range 3-928, 95% CI 73.7-118.3). Longer SEMS patencies of more than 60 days were significantly associated with palliative chemotherapy (odds ratio = 2.539, 95% CI 1.031-6.252, p = .043). For salvage SEMS, covered-uncovered stents had a longer patency duration, as compared with other combinations of primary and salvage stent types. CONCLUSIONS: Longer patency durations for salvage SEMS were associated with palliative chemotherapy after salvage SEMS insertion. Salvage SEMS could be a feasible and effective treatment for primary stent malfunction in malignant GOO.

Nimbolide Inhibits Nuclear Factor-КB Pathway in Intestinal Epithelial Cells and Macrophages and Alleviates Experimental Colitis in Mice.

Nimbolide is a limonoid extracted from neem tree (Azadirachta indica) that has antiinflammatory properties. The effect of nimbolide on the nuclear factor-kappa B (NF-κB) pathway in intestinal epithelial cells (IECs), macrophages and in murine colitis models was investigated. The IEC COLO 205, the murine macrophage cell line RAW 264.7, and peritoneal macrophages from interleukin-10-deficient (IL-10-/- ) mice were preconditioned with nimbolide and then stimulated with tumor necrosis factor-α (TNF-α) or lipopolysaccharide. Dextran sulfate sodium-induced acute colitis model and chronic colitis model in IL-10-/- mice were used for in vivo experiments. Nimbolide significantly suppressed the expression of inflammatory cytokines (IL-6, IL-8, IL-12, and TNF-α) and inhibited the phosphorylation of IκBα and the DNA-binding affinity of NF-κB in IECs and macrophages. Nimbolide ameliorated weight loss, colon shortening, disease activity index score, and histologic scores in dextran sulfate sodium colitis. It also improved histopathologic scores in the chronic colitis of IL-10-/- mice. Staining for phosphorylated IκBα was significantly decreased in the colon tissue after treatment with nimbolide in both models. Nimbolide inhibits NF-κB signaling in IECs and macrophages and ameliorates experimental colitis in mice. These results suggest nimbolide could be a potentially new treatment for inflammatory bowel disease. Copyright © 2016 John Wiley & Sons, Ltd.

Anti-Neuroinflammatory ent-Kaurane Diterpenoids from Pteris multifida Roots.

Activated microglia are known to be a major source of cellular neuroinflammation which causes various neurodegenerative diseases, including Alzheimer's disease. In our continuing efforts to search for new bioactive phytochemicals against neuroinflammatory diseases, the 80% methanolic extract of Pteris multifida (Pteridaceae) roots was found to exhibit significant NO inhibitory activity in lipopolysaccharide (LPS)-activated BV-2 microglia cells. Three new ent-kaurane diterpenoids, pterokaurane M1 2-O-ß-d-glucopyranoside (4), 2ß,16α-dihydroxy-ent-kaurane 2,16-di-O-ß-d-glucopyranoside (10), and 2ß,16α,17-trihydroxy-ent-kaurane 2-O-ß-d-glucopyranoside (12), were isolated along with nine other known compounds from P. multifida roots. The chemical structures of the new compounds were determined by 1D- and 2D-NMR, HR-ESI-MS, and CD spectroscopic data analysis. Among the isolates, compounds 1 and 7 significantly inhibited NO production in LPS-stimulated BV-2 cells reducing the expression of the cyclooxygenase-2 (COX-2) protein and the level of pro-inflammatory mediators such as prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6. These results suggest that ent-kaurane diterpenes from P. multifida could be potential lead compounds that act as anti-neuroinflammatory agents.