A small molecule UPR modulator for diabetes identified by high throughput screening

Unfolded protein response (UPR) is a stress response that is specific to the endoplasmic reticulum (ER). UPR is activated upon accumulation of unfolded (or misfolded) proteins in the ER's lumen to restore protein folding capacity by increasing the synthesis of chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, we describe a cell-based ultra-high throughput screening (uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and

Cholesterol-associated lysosomal disorder triggers cell death of hematological malignancy: Dynamic analysis on cytotoxic effects of LW-218

The integrity of lysosomes is of vital importance to survival of tumor cells. We demonstrated that LW-218, a synthetic flavonoid, induced rapid lysosomal enlargement accompanied with lysosomal membrane permeabilization in hematological malignancy. LW-218-induced lysosomal damage and lysosome-dependent cell death were mediated by cathepsin D, as the lysosomal damage and cell apoptosis could be suppressed by depletion of cathepsin D or lysosome alkalization agents, which can alter the activity of cathepsins. Lysophagy, was initiated for cell self-rescue after LW-218 treatment and correlated with calcium release and nuclei translocation of transcription factor EB. LW-218 treatment enhanced the expression of autophagy-related genes which could be inhibited by intracellular calcium chelator. Sustained exposure to LW-218 exhausted the lysosomal capacity so as to repress the normal autophagy. LW-218-induced enlargement and damage of lysosomes were triggered by abnormal cholesterol deposition on lysosome membrane which caused by interaction between LW-218 and NPC intracellular cholesterol transporter 1. Moreover, LW-218 inhibited the leukemia cell growth

Body image disturbance in eating disorders: concept and development / 上海交通大学学报（医学版）

Body image disturbance (BID) in eating disorders (ED) has always been a focus of intense investigations and debates since its concept was brought out. Experimental studies conducted in clinical ED patients have not only provided insights into the components, mechanisms and roles of BID in ED psychopathology, but also brought changes to relevant theories and concepts. This article provided a review of theoretical and empirical literatures on BID in ED, as well as a summary and analysis of recent developments and future prospects in this field.

Determinantion of visitors' willingness to pay to enter Karagol Natural Park of Ankara, Turkey / Determinantes para a "vontade de pagar" dos visitantes do Parque Natural Karagol de Ancara, Turquia

ABSTRACT: The objectives of this study were to assess visitors' attitudes, if visitors would be willing to pay to enter Lake Karagol, and what factors affect their decision to pay. The contingent valuation method was used to estimate the economic value of the lake by assessing willingness to pay (WTP). Double dichotomous questions were used in the survey. Respondents were first asked whether or not they would be willing to pay the starting bid. They could either answer in the affirmative (that is, accepted bid) or in the negative (that is, reject the starting bid). The average WTP for an entrance fee was found to be about USD 0.22 for all observations when zero bids were included, and about USD 4.40 when zero bids were excluded. Result of the probit model showed that respondents with a higher income, respondents who were young, and the working status of the respondents had significant impacts on the probability of the WTP.

RESUMO: O objetivo deste estudo foi analisar as atitudes dos visitantes e se eles estavam dispostos a pagar entrada no Lago Karago e quais eram os fatores que afetavam a sua decisão. O método de avaliação contingente foi usado para estimar o valor econômico do Lago usando a decisão dos visitantes de estarem dispostos a pagar entrada. Perguntas duplamente dicotômicas foram usadas no questionário. Os inquiridos foram questionados primeiro se estariam dispostos a pagar um valor inicial. Eles poderiam responder afirmativamente (aceitavam o valor) ou negativamente (rejeitavam o valor). O valor médio (vontade de pagar) de uma entrada foi de 0.22 dólares estadunidenses para todas as respostas, incluindo o mínimo de 0 e de 4.40 dólares estadunidenses excluindo o mínimo de 0. O resultado do modelo de lucro mostrou que os inquiridos com maior valor salarial e mais jovens com estatuto de trabalhadores tinham mais impacto na probabilidade de vontade de pagar.

TNF-α induced RIP1-dependent apoptosis in L929-A cells by interrupting mitochondrial respiratory chain complex Ⅲ / 军事医学

Objective To explore the mechanism by which tumor necrosis factor alpha(TNF-α) induces RIP1 kinase-dependented apoptosis in L929-A fibroblastoma cells.Methods The sub-mitochondrial localization of receptor-interacting protein 1(RIP1),caspase-8 and Bid proteins was detected by dose-gradient trypsin digestion and Western blotting.The levels of reactive oxygen species (ROS),intracellular calcium concentration,mitochondrial membrane potential (MMP),and cellular adenosine triphosphate(ATP) content were determined by fluorescent probe labeling and flow cytometry assay.The mitochondrial respiratory chain complex Ⅰ and Ⅲ activities were detected by commercial kits.Nec-1,A RIP1 kinase specific inhibitor,and RIP1-/-or Bid-/-L929-A cells were used to detect the roles of RIP1 kinase and Bid protein in cell death.Results RIP1,caspase-8 and Bid proteins were co-located in the outer membrane of mitochondrial.TNF-α exposure for 3 h could induce Bid cleavage,inhibit mitochondrial respiratory chain complex Ⅲ activity and reduce MMP.Following these changes and after TNF-α exposure for 6-12 h,the intracellular calcium concentration and ROS were increased,whereas the ATP concentration was decreased,and the cells were killed.Inhibiting RIP1 kinase or knockdown RIP1 or Bid protein could suppress all the cytotoxic effects of TNF-α.Conclusion TNF-α treatment can result in RIP1 kinase-mediated Bid cleavage and inhibit mitochondrial respiratory chains and cell energy metabolism,which ultimately leads to the death of L929-A cells.

Design and implementation of Internet Public Opinion Monitoring and Early Warning System for medical and health industry / 中华医学图书情报杂志

The Internet Public Opinion Monitoring and Early Warning System for medical and health industry was designed and implemented due to the frequent occurrence of Internet public opinion, which has all-directional data collecting and analyzing functions, including big data collection, near duplicate detection, spam filtration, key public opinion early warning, region identification and tendency analysis, and can thus provide evidence for relevant departments to take effective measures for the control of Internet public opinion.

Apoptose e maturação placentária bovina: um estudo imunohistoquímico e morfométrico / Apoptosis and maturation of the bovine placenta: an immunohistochemical and morphometric study

A liberação da placenta após o parto envolve a perda da adesão materno-fetal e ocorre somente após a maturação completa do placentoma, que está relacionada com a diminuição da celularidade dos tecidos fetal e materno. A apoptose é requerida tanto para a maturação quanto para a liberação normal da placenta após o parto. O objetivo do presente estudo foi avaliar a ocorrência de apoptose em amostras de placenta de vacas em diferentes fases de gestação. Amostras de placentomas de 15 vacas saudáveis com 4 (n=5), 6 (n=5) e 9 (n=5) meses de gestação foram colhidas e processadas rotineiramente para a histologia, imunoistoquímica e histoquímica. As lâminas obtidas foram coradas em HE, Picrosirius Red e submetidas à análise imunoistoquímica das proteínas Caspase 3, Caspase 8, Bax e Bid. O aumento no número de vasos não necessariamente se associou ao aumento do calibre destes durante a evolução da gestação. Os resultados de histomorfometria revelaram aumento da marcação para Bax e Caspases 3 e 8 em células trofoblásticas binucleadas no final da gestação, enquanto o Bid se manteve sem alteração significativa. A histomorfometria das células trofoblásticas mononucleadas revelou expressão alta para Bax no início de gestação, com diminuição aos 6 meses de gestação e aumento das imunomarcações para Caspases 3 e 8, e Bid com o avanço gestacional. Os colágenos tipo I e III não aumentaram do terço médio ao final da gestação, o que é importante para a diminuição da adesão materno-fetal. Esses resultados confirmam que as Caspases 3 e 8, e o Bax estão envolvidos nos mecanismos de ativação da apoptose pela via intrínseca mitocondrial e/ou extrínseca ao longo da gestação em células trofoblásticas binucleadas, e que nas células trofoblásticas mononucleadas o Bax deixa de ser importante, enquanto o Bid e as Caspases 3 e 8 se tornam os mais significativos.

Placental release after birth involves loss of maternal-fetal adhesion and occurs only after complete maturation of the placentoma related to the decrease in cellularity of fetal and maternal tissues. Apoptosis is required for both the normal maturation and release of the placenta after birth. The aim of this study was to evaluate the occurrence of apoptosis in samples of the placenta of cows in different stages of gestation. Samples of 15 healthy cow placentomas at 4 (n=5), 6 (n=5) and 9 (n=5) months of gestation were harvested and processed for routine histology, immunohistochemistry and histochemistry. The slides were stained with HE, PicroSirius Red and subjected to immunohistochemical analysis of proteins Caspase 3, Caspase 8, Bax and Bid. Increase in number of vessels was not associated with increase in vascular area during progression of gestation. The results of histomorphometry revealed increased labeling for Bax and Caspases 3 and 8 in trophoblastic binucleated cells in late pregnancy, where the Bid remained without significant change. Histomorphometry analyzing the mononuclear trophoblast cells showed a high expression for Bax in early pregnancy, but decreased at 6 months of gestation. Immunolabeling revealed increased Caspases 3/8 and Bid with advancing of gestation. Further evaluation of type I and III collagen showed a decrease of both types of collagens at the end of gestation, what is very important for the reduction of maternal-fetal adhesion. These results confirm that Caspases 3 and 8 and Bax are involved in the mechanisms of activation of apoptosis through mitochondrial intrinsic and/or extrinsic pathway during pregnancy in trophoblastic binucleated cells. In mononuclear trophoblast cells Bax looses importance in the apoptosis process, awhile Bid and caspases 3 and 8 become the most significant.

Comparación de biomarcadores inflamatorios en pacientes con trastorno afectivo bipolar tipo I y sujetos controles / Comparison of Inflammatory Biomarkers Between Bipolar Disorder I Patients and Control Subjects

Introducción: En el trastorno afectivo bipolar tipo I (TABI) se han descrito cambios inflamatorios en los diferentes episodios afectivos y en la etapa de eutimia, propuestos como posibles marcadores periféricos del trastorno, razón por la cual son necesarios estudios con adecuados criterios de inclusión para explorar esta hipótesis. Objetivo: Cuantificar y comparar las concentraciones séricas de interleucinas (IL) y factor de necrosis tumoral (TNF) en pacientes con TABI y en sujetos controles, incluyendo un análisis de comparación según el estado afectivo. Métodos: Estudio transversal sobre 41 pacientes con TABI y 11 controles, en los que se determinaron concentraciones de IL-1B, IL-RA, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 y TNF durante las fases de eutimia, depresión y manía, y se compararon con los de los sujetos controles. Resultados y conclusiones: El subgrupo de pacientes en manía tenía menor escolaridad y mayor número de hospitalizaciones, y el subgrupo de pacientes en depresión mostró mayor número de episodios depresivos a lo largo de la vida. No se encontraron diferencias estadísticamente significativas entre las concentraciones de IL y TNF de sujetos con TABI y sujetos controles ni entre los diferentes subgrupos de TABI (eutimia, depresión y manía). Es necesario aumentar la muestra en estudios posteriores con el fin de mejorar el poder estadístico y explorar la hipótesis infamatoria del trastorno bipolar.

Introduction: Inflammatory changes have been described in different affective episodes, as well as in the euthymic phase of Bipolar I Disease. These changes have been proposed as possible peripheral markers of the disease. For this reason well-designed studies are needed to explore this hypothesis. Objective: Quantify and compare the serum levels of interleukins (IL) and tumour necrosis factor (TNF) in bipolar I patients and healthy subjects, including the comparison between the affective episodes of the disease. Methods: Cross-sectional study including 41 bipolar I patients and 11 healthy control subjects. Serum levels of IL-1B, IL-RA, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12, and TNF were measured during the euthymic, depressive, and manic phases and were compared with the serum levels of the healthy subjects. Conclusions: Manic phase patients had low education and high number of hospitalisations. Depressive phase patients showed high number of depressive episodes throughout life. No statistically significant differences were found in IL and TNF levels between bipolar I patients and healthy controls, or between the bipolar I subgroups (euthymic, manic and depressive states). An increase in the size of the sample is necessary in future studies, in order to enhance the statistical value of the results, and explore the inflammatory hypothesis of the bipolar disease.

The impacts of medicine centralized bidding and purchasing policy:An empirical study on the relationship between the bid winners and the bidden prices / 中国卫生政策研究

Objective:This paper aims to analyze the impacts of medicine centralized bidding and purchasing policy based on the relationship between the bid winners and the bidden prices. Methods: A data collection method was used to collect data from medicine centralized bidding and purchasing policy in 31 provinces and OLS method has been employed to analyze impacts of the number of bid winners on the medicine prices. Results:The results showed a positive correlation between the number of bid winners and the bidden prices, which was a counter-intuitive appeal. In the group of non-essential medicines, the number of bid winners had a stronger impact on the bidden prices than in the group of essential medicines. Conclusions:The current medicine centralized bidding and purchasing policy does not achieve the expected objective and needs to be further improved.

Application of electronic medical records, hand-holding mobile terminals, bid data collection and analysis, and data security in medical quality control / 中华医学图书情报杂志

Described in this paper is the application of electronic medical records, hand-holding mobile terminals,bid data collection and analysis, and data security in medical quality control.

Research on the application of Fuzzy synthesis in medical equipment procurement bidding / 中国医学装备

Objective:To discuss and set up indicator system of medical equipment procurement bidding, propose the evaluation methods which based on Fuzzy synthesis and confirm the most appropriate bidder for improving the management level of hospital in medical equipment purchase. Methods: From the bidder's ability to compete and innovation ability and financial standing and development potential and corporate credibility, five aspects to determine the evaluation index. Establish evaluation index system, the application of fuzzy comprehensive method to analyze the bid scheme offered by the tender.Results: According to the maximum subordinate principle, the evaluation value of the bidder is 0.28, the evaluation value of the B tender is 0.32, the value of the bid quotient is 0.23. Comparison of the comprehensive evaluation of the bid evaluation of the tender score of three, B the highest bid quotient, choose B tender bid.Conclusion:Facing different bidders, in the case of each of the advantages and making program quantification, conducting analysis of fuzzy synthetic method can realize the reasonable choice for medical equipment suppliers.

The preliminary study of expression and clinical significance of GrB/Bid in gastric carcinoma / 国际外科学杂志

Objective To investigate the expression of GrB and Bid gene in gastric carcinoma and development of gastric carcinoma,exploring their effect on the mechanism of immune tolerance of tumor.Methods S-P method was used to detect the expression status of GrB and Bid gene in gastric carcinoma and margin tissue.Results The positive expression rate of GrB of gastric carcinoma tissues was 47.62％,the positive rate in the margin tissue was 40.48％,there was no significant difference(P ＞ 0.05) ; The positive expression rate of Bid of gastric carcinoma tissues (26.19％) was significantly lower than that of margin tissue(76.19％) (P ＜ 0.05) ; The expression of GrB had significantly correlation with TNM stage and lymph node metastasis of the tumor (P ＜ 0.05),the expression of Bid in gastric cancer had significantly correlation with differentiation,invasive depth,TNM stage and lymph node metastasis of the tumor (P ＜ 0.05) ; the expression of GrB was negatively correlated with that of Bid in gastric cancaer(rs =-0.311,P ＜ 0.05).Conclusion The expression of GrB and Bid may be involved in development of gastric carcinoma,down-regulated or scarce expression of Bid may be cause cancer cells escaping from endogenous or exogenous GrB-mediated cell apoptosis,and acquire immune tolerance,potential,to escape the immune response.

The study progress of Bid gene / 白血病·淋巴瘤

The study progress of the function of Bid gene, Bid regulate to cell apoptosis, and it can affected by which factors has impulse clinical treatment to develop in recent years. Bid can change into tBid which urge cytochrome C releasing after stimulated by apoptosis signal, and release of cytochrome C induce apoptosis. Apoptosis mediated by Bid is very important to taking place and developing of many diseases. Bid also show dual role that promote apoptosis or proliferation in a few decreas. Studies in influencing factors of Bid mediate apoptosis also provid new ideas to treatment of solid tumor and malignancy hematopathy.

Using FRET Technique to Investigate The Apoptotic Mechanism Induced by Cisplatin in Living Cells / 生物化学与生物物理进展

Cisplatin, an efficient anticancer agent, can trigger multiple apoptotic pathways in cancer cell. However, the signal transduction pathways in response to cisplatin-based chemotherapy are complicated, and the mechanism is not fully understood. Using fluorescence resonance energy transfer (FRET) technique, the molecular mechanism of cisplatin-induced apoptosis in living human lung adenocarcinoma cells (ASTC-a-1) were investigated. After cisplatin treatment, the recombinant pFRET-Bid and pSCAT-3 probes were used to determine the kinetics of Bid cleavage and Caspase-3 activation, respectively. The fluorescence probes Bid-CFP and DsRed-Mit were also used to detect the spatial and temporal changes of Bid in real-time in sub-cell level. The results showed that a cleavage of the Bid-FRET probe occurring at about 4～5 h after treated with 20 ?mol/L cisplatin. Cleavage of the Bid-FRET probe coincided with a translocation of tBid from the cytosolic to the mitochondria, and the translocation lasted about 1.5 h. At the anaphase of cell apoptosis, Caspase-3 was activated obviously as detected by FRET and Western blotting techniques. Using real-time single-cell analysis, it was observed the kinetics of Bid and Caspase-3 activation for the first time in living cells during cisplatin-induced apoptosis.

Promotion of disequilibrium of cell proliferation and apoptosis of BID as a potential mechanism of IgAN / 基础医学与临床

Objective To explore the expression of BID protein and the relation ship of cell proliferation with apoptosis at different stages of IgAN.Methods The expression of BID protein、PCNA and FN in renal tissue was detected by immunohistochemistry,TUNEL and light microscopy were used to detect apoptotic cells.Results With the progress of IgAN,the expression of BID protein、PCNA、the number of apoptotic cells and FN increased gradually(P

Apoptosis of cardiocytes of neonatal rats with simulated ischemia/reperfusion injury mediated by pro-apoptosis by protein Bid / 吉林大学学报(医学版)

Objective To study the role of Bid in simulated ischemia/reperfusion injury in cultured neonatal rat cardiocytes and its possible mechanism.Methods A cell culture model of neonatal rat(born within 3 days) cardiocytes was used to establish simulated ischemia/reperfusion model.Unrelated siRNA or Bid specific siRNA was transfected into rat cardiocytes by Oligofectamine.The activation of Bid and caspase-8 was detected by Western blotting.The apoptotic rate of cardiocytes was determined by flow cytometry.Results Bid and caspase-8 of cardiocytes were activatied in simulated ischemia/reperfusion injury model.The activation of caspase-8 of cardiocytes in Bid-specific siRNA group decreased significantly compared with those in simulated(ischemia/reperfusion) group and unrelated siRNA group;the apoptotic rate of cardrocytes(7.4%) was lower than those in simulated ischemia/reperfusion group(51.2%) and unrelated siRNA group(48.7%)(P

Over Expression and Its Significance of Bid Protein in Keloid / 中国微创外科杂志

0.05),there were more apoptosis-starting cells found in normal skin(1738.33?348.89/mm2)than in keloid(891.67?395.00/mm2)(t=-5.565,P=0.000).The number of positive stained fibroblast cells in dermis significantly increased in keloid group(911.67?323.61/mm2),compared with that in normal skin group(220.00?80.00/mm2)(t=7.188,P=0.000).This result that the protein expression level of Bid was higher in keloid(0.46?0.08)than that in normal skin tissue(0.02?0.01)(t=18.905,P=0.000)was proven by western blotting test.Conclusions The number of apoptosis-starting cells in epidermis of normal skin is more than that in keloid.Bid protein in dermis of keloid is over expressed.

Analysis of Purchasing Data of Oral Antidiabetic Agents in 18 University Hospitals in Beijing During 2007～2008 / 中国药房

OBJECTIVE:To probe into the status quo and tendency of the utilization of oral hypoglycemic agents in university-affiliated hospitals in Beijing area.METHODS:As one of the zero-difference rate drugs that won the bid,the oral hypoglycemic drugs purchased between 2007 and 2008 by 18 university hospitals in Beijing area were analyzed statistically in respect of the drug variety,DDDs and DDC etc.RESULTS:Of all the oral hypoglycemic agents purchased,?-glycosidase inhibitors took the lead in terms of purchase sum,DDDs as well as DDC.Gliquidone Tablets ranked at the second place and metformin enteric-coated tablets(0.25 g)the third place in terms of DDDs while the DDC of the two drugs ranked at the fifth and the sixth,respectively.CONCLUSION:?-glycosidase inhibitors are the first choice drugs for patients with diabetes in university hospitals in Beijing area.However,the purchase sum and medication person-time of it showed poor synchronism.The utilization of Gliquidone Tablets and Metformin Enteric-coated Tablets(0.25 g)were rational and economicalwhich thus deserve to be used preferably in clinical practice.

Involvement of apoptotic signals in cyclosporin A-induced proliferation of human gingival fibroblast / 대한치주과학회지

No abstract available.

Effect of Dexamethasone on bid Gene Expression and Cerebral Apoptosis in Brain after Cerebral Hypoxia-Ischemia / 实用儿科临床杂志

Objective To investigate the bid gene expression and cell death in brain after cerebral hypoxia-ischemia in neonatal rats and the effects of dexamethasone(DEX)on bid gene expression,so as to elucidate the possible mechanism of the neuroprotective effect of DEX pretreatment on rats following cerebral hypoxia-ischemia.Methods Twenty-four SD neonatal rats were divided randomly into hypoxia-ischemia brain damage(HIBD),normal,dexamethasone-pretreated and 9 g/L NaCl(NS)control group.The animal models of HIBD were made.Total RNA from ipsilateral cerebral hemisphere was extracted.Reverse transcription polymerase chain reaction(RT-PCR)was used to evaluate the level of bid gene expression after hypoxia-ischemia.Cerebral apoptosis was determined by terminal-deoxynucleotidy transferase mediated d-UTP nick end labeling(TUNEL).Results The levels of bid mRNA were higher in HIBD rats than those in normal rats.The number of positive apoptosis cells significantly increased in HIBD group(P