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The use of Clinical Data Warehouse (CDW) for research and quality improvement has become more frequent in the last 10 years. In this study, we used CDW to determine the effectiveness of pressure ulcer interventions offered by ward nurses and wound care nursing specialists. A retrospective clinical outcomes study that utilise CDW has been carried out. We identified 1415 patients who were evaluated as pressure ulcer risk group from 1 July 2019 to 31 December 2019. Kaplan-Meier survival analyses were used to estimate the time to occurrence of pressure ulcers. We compared the survival curves of each group by applying the log-rank test for significance. The overall median time to occurrence for both groups was 13 days (95% CI range: 11-14 days). The control group showed a longer median time (14 days) to occurrence than the case group (12 days). In the pressure ulcer stage I, the case group showed a longer median time (14 days) to occurrence than the control group (8 days), indicating that the intervention provided by the wound care nursing specialist was effective in stage I, and delayed the occurrence of pressure ulcers. The findings may be used as preliminary data for the utilisation of the CDW in the field of nursing research in the future. Also, facilitating the accessibility of the wound care nursing specialist in the general wards should be effective to decrease the incidence rates.

Neuronal cell death has been well acknowledged as the primary pathological basis underlying developmental neurotoxicity following sevoflurane exposure, whereas the exact mechanism remains elusive. Ferroptosis is a programmed cell death featured by iron-dependent lipid peroxidation that is driven by hydrogen peroxide (H2O2) and ferrous iron through Fenton reaction, and participates in the pathogenesis of multiple neurological diseases. As stress response factor, activating transcription factor 3 (ATF3) can be activated by PERK/ATF4-mediated pathway during endoplasmic reticulum (ER) stress and followed by increased intracellular H2O2, which is involved in regulation of apoptosis, autophagy and ferroptosis. Here, we investigated whether ferroptosis and ATF3 activation are implicated in sevoflurane-triggered neuronal cell death in the developing brain. Results showed that sevoflurane exposure induced neuronal death as a result of iron-dependent lipid peroxidation damage secondary to H2O2 accumulation and ferrous iron increase, which was consistent with the criteria for ferroptosis. Furthermore, we observed that increases of iron and H2O2 induced by sevoflurane exposure were associated with the upregulation and nuclear translocation of ATF3 in response to ER stress. Knockdown of ATF3 expression alleviated iron-dependent lipid peroxidation, which prevented sevoflurane-triggered neuronal ferroptosis. Mechanistically, ATF3 promoted sevoflurane-induced H2O2 accumulation through activating NOX4 and suppressing catalase, GPX4 and SLC7A11. Additionally, we detected that increase of H2O2 was accompanied with upregulation of TFR and TF and downregulation of FPN which linked the iron overload to ferroptosis triggered by sevoflurane. Taken together, our results demonstrated ER stress-mediated ATF3 activation contributes to sevoflurane-induced neuronal ferroptosis via H2O2 accumulation and resultant iron overload.

BACKGROUND There has been growing public interest in maintaining personal health and preventing diseases through the adoption of healthy lifestyles. Within this paradigm, physical activity (PA) prescriptions are critical in facilitating healthy habits after undergoing health examinations. OBJECTIVE This study aimed to construct PA prediction models using clinical biomarkers that are commonly measured in clinical practice. METHODS We used the data from patients aged ≥20 years who underwent routine health screening in Korea from January 2021 to December 2021. Prediction models based on several machine learning algorithms, such as random forest classification, bagged decision trees, and gradient boosting (GB), were established. RESULTS A total of 30,769 patients who met the inclusion criteria were analyzed in the study. Of them, 13,653 were men and 17,116 were women. The prediction models using the GB algorithm exhibited the best performance, in particular, the GB-based models with female data only, with accuracy values close to or greater than 0.8. For these prediction models, the area under the receiver operating characteristic curve value was greater than 0.8, indicating high discrimination ability. For the PA assessment, the features that were most influential included the estimated glomerular filtration rate (eGFR), fasting blood sugar (FBS) level, serum creatinine (SCr) level, aspartate aminotransferase level, and alanine aminotransferase level. For the type of PA, the most influential features were weight, height, hemoglobin, FBS level, and high-density lipoprotein cholesterol level. For the weekly frequency of PA, the most influential features were eGFR, SCr level, height, FBS level, and weight. CONCLUSIONS The methodology used in this study can contribute to the provision of PA prescriptions using clinical biomarkers. Furthermore, it can be used as a supplementary tool for quantitatively measuring the effects of lifestyle and motivating patients to maintain healthy lifestyles.

FOXO3a (forkhead box transcription factor 3a) is involved in regulating multiple biological processes in cancer cells. BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a receptor accounting for priming damaged mitochondria for autophagic removal. In this study we investigated the role of FOXO3a in regulating the sensitivity of glioma cells to temozolomide (TMZ) and its relationship with BNIP3-mediated mitophagy. We showed that TMZ dosage-dependently inhibited the viability of human U87, U251, T98G, LN18 and rat C6 glioma cells with IC50 values of 135.75, 128.26, 142.65, 155.73 and 111.60 μM, respectively. In U87 and U251 cells, TMZ (200 μM) induced DNA double strand breaks (DSBs) and nuclear translocation of apoptosis inducing factor (AIF), which was accompanied by BNIP3-mediated mitophagy and FOXO3a accumulation in nucleus. TMZ treatment induced intracellular ROS accumulation in U87 and U251 cells via enhancing mitochondrial superoxide, which not only contributed to DNA DSBs and exacerbated mitochondrial dysfunction, but also upregulated FOXO3a expression. Knockdown of FOXO3a aggravated TMZ-induced DNA DSBs and mitochondrial damage, as well as glioma cell death. TMZ treatment not only upregulated BNIP3 and activated autophagy, but also triggered mitophagy by prompting BNIP3 translocation to mitochondria and reinforcing BNIP3 interaction with LC3BII. Inhibition of mitophagy by knocking down BNIP3 with SiRNA or blocking autophagy with 3MA or bafilomycin A1 exacerbated mitochondrial superoxide and intracellular ROS accumulation. Moreover, FOXO3a knockdown inhibited TMZ-induced BNIP3 upregulation and autophagy activation. In addition, we showed that treatment with TMZ (100 mg·kg−1·d−1, ip) for 12 days in C6 cell xenograft mice markedly inhibited tumor growth accompanied by inducing FOXO3a upregulation, oxidative stress and BNIP3-mediated mitophagy in tumor tissues. These results demonstrate that FOXO3a attenuates temozolomide-induced DNA double strand breaks in human glioma cells via promoting BNIP3-mediated mitophagy.

Metabolic syndrome (MS) is diagnosed using absolute criteria that do not consider age and sex, but most studies have shown that the prevalence of MS increases with age in both sexes. Thus, the evaluation of MS should consider sex and age. We aimed to develop a new index that considers the age and sex for evaluating an individual’s relative overall MS status. Data of 16,518,532 subjects (8,671,838 males and 7,846,694 females) who completed a validated health survey of the National Health Insurance Service of the Republic of Korea (2014‒2015) were analyzed to develop an MS-biological age model. Principal component score analysis using waist circumference, pulse pressure, fasting blood sugar, triglyceride levels, and high-density lipoprotein level, but not age, as independent variables were performed to derive an index of health status and biological age. In both sexes, the age according to the MS-biological age model increased with rising smoking and alcohol consumption habits and decreased with rising physical activity. Particularly, smoking and drinking affected females, whereas physical activity affected males. The MS-biological age model can be a supplementary tool for evaluating and managing MS, quantitatively measuring the effect of lifestyle changes on MS, and motivating patients to maintain a healthy lifestyle.

Although wearable electrocardiograms (ECGs) are being increasingly applied in clinical settings, validation methods have not been standardized. As an exploratory evaluation, we performed a multicenter clinical trial implementing an approved wearable patch ECG. Healthy male adults were enrolled in 2 study centers. The approved ECGs were deployed for 6 hours, and pulse rates were measured independently with conventional pulse oximetry at selected time points for correlation analyses. The transmission status of the data was evaluated by heart rates and classified into valid, invalid, and missing. A total of 55 subjects (40 in center 1 and 15 in center 2) completed the study. Overall, 77.40% of heart rates were within the valid range. Invalid and missing data accounted for 1.42% and 21.23%, respectively. There were significant differences in valid and missing data between centers. The proportion of missing data in center 1 (24.77%) was more than twice center 2 (11.77%). Heart rates measured by the wearable ECG and conventional pulse oximetry showed a poor correlation (intraclass correlation coefficient = 0.0454). In conclusion, we evaluated the multicenter feasibility of implementing wearable ECGs. The results suggest that systems to mitigate multicenter discrepancies and remove artifacts should be implemented prior to performing a clinical trial.ClinicalTrials.gov Identifier: NCT05182684.

BACKGROUND The analysis of the electrocardiogram (ECG) is critical for the diagnosis of arrhythmias. Recent advances in information and communications technology (ICT) have led to the development of wearable ECG devices. Accordingly, several patient monitoring systems have been proposed to automatically detect arrhythmia using wearable ECG data. OBJECTIVE This study aimed to develop an ICT-based clinical trial service platform using a self-reporting technique for real-time arrhythmia detection. METHODS A mobile application (app), used as an external network, a demilitarized zone (DMZ), an internal network, and Amazon web services virtual private cloud (AWS-VPC) were developed to establish a clinical trial service platform. RESULTS A single-channel, wearable ECG device was used on the platform. The acquired ECG data were transmitted to the mobile app, which collected the participants’ self-reported information. The mobile app transmitted raw ECG and self-reported data to the AWS-VPC and DMZ, respectively. In the AWS-VPC, the live streaming and playback reviewer services were operational to display the currently and previously acquired ECG data to clinicians through the web client. All the measured data were transmitted to the internal network, in which the arrhythmia detection algorithm was executed repeatedly. The entire data, including the raw ECG, arrhythmia detection results, and self-reported data, were saved. The interworking experiment showed that data transfer and saving were performed accurately without losses or delays. CONCLUSIONS An ICT-based clinical trial service platform was developed to detect eight types of arrhythmia from data obtained by a wearable ECG device. The information of multiple participants can be easily collected using a self-reporting technique. These features enable early diagnosis, which is particularly of critical importance for treating painless, sparsely occurring arrhythmias. This platform has the potential to be utilized in decentralized clinical trials, telemedicine services, and for monitoring other diseases. CLINICALTRIAL None

RSL3 is a type of small molecular compound which can inactivate glutathione peroxidase 4 (GPX4) and induce ferroptosis, but its role in glioma cell death remains unclear. In this study, we found RSL3 inhibited the viabilities of glioma cells and induced glioma cell death in a dose-dependent manner. In vitro studies revealed that RSL3-induced cell death was accompanied with the changes of autophagy-associated protein levels and was alleviated by pretreatment of 3-Methyladenine, bafilomycin A1 and knockdown of ATG5 with siRNA. The ATP and pyruvate content as well as the protein levels of HKII, PFKP, PKM2 were decreased in cells treated by RSL3, indicating that RSL3 induced glycolysis dysfunction in glioma cells. Moreover, supplement of exterior sodium pyruvate, which was a final product of glycolysis, not only inhibited the changes of autophagy-associated protein levels caused by RSL3, but also prevented RSL3-induced cell death. In vivo data suggested that the inhibitory effect of RSL3 on the growth of glioma cells was associated with glycolysis dysfunction and autophagy activation. Taken together, RSL3 induced autophagic cell death in glioma cells via causing glycolysis dysfunction.

Robotic systems are used to support inpatients and healthcare professionals and to improve the efficiency and quality of nursing. There is a lack of scientific literature on how applied robotic systems can be used to support inpatients. This study uses surveys and focus group interviews to identify the necessary aspects and functions of bedside robots for inpatients. A total of 90 healthcare professionals and 108 inpatients completed the questionnaire, and four physicians and five nurses participated in the focus group interviews. The most highly desired functionalities were related to patient care and monitoring, including alerting staff, measuring vital signs, and sensing falls. Nurses and physicians reported different needs for human-robot interaction. Nurses valued robotic functions such as nonverbal expression recognition, automatic movement, content suggestion, and emotional expressions. The results of the patients' open-ended questions and healthcare professionals' focus groups indicate that the purpose of the robots should primarily be treatment and nursing. Participants believe bedside robots would be helpful but have concerns regarding safety and utility. This study attempts to determine which aspects of robots may increase their acceptance. Our findings suggest that if robots are used in healthcare institutions, they may improve the effectiveness of care.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has been related to a series of harmful health consequences. The triglyceride-glucose index (TyG index) appears to be associated with MAFLD. However, no consistent conclusions about the TyG index and incident MAFLD have been reached. PubMed, MEDLINE, Web of Science, EMBASE and the Cochrane Library were searched. Sensitivities, specificities and the area under the receiver operating characteristic (AUC) with a random-effects model were used to assess the diagnostic performance of the TyG index in NAFLD/MAFLD participants. Potential threshold effects and publication bias were evaluated by Spearman’s correlation and Deeks’ asymmetry test, respectively. A total of 20 studies with 165725 MAFLD participants were included. The summary receiver operator characteristic (SROC) curve showed that the sensitivity, specificity and AUC were 0.73 (0.69–0.76), 0.67 (0.65, 0.70) and 0.75 (0.71–0.79), respectively. Threshold effects (r = 0.490, p < 0.05) were confirmed to exist. Subgroup analyses and meta-regression showed that some factors including country, number of samples, age and disease situation were the sources of heterogeneity (p < 0.05). Our meta-analysis suggests that the TyG index can diagnose and predict MAFLD patients with good accuracy. The number of studies remains limited, and prospective studies are needed.

Background Digital health care is an important strategy in the war against COVID-19. South Korea introduced living and treatment support centers (LTSCs) to control regional outbreaks and care for patients with asymptomatic or mild COVID-19. Seoul National University Hospital (SNUH) introduced information and communications technology (ICT)–based solutions to manage clinically healthy patients with COVID-19. Objective This study aims to investigate satisfaction and usability by patients and health professionals in the optimal use of a mobile app and wearable device that SNUH introduced to the LTSC for clinically healthy patients with COVID-19. Methods Online surveys and focus group interviews were conducted to collect quantitative and qualitative data. Results Regarding usability testing of the wearable device, perceived usefulness had the highest mean score of 4.45 (SD 0.57) points out of 5. Regarding usability of the mobile app, perceived usefulness had the highest mean score of 4.62 (SD 0.48) points out of 5. Regarding satisfaction items for the mobile app among medical professionals, the “self-reporting” item had the highest mean score of 4.42 (SD 0.58) points out of 5. In focus group interviews of health care professionals, hospital information system interfacing was the most important functional requirement for ICT-based COVID-19 telemedicine. Conclusions Improvement of patient safety and reduction of the burden on medical staff were the expected positive outcomes. Stability and reliability of the device, patient education, accountability, and reimbursement issues should be considered as part of the development of remote patient monitoring. In responding to a novel contagious disease, telemedicine and a wearable device were shown to be useful during a global crisis.

BACKGROUND The decrease in children’s vaccination rates resulted in outbreaks of vaccine-preventable diseases. Child vaccine hesitancy can occur due to the ongoing COVID-19 pandemic as we are going through a time of uncertainty. OBJECTIVE This study aimed to assess the efficacy of the “Child Vaccination Friend Chatbot” based on changes in the measurements of vaccination information, motivation, self-efficacy, and vaccination behavioral intention variables. METHODS From 30th Jan. 2020 to 15th Feb. 2020, a total of 65 people participated in the trial through online recruitment. The participants of this study were parents who were raising children from 0 to 35 months old and those whose children expected to be vaccinated within three months. Participants were randomly assigned to the experimental group (N=34) and the control group (N=31). During the 12 weeks of the research, the participants were provided with vaccination schedule reminder alarms, a real-time consultation messenger service, information about vaccinations, and motivation boosters. Also, vaccination information, motivation, self-efficacy, and vaccination behavioral intention variables were measured every four weeks. RESULTS The experimental group that used the chatbot scored higher for vaccination information, motivation, self-efficacy, and vaccination behavioral intention than the control group. Based on the results, it is assumed that the child vaccination chatbot provided useful and prompt information to parents raising children who needed to be vaccinated. The child vaccination chatbot increased vaccination motivation, self-efficacy, and vaccination rates by providing necessary information to parents. CONCLUSIONS This study provides evidence that chatbot can be used as a tool to promote immunization through the provision of reminders and real-time consultation messenger service during the global crisis.

BACKGROUND Digital health care is an important strategy in the war against COVID-19. South Korea introduced living and treatment support centers (LTSCs) to control regional outbreaks and care for patients with asymptomatic or mild COVID-19. Seoul National University Hospital (SNUH) introduced information and communications technology (ICT)–based solutions to manage clinically healthy patients with COVID-19. OBJECTIVE This study aims to investigate satisfaction and usability by patients and health professionals in the optimal use of a mobile app and wearable device that SNUH introduced to the LTSC for clinically healthy patients with COVID-19. METHODS Online surveys and focus group interviews were conducted to collect quantitative and qualitative data. RESULTS Regarding usability testing of the wearable device, perceived usefulness had the highest mean score of 4.45 (SD 0.57) points out of 5. Regarding usability of the mobile app, perceived usefulness had the highest mean score of 4.62 (SD 0.48) points out of 5. Regarding satisfaction items for the mobile app among medical professionals, the “self-reporting” item had the highest mean score of 4.42 (SD 0.58) points out of 5. In focus group interviews of health care professionals, hospital information system interfacing was the most important functional requirement for ICT-based COVID-19 telemedicine. CONCLUSIONS Improvement of patient safety and reduction of the burden on medical staff were the expected positive outcomes. Stability and reliability of the device, patient education, accountability, and reimbursement issues should be considered as part of the development of remote patient monitoring. In responding to a novel contagious disease, telemedicine and a wearable device were shown to be useful during a global crisis.

Induction of lethal autophagy has become a strategy to eliminate glioma cells, but it remains elusive whether autophagy contributes to cell death via causing mitochondria damage and nuclear translocation of apoptosis inducing factor (AIF). In this study, we find that silibinin induces AIF translocation from mitochondria to nuclei in glioma cells in vitro and in vivo, which is accompanied with autophagy activation. In vitro studies reveal that blocking autophagy with 3MA, bafilomycin A1 or by knocking down ATG5 with SiRNA inhibits silibinin-induced mitochondrial accumulation of superoxide, AIF translocation from mitochondria to nuclei and glioma cell death. Mechanistically, silibinin activates autophagy through depleting ATP by suppressing glycolysis. Then, autophagy improves intracellular H2O2 via promoting p53-mediated depletion of GSH and cysteine and downregulation of xCT. The increased H2O2 promotes silibinin-induced BNIP3 upregulation and translocation to mitochondria. Knockdown of BNIP3 with SiRNA inhibits silibinin-induced mitochondrial depolarization, accumulation of mitochondrial superoxide, and AIF translocation from mitochondria to nuclei, as well as prevents glioma cell death. Furthermore, we find that the improved H2O2 reinforces silibinin-induced glycolysis dysfunction. Collectively, autophagy contributes to silibinin-induced glioma cell death via promotion of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF.

Recent rapid development of medical and information technology has enabled the use of appropriate techniques for the delivery of healthcare. This project involved prediction of the meaning and structure of future health services, which are now commonly described through various keywords, without establishment of the concepts. The objectives of this study were to identify key concepts and values about future health services and to categorize the prediction of those from the perspectives of the concerned professionals using Q-methodology with 50 selected Q-statements. A total of 53 participants performed the Q-sort task using the 50 statements; collected data were analyzed using an associated program, pc-QUANL. Fifty Q-samples were selected to sort the concepts, and 53 professionals sorted the Q-samples. Six concepts were summarized, namely, the Optimistic Innovation Positive Type, Pessimistic Resistance to Technology-Driven Medicine Type, Intelligent Information Technology Centered Type, Bio-technology Centered Type, Personal Health Data Centered Type, and Customized Care Centered Type. The results could be used in the future design of consumer-centered health services. Advanced technology may accommodate the individual needs of different stakeholders and carve an ecosystem-wide suite of interacting complex adaptive systems.

Background Lack of time for exercise is common among office workers given their busy lives. Because of occupational restrictions and difficulty in taking time off, it is necessary to suggest effective ways for workers to exercise regularly. Sustaining lifestyle habits that increase nonexercise activity in daily life can solve the issue of lack of exercise time. Healthy Lifestyle Coaching Chatbot is a messenger app based on the habit formation model that can be used as a tool to provide a health behavior intervention that emphasizes the importance of sustainability and involvement. Objective This study aimed to assess the efficacy of the Healthy Lifestyle Coaching Chatbot intervention presented via a messenger app aimed at stair-climbing habit formation for office workers. Methods From February 1, 2018, to April 30, 2018, a total of 106 people participated in the trial after online recruitment. Participants were randomly assigned to the intervention group (n=57) or the control group (n=49). The intervention group received cues and intrinsic and extrinsic rewards for the entire 12 weeks. However, the control group did not receive intrinsic rewards for the first 4 weeks and only received all rewards as in the intervention group from the fifth to twelfth week. The Self-Report Habit Index (SRHI) of participants was evaluated every week, and the level of physical activity was measured at the beginning and end of the trial. SPSS Statistics version 21 (IBM Corp) was used for statistical analysis. Results After 4 weeks of intervention without providing the intrinsic rewards in the control group, the change in SRHI scores was 13.54 (SD 14.99) in the intervention group and 6.42 (SD 9.42) in the control group, indicating a significant difference between the groups (P=.04). When all rewards were given to both groups, from the fifth to twelfth week, the change in SRHI scores of the intervention and control groups was comparable at 12.08 (SD 10.87) and 15.88 (SD 13.29), respectively (P=.21). However, the level of physical activity showed a significant difference between the groups after 12 weeks of intervention (P=.045). Conclusions This study provides evidence that intrinsic rewards are important to enhance the sustainability and effectiveness of an intervention. The Healthy Lifestyle Coaching Chatbot program can be a cost-effective method for healthy habit formation. Trial Registration Clinical Research Information Service KCT0004009; https://tinyurl.com/w4oo7md

Osteosarcoma (OS) is a serious primary bone malignant tumor that can easily affect children and adolescents. Chemotherapy is one of the important and feasible clinical treatment strategies for the treatment of OS at present, which is severely limited due to insufficient retention time, poor penetration ability, and serious side effects of current anti-tumor drug preparations. In this work, a novel injectable thermo-sensitive hydrogel (mPEG45–PLV19) loaded with methotrexate and alendronate, and the sustained release at the tumor site synergistically inhibited the progression of OS. The mPEG45–PLV19 shows excellent physical and chemical properties. Compared with other treatment groups, the in vivo treatment of gel+ methotrexate + alendronate effectively inhibited the growth of tumor. More importantly, it significantly reduced bone destruction and lung metastasis caused by OS. Therefore, this injectable thermo-sensitive hydrogel drug delivery system has broad prospects for OS chemotherapy.

Most of the patients with type 2 diabetes mellitus suffer from renal injury. The current study explored the protective effects of dietary zinc against diabetic renal injury and the underlying molecular mechanisms. In experiments, ZnSO4 at 15 mg/kg was intragastrically administrated into type 2 diabetes mellitus-like Wistar rat models daily for continuously 53 days. Biochemical assay was performed to detect serum fasting blood glucose, blood urea nitrogen (BUN), creatinine, and insulin. The H&E staining, immunohistochemical assay, and Western blotting were performed to detect the changes in kidney tissues. In results, dietary zinc reduced the lipid peroxidation malondialdehyde levels and enhanced the total anti-oxidation capacity levels. The pathological changes in diabetic kidney were improved. The percentage of autophagy-associated LC3-II positive cells was lowered. Western blot levels of LC3-II proteins and endoplasmic reticulum (ER) stress-associated GRP78 proteins were lowered. In conclusion, dietary zinc can relieve ER stress and autophagy in diabetic kidney to improve kidney conditions of type 2 diabetes mellitus-like rat models. These findings may be useful to treat patients with diabetic renal injury.

RIP1 and RIP3 are necroptosis initiators, but their roles in regulation of glycolysis remain elusive. In this study, we found shikonin activated RIP1 and RIP3 in glioma cells in vitro and in vivo, which was accompanied with glycolysis suppression. Further investigation revealed that shikonin-induced decreases of glucose-6-phosphate and pyruvate and downregulation of HK II and PKM2 were significantly prevented when RIP1 or RIP3 was pharmacologically inhibited or genetically knocked down with SiRNA. Moreover, shikonin also triggered accumulation of intracellular H2O2 and depletion of GSH and cysteine. Mitigation of intracellular H2O2 via supplement of GSH reversed shikonin-induced glycolysis suppression. The role of intracellular H2O2 in regulation of glycolysis suppression was further confirmed in the cells treated with exogenous H2O2. Notably, inhibition of RIP1 or RIP3 prevented intracellular H2O2 accumulation, which was correlated with preventing shikonin-induced downregulation of x-CT and depletion of GSH and cysteine. In addition, supplement of pyruvate effectively inhibited shikonin- or exogenous H2O2-induced accumulation of intracellular H2O2 and glioma cell death. Taken together, we demonstrated in this study that RIP1 and RIP3 contributed to shikonin-induced glycolysis suppression via increasing intracellular H2O2.

Shikonin has been reported to induce glioma cell death via necroptosis, a type of programmed necrosis primarily mediated by RIP1 and RIP3. Although RIP1 and RIP3 are found to regulate some features of necrosis such as energy depletion and cellular membrane disruption, it remains unclear whether RIP1 and RIP3 could modulate DNA double strand breaks (DSBs), which is a crucial event leading to chromatinolysis. In this study, we used glioma cell lines and mice model of xenograft glioma to investigate the roles of RIP1 and RIP3 in shikonin-induced DNA DSBs. We found that shikonin induced upregulation of RIP1 and RIP3, necrosome formation and DNA DSBs in vitro and in vivo. In vitro investigation showed that the DNA DSBs and the reduction of cellular viabilities induced by shikonin were both prevented when RIP1 or RIP3 was pharmacologically inhibited by specific inhibitor or genetically knocked down with siRNA. Then, we proved that suppression of intracellular ROS with antioxidant NAC inhibited DNA DSBs caused by either hydrogen peroxide or shikonin, suggesting that ROS played a crucial role in regulation of DNA DSBs of glioma cells induced by shikonin. Further, we found that RIP1 and RIP3 regulated shikonin-induced overproduction of ROS via causing excessive generation of mitochondrial superoxide and depletion of GSH, indicating that ROS was the downstream signal of RIP1 and RIP3. Taken together, we demonstrated that RIP1 and RIP3 contributed to shikonin-induced DNA DSBs in glioma cells via increase of intracellular ROS levels.

Chromatinolysis refers to enzymatic degradation of nuclear DNA and is regarded as one of the crucial events leading to cell death. Mixed-lineage kinase domain-like protein (MLKL) has been identified as a key executor of necroptosis, but it remains unclear whether MLKL contributes to necroptosis via regulation of chromatinolysis. In this study, we find that shikonin induces MLKL activation and chromatinolysis in glioma cells in vitro and in vivo, which are accompanied with nuclear translocation of AIF and γ-H2AX formation. In vitro studies reveal that inhibition of MLKL with its specific inhibitor NSA or knockdown of MLKL with siRNA abrogates shikonin-induced glioma cell necroptosis, as well as chromatinolysis. Mechanistically, activated MLKL targets mitochondria and triggers excessive generation of mitochondrial superoxide, which promotes AIF translocation into nucleus via causing mitochondrial depolarization and aggravates γ-H2AX formation via improving intracellular accumulation of ROS. Inhibition of nuclear level of AIF by knockdown of AIF with siRNA or mitigation of γ-H2AX formation by suppressing ROS with antioxidant NAC effectively prevents shikonin-induced chromatinolysis. Then, we found that RIP3 accounts for shikonin-induced activation of MLKL, and activated MLKL reversely up-regulates the protein level of CYLD and promotes the activation of RIP1 and RIP3. Taken together, our data suggest that MLKL contributes to shikonin-induced glioma cell necroptosis via promotion of chromatinolysis, and shikonin induces a positive feedback between MLKL and its upstream signals RIP1 and RIP3.

BACKGROUND Lack of time for exercise is common among office workers given their busy lives. Because of occupational restrictions and difficulty in taking time off, it is necessary to suggest effective ways for workers to exercise regularly. Sustaining lifestyle habits that increase nonexercise activity in daily life can solve the issue of lack of exercise time. Healthy Lifestyle Coaching Chatbot is a messenger app based on the habit formation model that can be used as a tool to provide a health behavior intervention that emphasizes the importance of sustainability and involvement. OBJECTIVE This study aimed to assess the efficacy of the Healthy Lifestyle Coaching Chatbot intervention presented via a messenger app aimed at stair-climbing habit formation for office workers. METHODS From February 1, 2018, to April 30, 2018, a total of 106 people participated in the trial after online recruitment. Participants were randomly assigned to the intervention group (n=57) or the control group (n=49). The intervention group received cues and intrinsic and extrinsic rewards for the entire 12 weeks. However, the control group did not receive intrinsic rewards for the first 4 weeks and only received all rewards as in the intervention group from the fifth to twelfth week. The Self-Report Habit Index (SRHI) of participants was evaluated every week, and the level of physical activity was measured at the beginning and end of the trial. SPSS Statistics version 21 (IBM Corp) was used for statistical analysis. RESULTS After 4 weeks of intervention without providing the intrinsic rewards in the control group, the change in SRHI scores was 13.54 (SD 14.99) in the intervention group and 6.42 (SD 9.42) in the control group, indicating a significant difference between the groups (P=.04). When all rewards were given to both groups, from the fifth to twelfth week, the change in SRHI scores of the intervention and control groups was comparable at 12.08 (SD 10.87) and 15.88 (SD 13.29), respectively (P=.21). However, the level of physical activity showed a significant difference between the groups after 12 weeks of intervention (P=.045). CONCLUSIONS This study provides evidence that intrinsic rewards are important to enhance the sustainability and effectiveness of an intervention. The Healthy Lifestyle Coaching Chatbot program can be a cost-effective method for healthy habit formation. CLINICALTRIAL Clinical Research Information Service KCT0004009; https://tinyurl.com/w4oo7md

Zinc (Zn) is known to play crucial roles in numerous brain functions including learning and memory. Zn deficiency is believed to be widespread throughout the world, particularly in patients with Alzheimer's disease (AD). A number of studies have shown that volatile anesthetics, such as isoflurane, might be potential risk factors for the development of AD. However, whether isoflurane exposure accelerates the process of AD and cognitive impairment in AD patients with Zn deficiency is yet to be documented. The aim of the present study was to explore the effects of 1.4% isoflurane exposure for 2 h on learning and memory function, and neuropathogenesis in 10-month-old Zn-adequate, Zn-deficient, and Zn-treated APP/PS1 mice with the following parameters: behavioral tests, neuronal apoptosis, Aβ, and tau pathology. The results demonstrated that isoflurane exposure showed no impact on learning and memory function, but induced transient elevation of neuroapoptosis in Zn-adequate APP/PS1 mice. Exposure of isoflurane exhibited significant neuroapoptosis, Aβ generation, tau phosphorylation, and learning and memory impairment in APP/PS1 mice in the presence of Zn deficiency. Appropriate Zn treatment improved learning and memory function, and prevented isoflurane-induced neuroapoptosis in APP/PS1 mice. Isoflurane exposure may cause potential neurotoxicity, which is tolerated to some extent in Zn-adequate APP/PS1 mice. When this tolerance is limited, like in AD with Zn deficiency, isoflurane exposure markedly exacerbated learning and memory impairment, and neuropathology, indicating that AD patients with certain conditions such as Zn deficiency may be vulnerable to volatile anesthetic isoflurane.

Endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and the subsequent cell deaths are essential steps in the pathogenesis of diabetic cardiomyopathy (DCM), a main cause of diabetics' morbidity and mortalities. The bis(maltolato)oxovanadium(IV) (BMOV), a potent oral vanadium complex with anti-diabetic properties and insulin-mimicking effects, was shown to improve cardiac dysfunctions in diabetic models. Here, we examined the effects of BMOV on UPR pathway protein expression and apoptotic cell deaths in both high glucose-treated cardiac H9C2 cells and in the hearts of diabetic rats. We show that in both the high glucose-treated cardiac cells and in the hearts of streptozotocin (STZ) diabetic rats, there was an overall activation of the UPR signaling, including both apoptotic (e.g., the cascades of PERK/EIf2α/ATF4/CHOP and of IRE1/caspase 12/caspase 3) and pro-survival (GRP78 and XBP1) signaling. A high amount of apoptotic cell deaths was also detected in both diabetic conditions. The administration of BMOV suppressed both the apoptotic and pro-survival UPR signaling and significantly attenuated apoptotic cell deaths in both conditions. The overall suppression of UPR signaling by BMOV suggests that the drug protects diabetic cardiomyopathy by counteracting reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Our findings lend support to promote the use of BMOV in the treatment of diabetic heart diseases.

How rising temperature and changing solar radiation affect evaporation of natural water bodies remains poor understood. In this study, evaporation from Lake Taihu, a large (area 2400 km2) freshwater lake in the Yangtze River Delta, China, was simulated by the CLM4-LISSS offline lake model and estimated with pan evaporation data. Both methods were calibrated against lake evaporation measured directly with eddy covariance in 2012. Results show a significant increasing trend of annual lake evaporation from 1979 to 2013, at a rate of 29.6 mm decade−1 according to the lake model and 25.4 mm decade−1 according to the pan method. The mean annual evaporation during this period shows good agreement between these two methods (977 mm according to the model and 1007 mm according to the pan method). A stepwise linear regression reveals that downward shortwave radiation was the most significant contributor to the modeled evaporation trend, while air temperature was the most significant contributor to the pan evaporation trend. Wind speed had little impact on the modeled lake evaporation but had a negative contribution to the pan evaporation trend offsetting some of the temperature effect. Reference evaporation was not a good proxy for the lake evaporation because it was on average 20.6 % too high and its increasing trend was too large (56.5 mm decade−1).

Aims Epithelial-to-mesenchymal transition (EMT) facilitates cell migration and invasion, and contributes to metastasis in bladder cancer. Within the perioperative period, anesthetic such as isoflurane have been found to affect cancer prognosis. In the study, we reported the tumor-promoting effect of isoflurane in bladder cancer. Materials and Methods Human bladder cancer cell lines T24 and BIU-87 were exposed to isoflurane at different concentrations. The immunofluorescent staining of Ki67, Annexin V-FITC/PI staining, Transwell invasion assays and wound-healing assays were performed to assess cell proliferation, apoptosis, invasion and migration. Expressions of EMT markers (E-cadherin, N-cadherin and Vimentin) and metastatic markers (Snail-1, Slug-1 and MMP-2/9) were determined by immunoblotting. Orthotopic tumor models and mice given tail vein injection of T24 cells were developed with or without 4-h exposure to 2% isoflurane. Key findings We found isoflurane promoted bladder cancer cell proliferation, invasion and migration but reduce apoptosis in a concentration-dependent manner. In addition, isoflurane was shown to increase HIF-1α and its nuclear accumulation in bladder cancer cells. HIF-1α knockdown inhibited bladder cancer cell proliferation and delayed EMT, which was reversed in the presence of 4-h exposure to 2% isoflurane. Likewise, we found isoflurane modulated β-catenin/Notch1 pathways via HIF-1α. In vivo studies showed that isoflurane exposure accelerated formation of orthotopic bladder tumor and promoted hepatic metastases from carcinoma of the bladder. Significance Taken together, our study demonstrates that a frequently used anesthetic can exert a protumorigenic effect on bladder cancer. Isoflurane may serve as an important contributory factor to high recurrence following surgery.