Analysis of Crossing Speed of the Pedestrians in Marked and Unmarked Crosswalks in the Signalized and Un-Signalized Intersections (Case Study: Rasht city)

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Behbahani, Hamid; Najafi Moghaddam Gilani, Vahid; Jahangir Samet, Mehdi; Salehfard, Reza

2017-10-01

Pedestrians affect the traffic in the signalized and un-signalized intersections. Therefore, identifying the behavioural features of the pedestrians is of great importance and may result in better designing facilities for them. In this study, by shooting the four intersections in Rasht for 15 hours and inventory from 4568 pedestrians, crossing speed of the pedestrians in the marked crosswalks and unmarked crosswalks was evaluated and analysed. Results showed that pedestrians‧ crossing speed in the marked crosswalks is higher than their crossing speed in the unmarked crosswalks in both signalized and un-signalized intersections. Moreover, in the unmarked crosswalks in the signalized intersections, 15th percentile speed of male pedestrians, female pedestrians and group of pedestrians’ decrease 6.4%, 5.4% and 12.2%, respectively, compared with the 15th percentile speed in the marked crosswalks. Above-mentioned values in the unmarked crosswalks in the un-signalized intersections for male pedestrians, female pedestrians, and group of pedestrians decrease 1.2%, 3.8%, and 1.4%, respectively.

Vehicle speed guidance strategy at signalized intersection based on cooperative vehicle infrastructure system

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Fengyuan JIA

2017-10-01

Full Text Available In order to reduce stopping time of vehicle at a signalized intersection, aiming at the difficulty, even the impossibility to obtain real-time queue length of intersection in third and fourth-tier cities in China sometimes, a speed guidance strategy based on cooperative vehicle infrastructure system is put forward and studied. For validating the strategy, the traffic signal timing data of the intersection at Hengshan Road and North Fengming Lake Road in Wuhu is collected by a vehicular traffic signal reminder system which is designed. The simulation experiments using the acquired data are done by software VISSIM. The simulation results demonstrate that the strategy under high and low traffic flow can effectively decrease the link travel-time, reducing average ratio is 9.2 % and 13.0 %, respectively, and the effect under low traffic flow is better than that under high traffic flow. The strategy improves efficiency of traffic at a signalized intersection and provides an idea for the application of vehicle speed guidance based on cooperative vehicle infrastructure system.

Signaling Pathways in Cardiac Myocyte Apoptosis

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Xia, Peng; Liu, Yuening

2016-01-01

Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation. PMID:28101515

Delays at signalized intersections with exhaustive traffic control

NARCIS (Netherlands)

Boon, M.A.A.; Adan, I.J.B.F.; Winands, E.M.M.; Down, D.G.

2012-01-01

In this paper, we study a traffic intersection with vehicle-actuated traffic signal control. Traffic lights stay green until all lanes within a group are emptied. Assuming general renewal arrival processes, we derive exact limiting distributions of the delays under heavy traffic (HT) conditions.

A new traffic control design method for large networks with signalized intersections

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Leininger, G. G.; Colony, D. C.; Seldner, K.

1979-01-01

The paper presents a traffic control design technique for application to large traffic networks with signalized intersections. It is shown that the design method adopts a macroscopic viewpoint to establish a new traffic modelling procedure in which vehicle platoons are subdivided into main stream queues and turning queues. Optimization of the signal splits minimizes queue lengths in the steady state condition and improves traffic flow conditions, from the viewpoint of the traveling public. Finally, an application of the design method to a traffic network with thirty-three signalized intersections is used to demonstrate the effectiveness of the proposed technique.

Delay-based Passenger Car Equivalent at Signalized Intersections in Iran

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Habibollah Nassiri

2017-04-01

Full Text Available Due to their different sizes and operational characteristics, vehicles other than passenger cars have a different influence on traffic operations especially at intersections. The passenger car equivalent (PCE is the parameter that shows how many passenger cars must be substituted for a specific heavy vehicle to represent its influence on traffic operation. PCE is commonly estimated using headway-based methods that consider the excess headway utilized by heavy vehicles. In this research, the PCE was estimated based on the delay parameter at three signalized intersections in Tehran, Iran. The data collected were traffic volume, travel time for each movement, signalization, and geometric design information. These data were analysed and three different models, one for each intersection, were constructed and calibrated using TRAF-NETSIM simulation software for unsaturated traffic conditions. PCE was estimated under different scenarios and the number of approach movements at each intersection. The results showed that for approaches with only one movement, PCE varies from 1.1 to 1.65. Similarly, for approaches with two and three movements, the PCE varies from 1.07 to 1.99 and from 0.76 to 3.6, respectively. In addition, a general model was developed for predicting PCE for intersections with all of the movements considered. The results obtained from this model showed that the average PCE of 1.5 is similar to the value recommended by the HCM (Highway Capacity Manual 1985. However, the predicted PCE value of 1.9 for saturated threshold is closer to the PCE value of 2 which was recommended by the HCM 2000 and HCM 2010.

Waiting Endurance Time Estimation of Electric Two-Wheelers at Signalized Intersections

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Mei Huan

2014-01-01

Full Text Available The paper proposed a model for estimating waiting endurance times of electric two-wheelers at signalized intersections using survival analysis method. Waiting duration times were collected by video cameras and they were assigned as censored and uncensored data to distinguish between normal crossing and red-light running behavior. A Cox proportional hazard model was introduced, and variables revealing personal characteristics and traffic conditions were defined as covariates to describe the effects of internal and external factors. Empirical results show that riders do not want to wait too long to cross intersections. As signal waiting time increases, electric two-wheelers get impatient and violate the traffic signal. There are 12.8% of electric two-wheelers with negligible wait time. 25.0% of electric two-wheelers are generally nonrisk takers who can obey the traffic rules after waiting for 100 seconds. Half of electric two-wheelers cannot endure 49.0 seconds or longer at red-light phase. Red phase time, motor vehicle volume, and conformity behavior have important effects on riders’ waiting times. Waiting endurance times would decrease with the longer red-phase time, the lower traffic volume, or the bigger number of other riders who run against the red light. The proposed model may be applicable in the design, management and control of signalized intersections in other developing cities.

Waiting endurance time estimation of electric two-wheelers at signalized intersections.

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Huan, Mei; Yang, Xiao-bao

2014-01-01

The paper proposed a model for estimating waiting endurance times of electric two-wheelers at signalized intersections using survival analysis method. Waiting duration times were collected by video cameras and they were assigned as censored and uncensored data to distinguish between normal crossing and red-light running behavior. A Cox proportional hazard model was introduced, and variables revealing personal characteristics and traffic conditions were defined as covariates to describe the effects of internal and external factors. Empirical results show that riders do not want to wait too long to cross intersections. As signal waiting time increases, electric two-wheelers get impatient and violate the traffic signal. There are 12.8% of electric two-wheelers with negligible wait time. 25.0% of electric two-wheelers are generally nonrisk takers who can obey the traffic rules after waiting for 100 seconds. Half of electric two-wheelers cannot endure 49.0 seconds or longer at red-light phase. Red phase time, motor vehicle volume, and conformity behavior have important effects on riders' waiting times. Waiting endurance times would decrease with the longer red-phase time, the lower traffic volume, or the bigger number of other riders who run against the red light. The proposed model may be applicable in the design, management and control of signalized intersections in other developing cities.

MicroRNAs regulate B-cell receptor signaling-induced apoptosis

NARCIS (Netherlands)

Kluiver, J. L.; Chen, C-Z

Apoptosis induced by B-cell receptor (BCR) signaling is critical for antigen-driven selection, a process critical to tolerance and immunity. Here, we examined the roles of microRNAs (miRNAs) in BCR signaling-induced apoptosis using the widely applied WEHI-231 model. Comparison of miRNA levels in

Evaluation of Red Light Camera Enforcement at Signalized Intersections

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Abdulrahman AlJanahi

2007-12-01

Full Text Available The study attempts to find the effectiveness of adopting red light cameras in reducing red light violators. An experimental approach was adopted to investigate the use of red light cameras at signalized intersections in the Kingdom of Bahrain. The study locations were divided into three groups. The first group was related to the approaches monitored with red light cameras. The second group was related to approaches without red light cameras, but located within an intersection that had one of its approaches monitored with red light cameras. The third group was related to intersection approaches located at intersection without red light cameras (controlled sites. A methodology was developed for data collection. The data were then tested statistically by Z-test using proportion methods to compare the proportion of red light violations occurring at different sites. The study found that the proportion of red light violators at approaches monitored with red light cameras was significantly less than those at the controlled sites for most of the time. Approaches without red light cameras located within intersections having red light cameras showed, in general, fewer violations than controlled sites, but the results were not significant for all times of the day. The study reveals that red light cameras have a positive effect on reducing red light violations. However, these conclusions need further evaluations to justify their safe and economic use.

Mycobacterium tuberculosis effectors interfering host apoptosis signaling.

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Liu, Minqiang; Li, Wu; Xiang, Xiaohong; Xie, Jianping

2015-07-01

Tuberculosis remains a serious human public health concern. The coevolution between its pathogen Mycobacterium tuberculosis and human host complicated the way to prevent and cure TB. Apoptosis plays subtle role in this interaction. The pathogen endeavors to manipulate the apoptosis via diverse effectors targeting key signaling nodes. In this paper, we summarized the effectors pathogen used to subvert the apoptosis, such as LpqH, ESAT-6/CFP-10, LAMs. The interplay between different forms of cell deaths, such as apoptosis, autophagy, necrosis, is also discussed with a focus on the modes of action of effectors, and implications for better TB control.

Investigation of new vehicle detectors for high-speed signalized intersections.

Science.gov (United States)

2015-09-01

Early indications from the use of the newest vehicle detectors for high-speed signalized intersections : suggested that they perform well as replacements for the Texas Department of Transportations : (TxDOTs) legacy systems, but this early conc...

Real-time bicycle detection at signalized intersections using thermal imaging technology

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Collaert, Robin

2013-02-01

More and more governments and authorities around the world are promoting the use of bicycles in cities, as this is healthy for the bicyclist and improves the quality of life in general. Safety and efficiency of bicyclists has become a major focus. To achieve this, there is a need for a smarter approach towards the control of signalized intersections. Various traditional detection technologies, such as video, microwave radar and electromagnetic loops, can be used to detect vehicles at signalized intersections, but none of these can consistently separate bikes from other traffic, day and night and in various weather conditions. As bikes should get a higher priority and also require longer green time to safely cross the signalized intersection, traffic managers are looking for alternative detection systems that can make the distinction between bicycles and other vehicles near the stop bar. In this paper, the drawbacks of a video-based approach are presented, next to the benefits of a thermal-video-based approach for vehicle presence detection with separation of bicycles. Also, the specific technical challenges are highlighted in developing a system that combines thermal image capturing, image processing and output triggering to the traffic light controller in near real-time and in a single housing.

Traffic signal phasing at intersections to improve safety for alcohol-affected pedestrians.

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Lenné, Michael G; Corben, Bruce F; Stephan, Karen

2007-07-01

Alcohol-affected pedestrians are among the highest-risk groups involved in pedestrian casualty crashes. This paper investigates the opportunities to use a modified form of traffic signal operation during high-risk periods and at high-risk locations to reduce alcohol-affected pedestrian crashes and the severity of injuries that might otherwise occur. The 'Dwell-on-Red' treatment involves displaying a red traffic signal to all vehicle directions during periods when no vehicular traffic is detected, so that drivers approach high-risk intersections at a lower speed than if a green signal were displayed. Vehicle speed data were collected before and after treatment activation at both a control and treatment site. Speed data were collected both 30 m prior to and at the intersection stop line. The treatment was associated with a reduction in mean vehicle speeds of 3.9 kph (9%) and 11.0 kph (28%) at 30 m and stop line collection points, respectively, and substantial reductions in the proportion of vehicles travelling at threatening speeds with regard to the severity of pedestrian injury. Other important road safety concerns may also benefit from this form of traffic signal modification, and it is recommended that other areas of application be explored, including the other severe trauma categories typically concentrated around signalised intersections.

Road Impedance Model Study under the Control of Intersection Signal

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Yunlin Luo

2015-01-01

Full Text Available Road traffic impedance model is a difficult and critical point in urban traffic assignment and route guidance. The paper takes a signalized intersection as the research object. On the basis of traditional traffic wave theory including the implementation of traffic wave model and the analysis of vehicles’ gathering and dissipating, the road traffic impedance model is researched by determining the basic travel time and waiting delay time. Numerical example results have proved that the proposed model in this paper has received better calculation performance compared to existing model, especially in flat hours. The values of mean absolute percentage error (MAPE and mean absolute deviation (MAD are separately reduced by 3.78% and 2.62 s. It shows that the proposed model has feasibility and availability in road traffic impedance under intersection signal.

A real-time traffic control method for the intersection with pre-signals under the phase swap sorting strategy.

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Yiming Bie

Full Text Available To deal with the conflicts between left-turn and through traffic streams and increase the discharge capacity, this paper addresses the pre-signal which is implemented at a signalized intersection. Such an intersection with pre-signal is termed as a tandem intersection. For the tandem intersection, phase swap sorting strategy is deemed as the most effective phasing scheme in view of some exclusive merits, such as easier compliance of drivers, and shorter sorting area. However, a major limitation of the phase swap sorting strategy is not considered in previous studies: if one or more vehicle is left at the sorting area after the signal light turns to red, the capacity of the approach would be dramatically dropped. Besides, previous signal control studies deal with a fixed timing plan that is not adaptive with the fluctuation of traffic flows. Therefore, to cope with these two gaps, this paper firstly takes an in-depth analysis of the traffic flow operations at the tandem intersection. Secondly, three groups of loop detectors are placed to obtain the real-time vehicle information for adaptive signalization. The lane selection behavior in the sorting area is considered to set the green time for intersection signals. With the objective of minimizing the vehicle delay, the signal control parameters are then optimized based on a dynamic programming method. Finally, numerical experiments show that average vehicle delay and maximum queue length can be reduced under all scenarios.

A real-time traffic control method for the intersection with pre-signals under the phase swap sorting strategy.

Science.gov (United States)

Bie, Yiming; Liu, Zhiyuan; Wang, Yinhai

2017-01-01

To deal with the conflicts between left-turn and through traffic streams and increase the discharge capacity, this paper addresses the pre-signal which is implemented at a signalized intersection. Such an intersection with pre-signal is termed as a tandem intersection. For the tandem intersection, phase swap sorting strategy is deemed as the most effective phasing scheme in view of some exclusive merits, such as easier compliance of drivers, and shorter sorting area. However, a major limitation of the phase swap sorting strategy is not considered in previous studies: if one or more vehicle is left at the sorting area after the signal light turns to red, the capacity of the approach would be dramatically dropped. Besides, previous signal control studies deal with a fixed timing plan that is not adaptive with the fluctuation of traffic flows. Therefore, to cope with these two gaps, this paper firstly takes an in-depth analysis of the traffic flow operations at the tandem intersection. Secondly, three groups of loop detectors are placed to obtain the real-time vehicle information for adaptive signalization. The lane selection behavior in the sorting area is considered to set the green time for intersection signals. With the objective of minimizing the vehicle delay, the signal control parameters are then optimized based on a dynamic programming method. Finally, numerical experiments show that average vehicle delay and maximum queue length can be reduced under all scenarios.

Role of CSL-dependent and independent Notch signaling pathways in cell apoptosis.

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Zeng, Chong; Xing, Rui; Liu, Jing; Xing, Feiyue

2016-01-01

Apoptosis is a normally biological phenomenon in various organisms, involving complexly molecular mechanisms with a series of signaling processes. Notch signaling is found evolutionarily conserved in many species, playing a critical role in embryonic development, normal tissue homeostasis, angiogenesis and immunoregulation. The focus of this review is on currently novel advances about roles of CSL-dependent and independent Notch signaling pathways in cell apoptosis. The CSL can bind Notch intracellular domain (NIC) to act as a switch in mediating transcriptional activation or inactivation of the Notch signaling pathway downstream genes in the nucleus. It shows that CSL-dependent signaling regulates the cell apoptosis through Hes-1-PTEN-AKT-mTOR signaling, but rather the CSL-independent signaling mediates the cell apoptosis possibly via NIC-mTORC2-AKT-mTOR signaling, providing a new insight into apoptotic mechanisms.

Apoptosis and signalling in acid sphingomyelinase deficient cells

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Sillence Dan J

2001-11-01

Full Text Available Abstract Background Recent evidence suggests that the activation of a non-specific lipid scramblase during apoptosis induces the flipping of sphingomyelin from the cell surface to the cytoplasmic leaftet of the plasma membrane. Inner leaflet sphingomyelin is then cleaved to ceramide by a neutral sphingomyelinase. The production of this non-membrane forming lipid induces blebbing of the plasma membrane to aid rapid engulfment by professional phagocytes. However contrary evidence suggests that cells which are deficient in acid sphingomyelinase are defective in apoptosis signalling. This data has been interpreted as support for the activation of acid sphingomyelinase as an early signal in apoptosis. Hypothesis An alternative explanation is put forward whereby the accumulation of intracellular sphingomyelin in sphingomyelinase deficient cells leads to the formation of intracellular rafts which lead to the sequestration of important signalling molecules that are normally present on the cell surface where they perform their function. Testing the hypothesis It is expected that the subcellular distribution of important signalling molecules is altered in acid sphingomyelinase deficient cells, leading to their sequestration in late endosomes / lysosomes. Other sphingolipid storage diseases such as Niemann-Pick type C which have normal acid sphingomyelinase activity would also be expected to show the same phenotype. Implications of the hypothesis If true the hypothesis would provide a mechanism for the pathology of the sphingolipid storage diseases at the cellular level and also have implications for the role of ceramide in apoptosis.

An Eco-Driving Advisory System for Continuous Signalized Intersections by Vehicular Ad Hoc Network

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Wei-Hsun Lee

2018-01-01

Full Text Available With the vehicular ad hoc network (VANET technology which support vehicle-to-vehicle (V2V and vehicle to road side unit (V2R/R2V communications, vehicles can preview the intersection signal plan such as signal countdown message. In this paper, an ecodriving advisory system (EDAS is proposed to reduce CO2 emissions and energy consumption by letting the vehicle continuously pass through multiple intersections with the minimum possibilities of stops. We extend the isolated intersection model to multiple continuous intersections scenario. A hybrid method combining three strategies including maximized throughput model (MTM, smooth speed model (SSM, and minimized acceleration and deceleration (MinADM is designed, and it is compared with related works maximized throughput model (MaxTM, open traffic light control model (OTLCM, and predictive cruise control (PCC models. Some issues for the practical application including safe car following, queue clearing, and gliding mode are discussed and conquered. Simulation results show that the proposed model outperforms OTLCM 25.1%~81.2% in the isolated intersection scenario for the CO2 emissions and 20.5%~84.3% in averaged travel time. It also performs better than the compared PCC model in CO2 emissions (19.9%~31.2% as well as travel time (24.5%~35.9% in the multiple intersections scenario.

Contributory factors to traffic crashes at signalized intersections in Hong Kong.

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Wong, S C; Sze, N N; Li, Y C

2007-11-01

Efficient geometric design and signal timing not only improve operational performance at signalized intersections by expanding capacity and reducing traffic delays, but also result in an appreciable reduction in traffic conflicts, and thus better road safety. Information on the incidence of crashes, traffic flow, geometric design, road environment, and traffic control at 262 signalized intersections in Hong Kong during 2002 and 2003 are incorporated into a crash prediction model. Poisson regression and negative binomial regression are used to quantify the influence of possible contributory factors on the incidence of killed and severe injury (KSI) crashes and slight injury crashes, respectively, while possible interventions by traffic flow are controlled. The results for the incidence of slight injury crashes reveal that the road environment, degree of curvature, and presence of tram stops are significant factors, and that traffic volume has a diminishing effect on the crash risk. The presence of tram stops, number of pedestrian streams, road environment, proportion of commercial vehicles, average lane width, and degree of curvature increase the risk of KSI crashes, but the effect of traffic volume is negligible.

Survival signalling and apoptosis resistance in glioblastomas: opportunities for targeted therapeutics

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Krakstad Camilla

2010-06-01

Full Text Available Abstract Glioblastoma multiforme (GBM is the most common primary brain tumour in adults and one of the most aggressive cancers in man. Despite technological advances in surgical management, combined regimens of radiotherapy with new generation chemotherapy, the median survival for these patients is 14.6 months. This is largely due to a highly deregulated tumour genome with opportunistic deletion of tumour suppressor genes, amplification and/or mutational hyper-activation of receptor tyrosine kinase receptors. The net result of these genetic changes is augmented survival pathways and systematic defects in the apoptosis signalling machinery. The only randomised, controlled phase II trial conducted targeting the epidermal growth factor receptor (EGFR signalling with the small molecule inhibitor, erlotinib, has showed no therapeutic benefit. Survival signalling and apoptosis resistance in GBMs can be viewed as two sides of the same coin. Targeting increased survival is unlikely to be efficacious without at the same time targeting apoptosis resistance. We have critically reviewed the literature regarding survival and apoptosis signalling in GBM, and highlighted experimental, preclinical and recent clinical trials attempting to target these pathways. Combined therapies simultaneously targeting apoptosis and survival signalling defects might shift the balance from tumour growth stasis to cytotoxic therapeutic responses that might be associated with greater therapeutic benefits.

Estimation of fuel loss due to idling of vehicles at a signalized intersection in Chennai, India

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Vasantha Kumar, S.; Gulati, Himanshu; Arora, Shivam

2017-11-01

The vehicles while waiting at signalized intersections are generally found to be in idling condition, i.e., not switching off their vehicles during red times. This phenomenon of idling of vehicles during red times at signalized intersections may lead to huge economic loss as lot of fuel is consumed by vehicles when they are in idling condition. The situation may even be worse in countries like India as different vehicle types consume varying amount of fuel. Only limited studies have been reported on estimation of fuel loss due to idling of vehicles in India. In the present study, one of the busy intersections in Chennai, namely, Tidel Park Junction in Rajiv Gandhi salai was considered. Data collection was carried out in one approach road of the intersection during morning and evening peak hours on a typical working day by manually noting down the red timings of each cycle and the corresponding number of two-wheelers, three-wheelers, passenger cars, light commercial vehicles (LCV) and heavy motorized vehicles (HMV) that were in idling mode. Using the fuel consumption values of various vehicles types suggested by Central Road Research Institute (CRRI), the total fuel loss during the study period was found to be Rs. 4,93,849/-. The installation of red timers, synchronization of signals, use of non-motorized transport for short trips and public awareness are some of the measures which government need to focus to save the fuel wasted at signalized intersections in major cities of India.

Modeling Left-Turn Driving Behavior at Signalized Intersections with Mixed Traffic Conditions

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Hong Li

2016-01-01

Full Text Available In many developing countries, mixed traffic is the most common type of urban transportation; traffic of this type faces many major problems in traffic engineering, such as conflicts, inefficiency, and security issues. This paper focuses on the traffic engineering concerns on the driving behavior of left-turning vehicles caused by different degrees of pedestrian violations. The traffic characteristics of left-turning vehicles and pedestrians in the affected region at a signalized intersection were analyzed and a cellular-automata-based “following-conflict” driving behavior model that mainly addresses four basic behavior modes was proposed to study the conflict and behavior mechanisms of left-turning vehicles by mathematic methodologies. Four basic driving behavior modes were reproduced in computer simulations, and a logit model of the behavior mode choice was also developed to analyze the relative share of each behavior mode. Finally, the microscopic characteristics of driving behaviors and the macroscopic parameters of traffic flow in the affected region were all determined. These data are important reference for geometry and capacity design for signalized intersections. The simulation results show that the proposed models are valid and can be used to represent the behavior of left-turning vehicles in the case of conflicts with illegally crossing pedestrians. These results will have potential applications on improving traffic safety and traffic capacity at signalized intersections with mixed traffic conditions.

Empirical Analysis and Modeling of Stop-Line Crossing Time and Speed at Signalized Intersections

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Keshuang Tang

2016-12-01

Full Text Available In China, a flashing green (FG indication of 3 s followed by a yellow (Y indication of 3 s is commonly applied to end the green phase at signalized intersections. Stop-line crossing behavior of drivers during such a phase transition period significantly influences safety performance of signalized intersections. The objective of this study is thus to empirically analyze and model drivers’ stop-line crossing time and speed in response to the specific phase transition period of FG and Y. High-resolution trajectories for 1465 vehicles were collected at three rural high-speed intersections with a speed limit of 80 km/h and two urban intersections with a speed limit of 50 km/h in Shanghai. With the vehicle trajectory data, statistical analyses were performed to look into the general characteristics of stop-line crossing time and speed at the two types of intersections. A multinomial logit model and a multiple linear regression model were then developed to predict the stop-line crossing patterns and speeds respectively. It was found that the percentage of stop-line crossings during the Y interval is remarkably higher and the stop-line crossing time is approximately 0.7 s longer at the urban intersections, as compared with the rural intersections. In addition, approaching speed and distance to the stop-line at the onset of FG as well as area type significantly affect the percentages of stop-line crossings during the FG and Y intervals. Vehicle type and stop-line crossing pattern were found to significantly influence the stop-line crossing speed, in addition to the above factors. The red-light-running seems to occur more frequently at the large intersections with a long cycle length.

Characteristics of turn signal use at intersections in baseline naturalistic driving.

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Sullivan, John M; Bao, Shan; Goudy, Roy; Konet, Heather

2015-01-01

The purpose of this study was to determine whether a driver's use of turn signals is sufficiently reliable to forecast a vehicle's future path around an intersection, when detailed information about the intersection is unavailable. Naturalistic observations of turn signal use among 108 drivers on surface streets were extracted from the baseline portion of a field operational test of a safety system. Left and right turns that resulted in heading changes of between 70 and 110° and turn radii between 18 and 90 m were selected from the dataset. The odds that a driver would signal a turn were modeled as a function of road type, turn direction, presence of a forward vehicle, whether the vehicle stopped before the turn, and driver age and gender. Overall, 25 percent of left turns and 29 percent of right turns were not signaled. Road type, turn direction, and presence of a forward vehicle were found to influence the odds that a turn is signaled, while gender and age of the driver did not. The results suggest that situational factors like road type and turn direction are more powerful predictors of whether a turn will be signaled than either age or gender. Signaling on major and minor surface roads was about 5 times more likely than on local roads and 1.5 times more likely when a forward vehicle was present, suggesting a possible effect of traffic volume. It was concluded that turn signal activation alone may be insufficiently reliable to forecast a driver's path. Copyright © 2014 Elsevier Ltd. All rights reserved.

IMPACTS OF GROUP-BASED SIGNAL CONTROL POLICY ON DRIVER BEHAVIOR AND INTERSECTION SAFETY

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Keshuang TANG

2008-01-01

Full Text Available Unlike the typical stage-based policy commonly applied in Japan, the group-based control (often called movement-based in the traffic control industry in Japan refers to such a control pattern that the controller is capable of separately allocating time to each signal group instead of stage based on traffic demand. In order to investigate its applicability at signalized intersections in Japan, an intersection located in Yokkaichi City of Mie Prefecture was selected as an experimental application site by the Japan Universal Traffic Management Society (UTMS. Based on the data collected at the intersection before and after implementing the group-based control policy respectively, this study evaluated the impacts of such a policy on driver behavior and intersection safety. To specify those impacts, a few models utilizing cycle-based data were first developed to interpret the occurrence probability and rate of red-light-running (RLR. Furthermore, analyses were performed on the yellow-entry time (Ye of the last cleared vehicle and post encroachment time (PET during the phase switching. Conclusions supported that the group-based control policy, along with certain other factors, directly or indirectly influenced the RLR behavior of through and right-turn traffics. Meanwhile, it has potential safety benefits as well, indicated by the declined Ye and increased PET values.

State-Space Equations and the First-Phase Algorithm for Signal Control of Single Intersections

Institute of Scientific and Technical Information of China (English)

LI Jinyuan; PAN Xin; WANG Xiqin

2007-01-01

State-space equations were applied to formulate the queuing and delay of traffic at a single intersection in this paper. The signal control of a single intersection was then modeled as a discrete-time optimal control problem, with consideration of the constraints of stream conflicts, saturation flow rate, minimum green time, and maximum green time. The problem cannot be solved directly due to the nonlinear constraints.However, the results of qualitative analysis were used to develop a first-phase signal control algorithm. Simulation results show that the algorithm substantially reduces the total delay compared to fixed-time control.

[Mechanisms of signaling associated with reactive nitrogen and oxygen in apoptosis].

Science.gov (United States)

Piłat, Justyna; Ługowski, Mateusz; Saczko, Jolanta; Choromańska, Anna; Chwiłkowska, Agnieszka; Banaś, Teresa; Kulbacka, Julita

2016-05-01

The knowledge of apoptotic mechanisms is essential in many biologic aspects related to both normal and neoplastic cells. Cell death by apoptosis is a very desirable way to eliminate unwanted cells: prevents release of the cellular content, which, in contrast to necrosis, provides no activation of inflammatory reactions. Apoptosis is a multistep process in where an extremely important role is played by caspases. Functions of caspases and their modifications are fundamental to understanding the signaling pathways responsible for regulation of apoptosis. These enzymes belong to a family of cysteine proteases that have the potential to destroy the enzymatic and structural proteins, and in the final stages of apoptosis, to lead to the disintegration of the cell. Apoptosis can be modulated by certain signaling pathway. © 2016 MEDPRESS.

Kurarinol induces hepatocellular carcinoma cell apoptosis through suppressing cellular signal transducer and activator of transcription 3 signaling

International Nuclear Information System (INIS)

Shu, Guangwen; Yang, Jing; Zhao, Wenhao; Xu, Chan; Hong, Zongguo; Mei, Zhinan; Yang, Xinzhou

2014-01-01

Kurarinol is a flavonoid isolated from roots of the medical plant Sophora flavescens. However, its cytotoxic activity against hepatocellular carcinoma (HCC) cells and toxic effects on mammalians remain largely unexplored. Here, the pro-apoptotic activities of kurarinol on HCC cells and its toxic impacts on tumor-bearing mice were evaluated. The molecular mechanisms underlying kurarinol-induced HCC cell apoptosis were also investigated. We found that kurarinol dose-dependently provoked HepG2, Huh-7 and H22 HCC cell apoptosis. In addition, kurarinol gave rise to a considerable decrease in the transcriptional activity of signal transducer and activator of transcription 3 (STAT3) in HCC cells. Suppression of STAT3 signaling is involved in kurarinol-induced HCC cell apoptosis. In vivo studies showed that kurarinol injection substantially induced transplanted H22 cell apoptosis with low toxic impacts on tumor-bearing mice. Similarly, the transcriptional activity of STAT3 in transplanted tumor tissues was significantly suppressed after kurarinol treatment. Collectively, our current research demonstrated that kurarinol has the capacity of inducing HCC cell apoptosis both in vitro and in vivo with undetectable toxic impacts on the host. Suppressing STAT3 signaling is implicated in kurarinol-mediated HCC cell apoptosis. - Highlights: • Kurarinol induces hepatocellular carcinoma (HCC) cell apoptosis. • Kurarinol induces HCC cell apoptosis via inhibiting STAT3. • Kurarinol exhibits low toxic effects on tumor-bearing animals

AERIS : Eco-Vehicle Speed Control at Signalized Intersections Using I2V Communication

Science.gov (United States)

2012-06-01

This report concentrates on a velocity advisory tool, or decision support system, for vehicles approaching an intersection using communication capabilities between the infrastructure and vehicles. The system uses available signal change information, ...

TGF-β signaling controls FSHR signaling-reduced ovarian granulosa cell apoptosis through the SMAD4/miR-143 axis.

Science.gov (United States)

Du, Xing; Zhang, Lifan; Li, Xinyu; Pan, Zengxiang; Liu, Honglin; Li, Qifa

2016-11-24

Follicle-stimulating hormone receptor (FSHR) and its intracellular signaling control mammalian follicular development and female infertility. Our previous study showed that FSHR is downregulated during follicular atresia of porcine ovaries. However, its role and regulation in follicular atresia remain unclear. Here, we showed that FSHR knockdown induced porcine granulosa cell (pGC) apoptosis and follicular atresia, and attenuated the levels of intracellular signaling molecules such as PKA, AKT and p-AKT. FSHR was identified as a target of miR-143, a microRNA that was upregulated during porcine follicular atresia. miR-143 enhanced pGC apoptosis by targeting FSHR, and reduced the levels of intracellular signaling molecules. SMAD4, the final molecule in transforming growth factor (TGF)-β signaling, bound to the promoter and induced significant downregulation of miR-143 in vitro and in vivo. Activated TGF-β signaling rescued miR-143-reduced FSHR and intracellular signaling molecules, and miR-143-induced pGC apoptosis. Overall, our findings offer evidence to explain how TGF-β signaling influences and FSHR signaling for regulation of pGC apoptosis and follicular atresia by a specific microRNA, miR-143.

Comparison of proposed countermeasures for dilemma zone at signalized intersections based on cellular automata simulations.

Science.gov (United States)

Wu, Yina; Abdel-Aty, Mohamed; Ding, Yaoxian; Jia, Bin; Shi, Qi; Yan, Xuedong

2018-07-01

The Type II dilemma zone describes the road segment to a signalized intersection where drivers have difficulties to decide either stop or go at the onset of yellow signal. Such phenomenon can result in an increased crash risk at signalized intersections. Different types of warning systems have been proposed to help drivers make decisions. Although the warning systems help to improve drivers' behavior, they also have several disadvantages such as increasing rear-end crashes or red-light running (RLR) violations. In this study, a new warning system called pavement marking with auxiliary countermeasure (PMAIC) is proposed to reduce the dilemma zone and enhance the traffic safety at signalized intersections. The proposed warning system integrates the pavement marking and flashing yellow system which can provide drivers with better suggestions about stop/go decisions based on their arriving time and speed. In order to evaluate the performance of the proposed warning system, this paper presents a cellular automata (CA) simulation study. The CA simulations are conducted for four different scenarios in total, including the typical intersection without warning system, the intersection with flashing green countermeasure, the intersection with pavement marking, and the intersection with the PMAIC warning system. Before the specific CA simulation analysis, a logistic regression model is calibrated based on field video data to predict drivers' general stop/go decisions. Also, the rules of vehicle movements in the CA models under the influence by different warning systems are proposed. The proxy indicators of rear-end crash and potential RLR violations were estimated and used to evaluate safety levels for the different scenarios. The simulation results showed that the PMAIC countermeasure consistently offered best performance to reduce rear-end crash and RLR violation. Meanwhile, the results indicate that the flashing-green countermeasure could not effectively reduce either rear

Saturation flow versus green time at two-stage signal controlled intersections

Directory of Open Access Journals (Sweden)

A. Boumediene

2009-12-01

Full Text Available Intersections are the key components of road networks considerably affecting capacity. As flow levels and experience have increased over the years, methods and means have been developed to cope with growing demand for traffic at road junctions. Among various traffic control devices and techniques developed to cope with conflicting movements, traffic signals create artificial gaps to accommodate the impeded traffic streams. The majority of parameters that govern signalised intersection control and operations such as a degree of saturation, delays, queue lengths, the level of service etc. are very sensitive to saturation flow. Therefore, it is essential to reliably evaluate saturation flow for correctly setting traffic signals to avoid unnecessary delays and conflicts. Generally, almost all guidelines support the constancy of saturation flow irrespective of green time duration. This paper presents the results of field studies carried out to enable the performance of signalised intersections to be compared at different green time durations. It was found that saturation flow decreased slightly with growing green time. Reduction corresponded to between 2 and 5 pcus/gh per second of green time. However, the analyses of the discharge rate during the successive time intervals of 6-seconds showed a substantial reduction of 10% to 13% in saturation flow levels after 36 seconds of green time compared to those relating to 6–36 seconds range. No reduction in saturation flow levels was detected at the sites where only green periods of 44 seconds or less were implemented.

Driver behavior analysis for right-turn drivers at signalized intersections using SHRP 2 naturalistic driving study data.

Science.gov (United States)

Wu, Jianqing; Xu, Hao

2017-12-01

Understanding driver behavior is important for traffic safety and operation, especially at intersections where different traffic movements conflict. While most driver-behavior studies are based on simulation, this paper documents the analysis of driver-behavior at signalized intersections with the SHRP 2 Naturalistic Driving Study (NDS) data. This study analyzes the different influencing factors on the operation (speed control) and observation of right-turn drivers. A total of 300 NDS trips at six signalized intersections were used, including the NDS time-series sensor data, the forward videos and driver face videos. Different factors of drivers, vehicles, roads and environments were studied for their influence on driver behavior. An influencing index function was developed and the index was calculated for each influencing factor to quantitatively describe its influencing level. The influencing index was applied to prioritize the factors, which facilitates development and selection of safety countermeasures to improve intersection safety. Drivers' speed control was analyzed under different conditions with consideration of the prioritized influencing factors. Vehicle type, traffic signal status, conflicting traffic, conflicting pedestrian and driver age group were identified as the five major influencing factors on driver observation. This research revealed that drivers have high acceleration and low observation frequency under Right-Turn-On-Red (RTOR), which constituted potential danger for other roadway users, especially for pedestrians. As speed has a direct influence on crash rates and severities, the revealed speed patterns of the different situations also benefit selection of safety countermeasures at signalized intersections. Published by Elsevier Ltd.

A Heckman selection model for the safety analysis of signalized intersections.

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Xuecai Xu

Full Text Available The objective of this paper is to provide a new method for estimating crash rate and severity simultaneously.This study explores a Heckman selection model of the crash rate and severity simultaneously at different levels and a two-step procedure is used to investigate the crash rate and severity levels. The first step uses a probit regression model to determine the sample selection process, and the second step develops a multiple regression model to simultaneously evaluate the crash rate and severity for slight injury/kill or serious injury (KSI, respectively. The model uses 555 observations from 262 signalized intersections in the Hong Kong metropolitan area, integrated with information on the traffic flow, geometric road design, road environment, traffic control and any crashes that occurred during two years.The results of the proposed two-step Heckman selection model illustrate the necessity of different crash rates for different crash severity levels.A comparison with the existing approaches suggests that the Heckman selection model offers an efficient and convenient alternative method for evaluating the safety performance at signalized intersections.

Endoplasmic Reticulum Is at the Crossroads of Autophagy, Inflammation, and Apoptosis Signaling Pathways and Participates in the Pathogenesis of Diabetes Mellitus

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Jing Su

2013-01-01

Full Text Available Diabetes mellitus (DM is a chronic metabolic disease, and its incidence is growing worldwide. The endoplasmic reticulum (ER is a central component of cellular functions and is involved in protein folding and trafficking, lipid synthesis, and maintenance of calcium homeostasis. The ER is also a sensor of both intra- and extracellular stress and thus participates in monitoring and maintaining cellular homeostasis. Therefore, the ER is one site of interaction between environmental signals and a cell’s biological function. The ER is tightly linked to autophagy, inflammation, and apoptosis, and recent evidence suggests that these processes are related to the pathogenesis of DM and its complications. Thus, the ER has been considered an intersection integrating multiple stress responses and playing an important role in metabolism-related diseases including DM. Here, we review the relationship between the ER and autophagy, inflammation, and apoptosis in DM to better understand the molecular mechanisms of this disease.

Evaluation of the dispersion effect in through movement bicycles at signalized intersection via cellular automata simulation

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Jiang, Hang; Ma, Yongjian; Jiang, Lin; Chen, Guozhou; Wang, Dongwei

2018-05-01

At signalized intersection areas, bicycle traffic presents a dispersion feature which may influence the movements of vehicles during peak period. The primary objective of this study is to simulate the dispersion effect in through-movement bicycle traffic at intersection areas and evaluate its influence on through-movement traffic. A cellular automata (CA) model is developed and validated to simulate the operations of through-movement bicycle traffic departing from two types of intersection approaches. Simulation results show that bicycles benefit from the dispersion effect when they depart from the approach with an exclusive right-turn vehicle lane. But when bicycles travel from the approach with a shared right-turn and through vehicle lane, the dispersion effect will result in friction interference and block interference on through-movement vehicles. Bicycle interferences reduce the vehicle speed and increase the delay of through-movement vehicles. The policy implications in regard to the dispersion effect from two types of approaches are discussed to improve the performance of through-movement traffic operations at signalized intersections.

Multiobjective Traffic Signal Control Model for Intersection Based on Dynamic Turning Movements Estimation

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Pengpeng Jiao

2014-01-01

Full Text Available The real-time traffic signal control for intersection requires dynamic turning movements as the basic input data. It is impossible to detect dynamic turning movements directly through current traffic surveillance systems, but dynamic origin-destination (O-D estimation can obtain it. However, the combined models of dynamic O-D estimation and real-time traffic signal control are rare in the literature. A framework for the multiobjective traffic signal control model for intersection based on dynamic O-D estimation (MSC-DODE is presented. A state-space model using Kalman filtering is first formulated to estimate the dynamic turning movements; then a revised sequential Kalman filtering algorithm is designed to solve the model, and the root mean square error and mean percentage error are used to evaluate the accuracy of estimated dynamic turning proportions. Furthermore, a multiobjective traffic signal control model is put forward to achieve real-time signal control parameters and evaluation indices. Finally, based on practical survey data, the evaluation indices from MSC-DODE are compared with those from Webster method. The actual and estimated turning movements are further input into MSC-DODE, respectively, and results are also compared. Case studies show that results of MSC-DODE are better than those of Webster method and are very close to unavailable actual values.

Micro-simulation of vehicle conflicts involving right-turn vehicles at signalized intersections based on cellular automata.

Science.gov (United States)

Chai, C; Wong, Y D

2014-02-01

At intersection, vehicles coming from different directions conflict with each other. Improper geometric design and signal settings at signalized intersection will increase occurrence of conflicts between road users and results in a reduction of the safety level. This study established a cellular automata (CA) model to simulate vehicular interactions involving right-turn vehicles (as similar to left-turn vehicles in US). Through various simulation scenarios for four case cross-intersections, the relationships between conflict occurrences involving right-turn vehicles with traffic volume and right-turn movement control strategies are analyzed. Impacts of traffic volume, permissive right-turn compared to red-amber-green (RAG) arrow, shared straight-through and right-turn lane as well as signal setting are estimated from simulation results. The simulation model is found to be able to provide reasonable assessment of conflicts through comparison of existed simulation approach and observed accidents. Through the proposed approach, prediction models for occurrences and severity of vehicle conflicts can be developed for various geometric layouts and traffic control strategies. Copyright © 2013 Elsevier Ltd. All rights reserved.

Influences of motorcycle rider and driver characteristics and road environment on red light running behavior at signalized intersections.

Science.gov (United States)

Jensupakarn, Auearree; Kanitpong, Kunnawee

2018-04-01

In Thailand, red light running is considered as one of the most dangerous behaviors at intersection. Red light running (RLR) behavior is the failure to obey the traffic control signal. However, motorcycle riders and car drivers who are running through red lights could be influenced by human factors or road environment at intersection. RLR could be advertent or inadvertent behavior influenced by many factors. Little research study has been done to evaluate the contributing factors influencing the red-light violation behavior. This study aims to determine the factors influencing the red light running behavior including human characteristics, physical condition of intersection, traffic signal operation, and traffic condition. A total of 92 intersections were observed in Chiang Mai, Nakhon Ratchasima, and Chonburi, the major provinces in each region of Thailand. In addition, the socio-economic characteristics of red light runners were obtained from self-reported questionnaire survey. The Binary Logistic Regression and the Multiple Linear Regression models were used to determine the characteristics of red light runners and the factors influencing rates of red light running respectively. The results from this study can help to understand the characteristics of red light runners and factors affecting them to run red lights. For motorcycle riders and car drivers, age, gender, occupation, driving license, helmet/seatbelt use, and the probability to be penalized when running the red light significantly affect RLR behavior. In addition, the results indicated that vehicle travelling direction, time of day, existence of turning lane, number of lanes, lane width, intersection sight distance, type of traffic signal pole, type of traffic signal operation, length of yellow time interval, approaching speed, distance from intersection warning sign to stop line, and pavement roughness significantly affect RLR rates. Copyright © 2018 Elsevier Ltd. All rights reserved.

Safety surrogate histograms (SSH): A novel real-time safety assessment of dilemma zone related conflicts at signalized intersections.

Science.gov (United States)

Ghanipoor Machiani, Sahar; Abbas, Montasir

2016-11-01

Drivers' indecisiveness in dilemma zones (DZ) could result in crash-prone situations at signalized intersections. DZ is to the area ahead of an intersection in which drivers encounter a dilemma regarding whether to stop or proceed through the intersection when the signal turns yellow. An improper decision to stop by the leading driver, combined with the following driver deciding to go, can result in a rear-end collision, unless the following driver recognizes a collision is imminent and adjusts his or her behavior at or shortly after the onset of yellow. Considering the significance of DZ-related crashes, a comprehensive safety measure is needed to characterize the level of safety at signalized intersections. In this study, a novel safety surrogate measure was developed utilizing real-time radar field data. This new measure, called safety surrogate histogram (SSH), captures the degree and frequency of DZ-related conflicts at each intersection approach. SSH includes detailed information regarding the possibility of crashes, because it is calculated based on the vehicles conflicts. An example illustrating the application of the new methodology at two study sites in Virginia is presented and discussed, and a comparison is provided between SSH and other DZ-related safety surrogate measures mentioned in the literature. The results of the study reveal the efficacy of the SSH as complementary to existing surrogate measures. Copyright © 2015 Elsevier Ltd. All rights reserved.

Modeling the frequency of opposing left-turn conflicts at signalized intersections using generalized linear regression models.

Science.gov (United States)

Zhang, Xin; Liu, Pan; Chen, Yuguang; Bai, Lu; Wang, Wei

2014-01-01

The primary objective of this study was to identify whether the frequency of traffic conflicts at signalized intersections can be modeled. The opposing left-turn conflicts were selected for the development of conflict predictive models. Using data collected at 30 approaches at 20 signalized intersections, the underlying distributions of the conflicts under different traffic conditions were examined. Different conflict-predictive models were developed to relate the frequency of opposing left-turn conflicts to various explanatory variables. The models considered include a linear regression model, a negative binomial model, and separate models developed for four traffic scenarios. The prediction performance of different models was compared. The frequency of traffic conflicts follows a negative binominal distribution. The linear regression model is not appropriate for the conflict frequency data. In addition, drivers behaved differently under different traffic conditions. Accordingly, the effects of conflicting traffic volumes on conflict frequency vary across different traffic conditions. The occurrences of traffic conflicts at signalized intersections can be modeled using generalized linear regression models. The use of conflict predictive models has potential to expand the uses of surrogate safety measures in safety estimation and evaluation.

Low dose gamma irradiation enhances defined signaling components of intercellular reactive oxygen-mediated apoptosis induction

International Nuclear Information System (INIS)

Bauer, G

2011-01-01

Transformed cells are selectively removed by intercellular ROS-mediated induction of apoptosis. Signaling is based on the HOCl and the NO/peroxynitrite pathway (major pathways) and the nitryl chloride and the metal-catalyzed Haber-Weiss pathway (minor pathways). During tumor progression, resistance against intercellular induction of apoptosis is acquired through expression of membrane-associated catalase. Low dose radiation of nontransformed cells has been shown to enhance intercellular induction of apoptosis. The present study was performed to define the signaling components which are modulated by low dose gamma irradiation. Low dose radiation induced the release of peroxidase from nontransformed, transformed and tumor cells. Extracellular superoxide anion generation was strongly enhanced in the case of transformed cells and tumor cells, but not in nontransformed cells. Enhancement of peroxidase release and superoxide anion generation either increased intercellular induction of apoptosis of transformed cells, or caused a partial protection under specific signaling conditions. In tumor cells, low dose radiation enhanced the production of major signaling components, but this had no effect on apoptosis induction, due to the strong resistance mechanism of tumor cells. Our data specify the nature of low dose radiation-induced effects on specific signaling components of intercellular induction of apoptosis at defined stages of multistep carcinogenesis.

Apoptosis signaling and radiation protection

International Nuclear Information System (INIS)

Morita, Akinori; Suzuki, Norio; Hosoi, Yoshio

2005-01-01

Radiation protection by apoptosis control is the suppression of cell death in highly radiosensitive tissues. This paper describes the outline of radiation-induced apoptosis framework, apoptosis-concerned target molecules possibly related to apoptosis by radiation and their inhibitors. Although there are intrinsic (via mitochondria) and extrinsic (via death receptor) pathways in apoptosis, this review mainly mentions the former which is more important in radiation-induced apoptosis. Those molecules known at present in the apoptosis are caspase, Bcl-2 family and p53. Caspase, a group of cystein proteases, initiates apoptosis but its inhibition is known not always to result in apoptosis suppression, suggesting the existence of caspase-independent pathways. Bcl-2 family involves apoptosis-suppressing (possessing BH domains) and -promoting (lacking BH domains or possessing BH3 domain alone/BH3-only protein) groups. Two p53-transcription-dependent and one -independent pathways in p53-induced apoptosis are known and p53 can be a most possible target molecule since it positions at the start of apoptosis. Authors have found a vanadate inactivates p53. Inhibitors affecting upstream molecules of apoptosis will be the most useful candidate for apoptosis suppression/radiation protection. (S.I.) 106 refs

Influence of dimension box differences and time differences during operations of red box for motorcycles at signalized intersection

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Mulyadi, Agah Muhammad

2017-11-01

Performance of signalized intersection has declined due to a large number of motorcycles. The number of motorcycles reached 98.2 million units and the composition of motorcycles has reached around 81.7% of the total composition of vehicles in Indonesia (AISI, 2017). To solve that problem, the red box for motorcycles are provided at the signalized intersection. Red box for the motorcycle at signalized intersections was developed from the concept of Advance Stop Line (ASL) for bicycles. The Red Box was developed to split the queue between motorcycles and other vehicles when waiting at red light. This paper aims to evaluate the influence of the red box dimension and red time operation differences. The survey was conducted as many as 30 cycles of traffic signals per day. The data were analyzed using software IBM SPSS Statistics 20 by using Analysis of Variance (ANOVA) to obtain p-value (significant). The analysis shows that there are insignificant influences between the occupancy rates to the dimension of Red Box. Furthermore, that there is a significant difference that shows the dependency of only motorcycles in the Red Box Area towards red time operation.

Best response game of traffic on road network of non-signalized intersections

Science.gov (United States)

Yao, Wang; Jia, Ning; Zhong, Shiquan; Li, Liying

2018-01-01

This paper studies the traffic flow in a grid road network with non-signalized intersections. The nature of the drivers in the network is simulated such that they play an iterative snowdrift game with other drivers. A cellular automata model is applied to study the characteristics of the traffic flow and the evolution of the behaviour of the drivers during the game. The drivers use best-response as their strategy to update rules. Three major findings are revealed. First, the cooperation rate in simulation experiences staircase-shaped drop as cost to benefit ratio r increases, and cooperation rate can be derived analytically as a function of cost to benefit ratio r. Second, we find that higher cooperation rate corresponds to higher average speed, lower density and higher flow. This reveals that defectors deteriorate the efficiency of traffic on non-signalized intersections. Third, the system experiences more randomness when the density is low because the drivers will not have much opportunity to update strategy when the density is low. These findings help to show how the strategy of drivers in a traffic network evolves and how their interactions influence the overall performance of the traffic system.

Human-like motion planning model for driving in signalized intersections

Directory of Open Access Journals (Sweden)

Yanlei Gu

2017-10-01

Full Text Available Highly automated and fully autonomous vehicles are much more likely to be accepted if they react in the same way as human drivers do, especially in a hybrid traffic situation, which allows autonomous vehicles and human-driven vehicles to share the same road. This paper proposes a human-like motion planning model to represent how human drivers assess environments and operate vehicles in signalized intersections. The developed model consists of a pedestrian intention detection model, gap detection model, and vehicle control model. These three submodels are individually responsible for situation assessment, decision making, and action, and also depend on each other in the process of motion planning. In addition, these submodels are constructed and learned on the basis of human drivers' data collected from real traffic environments. To verify the effectiveness of the proposed motion planning model, we compared the proposed model with actual human driver and pedestrian data. The experimental results showed that our proposed model and actual human driver behaviors are highly similar with respect to gap acceptance in intersections.

A simulator-based analysis of engineering treatments for right-hook bicycle crashes at signalized intersections.

Science.gov (United States)

Warner, Jennifer; Hurwitz, David S; Monsere, Christopher M; Fleskes, Kayla

2017-07-01

A right-hook crash is a crash between a right-turning motor vehicle and an adjacent through-moving bicycle. At signalized intersections, these crashes can occur during any portion of the green interval when conflicting bicycles and vehicles are moving concurrently. The objective of this research was to evaluate the effectiveness of four types of engineering countermeasures - regulatory signage, intersection pavement marking, smaller curb radius, and protected intersection design - at modifying driver behaviors that are known contributing factors in these crashes. This research focused on right-hook crashes that occur during the latter stage of the circular green indication at signalized intersections with a shared right-turn and through lane. Changes in driver performance in response to treatments were measured in a high-fidelity driving simulator. Twenty-eight participants each completed 22 right-turn maneuvers. A partially counterbalanced experimental design exposed drivers to critical scenarios, which had been determined in a previous experiment. For each turn, driver performance measures, including visual attention, crash avoidance, and potential crash severity, were collected. A total of 75 incidents (47 near-collisions and 28 collisions) were observed during the 616 right turns. All treatments had some positive effect on measured driver performance with respect to the right-turn vehicle conflicts. Further work is required to map the magnitude of these changes in driver performance to crash-based outcomes. Copyright © 2017 Elsevier Ltd. All rights reserved.

V2I-based startup assistance system at signalized intersections

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Jianqiang Wang

2015-08-01

Full Text Available Traffic delays are caused by unskilled vehicle operation and driver distraction during the startup process at signalized intersections. To address this issue, we propose a V2I-based driver assistance system that can acquire the current traffic signal status and provide drivers with startup assistance. This article presents the proposed system’s architecture and an assistance algorithm, which contains two types of driver assistance methods: startup prompting and automatic startup control. The automatic startup control method, based on fuzzy logic control, is validated in simulation tests. We also implement startup prompting using a prototype system and validate its performance in field tests. The test results suggest that the proposed assistance algorithm can help drivers start up their vehicles with less delay, which will significantly improve traffic efficiency.

Research on the Method of Setting Waiting Area for Non-motor Vehicle at Signal Control Intersection

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Wang Yun Xia

2018-01-01

Full Text Available Electric bicycle has become an indispensable important component of the transportation system. The fact is that traffic organization and channelizing design of signal control intersection is not intensive, which cannot adapt to the current traffic demand of non-motor vehicle, such as unclear traffic rules and poor visibility, thus the traffic safety of non-motor vehicle is not optimistic. Therefore, it is necessary to study on traffic organization method based on the demand of non-motor vehicle, which can provide certain theoretical basis for traffic administrative department to make policy and traffic design. This article focuses on the method of setting waiting area for non-motor vehicle at signal control intersection, including the advantages, disadvantages and the applicable conditions.

An extended car-following model at un-signalized intersections under V2V communication environment

Science.gov (United States)

Wang, Tao; Li, Peng

2018-01-01

An extended car-following model is proposed in this paper to analyze the impacts of V2V (vehicle to vehicle) communication on the micro driving behavior at the un-signalized intersection. A four-leg un-signalized intersection with twelve streams (left-turn, through movement, and right turn from each leg) is used. The effect of the guidance strategy on the reduction of the rate of stops and total delay is explored by comparing the proposed model and the traditional FVD car-following model. The numerical results illustrate that potential conflicts between vehicles can be predicted and some stops can be avoided by decelerating in advance. The driving comfort and traffic efficiency can be improved accordingly. More benefits could be obtained under the long communication range, low to medium traffic density, and simple traffic pattern conditions. PMID:29425243

Apoptosis signal-regulating kinase 1 mediates denbinobin-induced apoptosis in human lung adenocarcinoma cells

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Pan Shiow-Lin

2009-05-01

Full Text Available Abstract In the present study, we explore the role of apoptosis signal-regulating kinase 1 (ASK1 in denbinobin-induced apoptosis in human lung adenocarcinoma (A549 cells. Denbinobin-induced cell apoptosis was attenuated by an ASK1 dominant-negative mutant (ASK1DN, two antioxidants (N-acetyl-L-cysteine (NAC and glutathione (GSH, a c-Jun N-terminal kinase (JNK inhibitor (SP600125, and an activator protein-1 (AP-1 inhibitor (curcumin. Treatment of A549 cells with denbinobin caused increases in ASK1 activity and reactive oxygen species (ROS production, and these effects were inhibited by NAC and GSH. Stimulation of A549 cells with denbinobin caused JNK activation; this effect was markedly inhibited by NAC, GSH, and ASK1DN. Denbinobin induced c-Jun phosphorylation, the formation of an AP-1-specific DNA-protein complex, and Bim expression. Bim knockdown using a bim short interfering RNA strategy also reduced denbinobin-induced A549 cell apoptosis. The denbinobin-mediated increases in c-Jun phosphorylation and Bim expression were inhibited by NAC, GSH, SP600125, ASK1DN, JNK1DN, and JNK2DN. These results suggest that denbinobin might activate ASK1 through ROS production to cause JNK/AP-1 activation, which in turn induces Bim expression, and ultimately results in A549 cell apoptosis.

Coordinated signal control for arterial intersections using fuzzy logic

Science.gov (United States)

Kermanian, Davood; Zare, Assef; Balochian, Saeed

2013-09-01

Every day growth of the vehicles has become one of the biggest problems of urbanism especially in major cities. This can waste people's time, increase the fuel consumption, air pollution, and increase the density of cars and vehicles. Fuzzy controllers have been widely used in many consumer products and industrial applications with success over the past two decades. This article proposes a comprehensive model of urban traffic network using state space equations and then using Fuzzy Logic Tool Box and SIMULINK Program MATLAB a fuzzy controller in order to optimize and coordinate signal control at two intersections at an arterial road. The fuzzy controller decides to extend, early cut or terminate a signal phase and phase sequence to ensure smooth flow of traffic with minimal waiting time and length of queue. Results show that the performance of the proposed traffic controller at novel fuzzy model is better that of conventional controllers under normal and abnormal traffic conditions.

An Optimization Model of Multi-Intersection Signal Control for Trunk Road under Collaborative Information

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Xun Li

2017-01-01

Full Text Available We proposed a signal control optimization model for urban main trunk line intersections. Four-phase intersection was analyzed and modeled based on the Cell Transmission Model (CTM. CTM and signal control model in our study had both been improved for multi-intersections by three-phase theory and information-exchanging. To achieve a real-time application, an improved genetic algorithm (GA was proposed finally, the DISCO traffic simulation software was used for numerical simulation experiment, and comparisons with the standard GA and CTM were reported in this paper. Experimental results indicate that our searching time is less than that of SGA by 38%, and our method needs only 1/3 iteration time of SGA. According to our DISCO traffic simulation processing, compared with SGA, if the input traffic flow is changed from free phase to synchronized phase, for example, less than 900 vel/h, the delay time can reduce to 87.99% by our method, and the minimum delay time is 77.76% of existing method. Furthermore, if input traffic volume is increased to 1200 vel/h or more at the synchronized phase, the summary and minimum values of average delay time are reduced to 81.16% and 75.83%, respectively, and the average delay time is reduced to 17.72 seconds.

Role of nuclear bodies in apoptosis signalling.

Science.gov (United States)

Krieghoff-Henning, Eva; Hofmann, Thomas G

2008-11-01

Promyelocytic leukemia nuclear bodies (PML NBs) are dynamic macromolecular multiprotein complexes that recruit and release a plethora of proteins. A considerable number of PML NB components play vital roles in apoptosis, senescence regulation and tumour suppression. The molecular basis by which PML NBs control these cellular responses is still just beginning to be understood. In addition to PML itself, numerous further tumour suppressors including transcriptional regulator p53, acetyl transferase CBP (CREB binding protein) and protein kinase HIPK2 (homeodomain interacting protein kinase 2) are recruited to PML NBs in response to genotoxic stress or oncogenic transformation and drive the senescence and apoptosis response by regulating p53 activity. Moreover, in response to death-receptor activation, PML NBs may act as nuclear depots that release apoptotic factors, such as the FLASH (FLICE-associated huge) protein, to amplify the death signal. PML NBs are also associated with other nuclear domains including Cajal bodies and nucleoli and share apoptotic regulators with these domains, implying crosstalk between NBs in apoptosis regulation. In conclusion, PML NBs appear to regulate cell death decisions through different, pathway-specific molecular mechanisms.

Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents.

Science.gov (United States)

Hickman, M J; Samson, L D

1999-09-14

All cells are unavoidably exposed to chemicals that can alkylate DNA to form genotoxic damage. Among the various DNA lesions formed, O(6)-alkylguanine lesions can be highly cytotoxic, and we recently demonstrated that O(6)-methylguanine (O(6)MeG) and O(6)-chloroethylguanine (O(6)CEG) specifically initiate apoptosis in hamster cells. Here we show, in both hamster and human cells, that the MutSalpha branch of the DNA mismatch repair pathway (but not the MutSbeta branch) is absolutely required for signaling the initiation of apoptosis in response to O(6)MeGs and is partially required for signaling apoptosis in response to O(6)CEGs. Further, O(6)MeG lesions signal the stabilization of the p53 tumor suppressor, and such signaling is also MutSalpha-dependent. Despite this, MutSalpha-dependent apoptosis can be executed in a p53-independent manner. DNA mismatch repair status did not influence the response of cells to other inducers of p53 and apoptosis. Thus, it appears that mismatch repair status, rather than p53 status, is a strong indicator of the susceptibility of cells to alkylation-induced apoptosis. This experimental system will allow dissection of the signal transduction events that couple a specific type of DNA base lesion with the final outcome of apoptotic cell death.

Analysis of Emission Effects Related to Drivers' Compliance Rates for Cooperative Vehicle-Infrastructure System at Signalized Intersections.

Science.gov (United States)

Liao, Ruohua; Chen, Xumei; Yu, Lei; Sun, Xiaofei

2018-01-12

Unknown remaining time of signal phase at a signalized intersection generally results in extra accelerations and decelerations that increase variations of operating conditions and thus emissions. A cooperative vehicle-infrastructure system can reduce unnecessary speed changes by establishing communications between vehicles and the signal infrastructure. However, the environmental benefits largely depend on drivers' compliance behaviors. To quantify the effects of drivers' compliance rates on emissions, this study applied VISSIM 5.20 (Planung Transport Verkehr AG, Karlsruhe, Germany) to develop a simulation model for a signalized intersection, in which light duty vehicles were equipped with a cooperative vehicle-infrastructure system. A vehicle-specific power (VSP)-based model was used to estimate emissions. Based on simulation data, the effects of different compliance rates on VSP distributions, emission factors, and total emissions were analyzed. The results show the higher compliance rate decreases the proportion of VSP bin = 0, which means that the frequencies of braking and idling were lower and light duty vehicles ran more smoothly at the intersection if more light duty vehicles complied with the cooperative vehicle-infrastructure system, and emission factors for light duty vehicles decreased significantly as the compliance rate increased. The case study shows higher total emission reductions were observed with higher compliance rate for all of CO₂, NO x , HC, and CO emissions. CO₂ was reduced most significantly, decreased by 16% and 22% with compliance rates of 0.3 and 0.7, respectively.

Analysis of Emission Effects Related to Drivers’ Compliance Rates for Cooperative Vehicle-Infrastructure System at Signalized Intersections

Science.gov (United States)

Liao, Ruohua; Yu, Lei; Sun, Xiaofei

2018-01-01

Unknown remaining time of signal phase at a signalized intersection generally results in extra accelerations and decelerations that increase variations of operating conditions and thus emissions. A cooperative vehicle-infrastructure system can reduce unnecessary speed changes by establishing communications between vehicles and the signal infrastructure. However, the environmental benefits largely depend on drivers’ compliance behaviors. To quantify the effects of drivers’ compliance rates on emissions, this study applied VISSIM 5.20 (Planung Transport Verkehr AG, Karlsruhe, Germany) to develop a simulation model for a signalized intersection, in which light duty vehicles were equipped with a cooperative vehicle-infrastructure system. A vehicle-specific power (VSP)-based model was used to estimate emissions. Based on simulation data, the effects of different compliance rates on VSP distributions, emission factors, and total emissions were analyzed. The results show the higher compliance rate decreases the proportion of VSP bin = 0, which means that the frequencies of braking and idling were lower and light duty vehicles ran more smoothly at the intersection if more light duty vehicles complied with the cooperative vehicle-infrastructure system, and emission factors for light duty vehicles decreased significantly as the compliance rate increased. The case study shows higher total emission reductions were observed with higher compliance rate for all of CO2, NOx, HC, and CO emissions. CO2 was reduced most significantly, decreased by 16% and 22% with compliance rates of 0.3 and 0.7, respectively. PMID:29329214

Analysis of Emission Effects Related to Drivers’ Compliance Rates for Cooperative Vehicle-Infrastructure System at Signalized Intersections

Directory of Open Access Journals (Sweden)

Ruohua Liao

2018-01-01

Full Text Available Unknown remaining time of signal phase at a signalized intersection generally results in extra accelerations and decelerations that increase variations of operating conditions and thus emissions. A cooperative vehicle-infrastructure system can reduce unnecessary speed changes by establishing communications between vehicles and the signal infrastructure. However, the environmental benefits largely depend on drivers’ compliance behaviors. To quantify the effects of drivers’ compliance rates on emissions, this study applied VISSIM 5.20 (Planung Transport Verkehr AG, Karlsruhe, Germany to develop a simulation model for a signalized intersection, in which light duty vehicles were equipped with a cooperative vehicle-infrastructure system. A vehicle-specific power (VSP-based model was used to estimate emissions. Based on simulation data, the effects of different compliance rates on VSP distributions, emission factors, and total emissions were analyzed. The results show the higher compliance rate decreases the proportion of VSP bin = 0, which means that the frequencies of braking and idling were lower and light duty vehicles ran more smoothly at the intersection if more light duty vehicles complied with the cooperative vehicle-infrastructure system, and emission factors for light duty vehicles decreased significantly as the compliance rate increased. The case study shows higher total emission reductions were observed with higher compliance rate for all of CO2, NOx, HC, and CO emissions. CO2 was reduced most significantly, decreased by 16% and 22% with compliance rates of 0.3 and 0.7, respectively.

Low-cost safety enhancements for stop-controlled and signalized intersections

Science.gov (United States)

2009-05-01

The purpose of this document is to present information on suggested effective, low-cost intersection countermeasures developed using intersection safety research results and input from an intersection safety expert panel. These low-cost countermeasur...

The necrotic signal induced by mycophenolic acid overcomes apoptosis-resistance in tumor cells.

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Gwendaline Guidicelli

Full Text Available BACKGROUND: The amount of inosine monophosphate dehydrogenase (IMPDH, a pivotal enzyme for the biosynthesis of the guanosine tri-phosphate (GTP, is frequently increased in tumor cells. The anti-viral agent ribavirin and the immunosuppressant mycophenolic acid (MPA are potent inhibitors of IMPDH. We recently showed that IMPDH inhibition led to a necrotic signal requiring the activation of Cdc42. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we strengthened the essential role played by this small GTPase in the necrotic signal by silencing Cdc42 and by the ectopic expression of a constitutive active mutant of Cdc42. Since resistance to apoptosis is an essential step for the tumorigenesis process, we next examined the effect of the MPA-mediated necrotic signal on different tumor cells demonstrating various mechanisms of resistance to apoptosis (Bcl2-, HSP70-, Lyn-, BCR-ABL-overexpressing cells. All tested cells remained sensitive to MPA-mediated necrotic signal. Furthermore, inhibition of IMPDH activity in Chronic Lymphocytic Leukemia cells was significantly more efficient at eliminating malignant cells than apoptotic inducers. CONCLUSIONS/SIGNIFICANCE: These findings indicate that necrosis and apoptosis are split signals that share few if any common hub of signaling. In addition, the necrotic signaling pathway induced by depletion of the cellular amount of GTP/GDP would be of great interest to eliminate apoptotic-resistant tumor cells.

Influential factors of red-light running at signalized intersection and prediction using a rare events logistic regression model.

Science.gov (United States)

Ren, Yilong; Wang, Yunpeng; Wu, Xinkai; Yu, Guizhen; Ding, Chuan

2016-10-01

Red light running (RLR) has become a major safety concern at signalized intersection. To prevent RLR related crashes, it is critical to identify the factors that significantly impact the drivers' behaviors of RLR, and to predict potential RLR in real time. In this research, 9-month's RLR events extracted from high-resolution traffic data collected by loop detectors from three signalized intersections were applied to identify the factors that significantly affect RLR behaviors. The data analysis indicated that occupancy time, time gap, used yellow time, time left to yellow start, whether the preceding vehicle runs through the intersection during yellow, and whether there is a vehicle passing through the intersection on the adjacent lane were significantly factors for RLR behaviors. Furthermore, due to the rare events nature of RLR, a modified rare events logistic regression model was developed for RLR prediction. The rare events logistic regression method has been applied in many fields for rare events studies and shows impressive performance, but so far none of previous research has applied this method to study RLR. The results showed that the rare events logistic regression model performed significantly better than the standard logistic regression model. More importantly, the proposed RLR prediction method is purely based on loop detector data collected from a single advance loop detector located 400 feet away from stop-bar. This brings great potential for future field applications of the proposed method since loops have been widely implemented in many intersections and can collect data in real time. This research is expected to contribute to the improvement of intersection safety significantly. Copyright © 2016 Elsevier Ltd. All rights reserved.

A PREDICTIVE STUDY: CARBON MONOXIDE EMISSION MODELING AT A SIGNALIZED INTERSECTION

Directory of Open Access Journals (Sweden)

FREDDY WEE LIANG KHO

2014-02-01

Full Text Available CAL3QHC dispersion model was used to predict the present and future carbonmonoxide (CO levels at a busy signalized intersection. This study attempted to identify CO “hot-spots” at nearby areas of the intersection during typical A.M. and P.M. peak hours. The CO concentration “hot-spots” had been identified at 101 Commercial Park and the simulated maximum 1-hour Time-Weighted Average (1-h TWA ground level CO concentrations of 18.3 ppm and 18.6 ppm had been observed during A.M. and P.M. peaks, respectively in year 2006. This study shows that there would be no significant increment in CO level for year 2014 although a substantial increase in the number of vehicles is assumed to affect CO levels. It was also found that CO levels would be well below the Malaysian Ambient Air Quality Guideline of 30 ppm (1-h TWA. Comparisons between the measured and simulated CO levels using quantitative data analysis technique and statistical methods indicated that CAL3QHC dispersion model correlated well with measured data.

O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.

Science.gov (United States)

Shi, Jianhua; Gu, Jin-hua; Dai, Chun-ling; Gu, Jianlan; Jin, Xiaoxia; Sun, Jianming; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

2015-09-28

Apoptosis plays an important role in neural development and neurological disorders. In this study, we found that O-GlcNAcylation, a unique protein posttranslational modification with O-linked β-N-acetylglucosamine (GlcNAc), promoted apoptosis through attenuating phosphorylation/activation of AKT and Bad. By using co-immunoprecipitation and mutagenesis techniques, we identified O-GlcNAc modification at both Thr308 and Ser473 of AKT. O-GlcNAcylation-induced apoptosis was attenuated by over-expression of AKT. We also found a dynamic elevation of protein O-GlcNAcylation during the first four hours of cerebral ischemia, followed by continuous decline after middle cerebral artery occlusion (MCAO) in the mouse brain. The elevation of O-GlcNAcylation coincided with activation of cell apoptosis. Finally, we found a negative correlation between AKT phosphorylation and O-GlcNAcylation in ischemic brain tissue. These results indicate that cerebral ischemia induces a rapid increase of O-GlcNAcylation that promotes apoptosis through down-regulation of AKT activity. These findings provide a novel mechanism through which O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling.

CD147 regulates extrinsic apoptosis in spermatocytes by modulating NFκB signaling pathways.

Science.gov (United States)

Wang, Chaoqun; Fok, Kin Lam; Cai, Zhiming; Chen, Hao; Chan, Hsiao Chang

2017-01-10

CD147 null mutant male mice are infertile with arrested spermatogenesis and increased apoptotic germ cells. Our previous studies have shown that CD147 prevents apoptosis in mouse spermatocytes but not spermatogonia. However, the underlying mechanism remains elusive. In the present study, we aim to determine the CD147-regulated apoptotic pathway in mouse spermatocytes. Our results showed that immunodepletion of CD147 triggered apoptosis through extrinsic apoptotic pathway in mouse testis and spermatocyte cell line (GC-2 cells), accompanied by activation of non-canonical NFκB signaling and suppression of canonical NFκB signaling. Furthermore, CD147 was found to interact with TRAF2, a factor known to regulate NFκB and extrinsic apoptotic signaling, and interfering CD147 led to the decrease of TRAF2. Consistently, depletion of CD147 by CRISPR/Cas9 technique in GC-2 cells down-regulated TRAF2 and resulted in cell death with suppressed canonical NFκB and activated non-canonical NFκB signaling. On the contrary, interfering of CD147 had no effect on NFκB signaling pathways as well as TRAF2 protein level in mouse spermatogonia cell line (GC-1 cells). Taken together, these results suggested that CD147 plays a key role in reducing extrinsic apoptosis in spermatocytes, but not spermatogonia, through modulating NFκB signaling pathway.

Modelling and simulation of signal transductions in an apoptosis ...

Indian Academy of Sciences (India)

Prakash

Structural Analysis of Metabolic Networks: Elementary Flux. Mode, Analogy to Petri Nets, and Application to Mycoplasma pneumoniae; German Conference on Bioinformatics 2000 pp 115–120. Takai-Igarashi T and Mizoguchi R 2004 Cell signalling networks ontology; In Silico Biol. 4 81–87. Thompson C 1995 Apoptosis in ...

Operation, analysis, and design of signalized intersections : a module for the introductory course in transportation engineering.

Science.gov (United States)

2014-02-01

This report presents materials that can be used as the basis for a module on signalized intersections in the introductory : course in transportation engineering. The materials were developed based on studies of the work of students who took : this in...

SPAG6 regulates cell apoptosis through the TRAIL signal pathway in myelodysplastic syndromes.

Science.gov (United States)

Li, Xinxin; Yang, Bihui; Wang, Li; Chen, Liping; Luo, Xiaohua; Liu, Lin

2017-05-01

Myelodysplastic syndromes (MDSs) are a group of malignant clone hematopoietic stem-cell diseases, and the evolution and progression of MDS depend on the abnormal apoptosis of bone marrow cells. Our previous studies have indicated that sperm-associated antigen 6 (SPAG6), located in the uniparental disomy regions of myeloid cells, is overexpressed in patients with MDS as compared to controls, and SPAG6 can inhibit apoptosis of SKM-1. However, the concrete mechanism is still unclear. In the present study, it was found that the TNF-related apoptosis-inducing ligand (TRAIL)signal pathway was activated when the expression of SPAG6 was inhibited by SPAG6-shRNA lentivirus in SKM-1 cells. Additionally, the results of flow cytometry, Cell Counting Kit-8 assay and western blot analysis implied that the TRAIL signal pathway could be inhibited by a high expression of SPAG6. However, SPAG6 cannot influence the expression of TRAIL death receptors, except for FADD. Additionally the interaction between FADD and TRAIL death receptors also increased in SKM-1 cells infected with SPAG6-shRNA lentivirus. Thus, our study demonstrates that SPAG6 may regulate apoptosis in SKM-1 through the TRAIL signal pathway, indicating that SPAG6 could be a potential therapeutic target.

Axin1 up-regulated 1 accelerates stress-induced cardiomyocytes apoptosis through activating Wnt/β-catenin signaling.

Science.gov (United States)

Ye, Xing; Lin, Junyi; Lin, Zebin; Xue, Aimin; Li, Liliang; Zhao, Ziqin; Liu, Li; Shen, Yiwen; Cong, Bin

2017-10-15

Stress-induced cardiomyocyte apoptosis contributes to the pathogenesis of a variety of cardiovascular diseases, but how stress induces cardiomyocyte apoptosis remains largely unclear. The present study aims to investigate the effects of Axin1 up-regulated 1 (Axud1), a novel pro-apoptotic protein, on the cardiomyocyte survival and the underlying mechanisms. To this end, a rat model under restraint stress (RS) was established and in vitro stress-induced cardiomyocytes culture was achieved. Our data showed that Axud1 was upregulated in the rat myocardia after exposure to RS. Anti-apoptotic Bcl-2 was decreased, whereas pro-apoptotic Bax and Cleaved caspase-3 (Cc3) were increased in a time-dependent manner. The Wnt/β-catenin signaling was observed to be interestingly activated in heart undergoing RS. In addition, the treatment of norepinephrine (NE) to in vitro cardiomyocytes increased Axud1 level and induced cell apoptosis. Wnt/β-catenin signaling was consistently activated. Knockdown of Axud1 using specific siRNA blunted NE-induced cardiomyocytes apoptosis and also inactivated the Wnt/β-catenin signaling. XAV-939, an inhibitor of Wnt/β-catenin signaling, partially reversed the pro-apoptotic effect of NE. In conclusion, Axud1 accelerated stress-induced cardiomyocytes apoptosis through activation of Wnt/β-catenin signaling pathway. Our data provided novel evidence that therapeutic strategies against Axud1 or Wnt/β-catenin signaling might be promising in relation to RS-induced myocardial injury. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Calculation of vehicle delay at signal-controlled intersections with adaptive traffic control algorithm

Directory of Open Access Journals (Sweden)

Andronov Roman

2018-01-01

Full Text Available By widely introducing information technology tools in the field of traffic control, it is possible to increase the capacity of hubs and reduce vehicle delays. Adaptive traffic light control is one of such tools. Its effectiveness can be assessed through traffic flow simulation. The aim of this study is to create a simulation model of a signal-controlled intersection that can be used to assess the effectiveness of adaptive control in various traffic situations, including the presence or absence of pedestrian traffic through an intersection. The model is based on a numerical experiment conducted using the Monte Carlo method. As a result of the study, vehicle delays, queue length and duration of traffic light cycles are calculated subject to different intensities of incoming traffic flows, and the presence or absence of pedestrian traffic.

Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells

International Nuclear Information System (INIS)

Wakao, Kazufumi; Watanabe, Tadashi; Takadama, Tadatoshi; Ui, Sadaharu; Shigemi, Zenpei; Kagawa, Hiroki; Higashi, Chizuka; Ohga, Rie; Taira, Takahiro; Fujimuro, Masahiro

2014-01-01

Highlights: • Sangivamycin induces the apoptosis of B cell lymphoma PEL cells. • Sangivamycin suppresses Erk signaling by inhibiting Erk phosphorylation in PEL cells. • The activation of Erk signaling is essential for PEL cell survival. • Sangivamycin induces the apoptosis of PEL cells without production of progeny virus. • Sangivamycin may serve as a novel drug for the treatment of PEL. - Abstract: Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males. PEL cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat PEL. We found that sangivamycin killed PEL cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of PEL cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of PEL cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and MEK suppressed the proliferation of PEL cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in PEL cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on PEL cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that

Sangivamycin induces apoptosis by suppressing Erk signaling in primary effusion lymphoma cells

Energy Technology Data Exchange (ETDEWEB)

Wakao, Kazufumi [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511 (Japan); Watanabe, Tadashi [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Takadama, Tadatoshi; Ui, Sadaharu [Department of Biotechnology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Kofu-shi 400-8511 (Japan); Shigemi, Zenpei; Kagawa, Hiroki [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan); Higashi, Chizuka; Ohga, Rie; Taira, Takahiro [Department of Molecular Cell Biology, Faculty of Medicine, University of Yamanashi, Chuoh-shi 409-3898 (Japan); Fujimuro, Masahiro, E-mail: fuji2@mb.kyoto-phu.ac.jp [Department of Cell Biology, Kyoto Pharmaceutical University, Misasagi-Shichonocho 1, Yamashinaku, Kyoto 607-8412 (Japan)

2014-02-07

Highlights: • Sangivamycin induces the apoptosis of B cell lymphoma PEL cells. • Sangivamycin suppresses Erk signaling by inhibiting Erk phosphorylation in PEL cells. • The activation of Erk signaling is essential for PEL cell survival. • Sangivamycin induces the apoptosis of PEL cells without production of progeny virus. • Sangivamycin may serve as a novel drug for the treatment of PEL. - Abstract: Sangivamycin, a structural analog of adenosine and antibiotic exhibiting antitumor and antivirus activities, inhibits protein kinase C and the synthesis of both DNA and RNA. Primary effusion lymphoma (PEL) is an aggressive neoplasm caused by Kaposi’s sarcoma-associated herpesvirus (KSHV) in immunosuppressed patients and HIV-infected homosexual males. PEL cells are derived from post-germinal center B cells, and are infected with KSHV. Herein, we asked if sangivamycin might be useful to treat PEL. We found that sangivamycin killed PEL cells, and we explored the underlying mechanism. Sangivamycin treatment drastically decreased the viability of PEL cell lines compared to KSHV-uninfected B lymphoma cell lines. Sangivamycin induced the apoptosis of PEL cells by activating caspase-7 and -9. Further, sangivamycin suppressed the phosphorylation of Erk1/2 and Akt, thus inhibiting activation of the proteins. Inhibitors of Akt and MEK suppressed the proliferation of PEL cells compared to KSHV-uninfected cells. It is known that activation of Erk and Akt signaling inhibits apoptosis and promotes proliferation in PEL cells. Our data therefore suggest that sangivamycin induces apoptosis by inhibiting Erk and Akt signaling in such cells. We next investigated whether sangivamycin, in combination with an HSP90 inhibitor geldanamycin (GA) or valproate (valproic acid), potentiated the cytotoxic effects of the latter drugs on PEL cells. Compared to treatment with GA or valproate alone, the addition of sangivamycin enhanced cytotoxic activity. Our data thus indicate that

Exposure to lateral collision in signalized intersections with protected left turn under different traffic control strategies.

Science.gov (United States)

Midenet, Sophie; Saunier, Nicolas; Boillot, Florence

2011-11-01

This paper proposes an original definition of the exposure to lateral collision in signalized intersections and discusses the results of a real world experiment. This exposure is defined as the duration of situations where the stream that is given the right-of-way goes through the conflict zone while road users are waiting in the cross-traffic approach. This measure, obtained from video sensors, makes it possible to compare different operating conditions such as different traffic signal strategies. The data from a real world experiment is used, where the adaptive real-time strategy CRONOS (ContRol Of Networks by Optimization of Switchovers) and a time-plan strategy with vehicle-actuated ranges alternately controlled an isolated intersection near Paris. Hourly samples with similar traffic volumes are compared and the exposure to lateral collision is different in various areas of the intersection and various traffic conditions for the two strategies. The total exposure under peak hour traffic conditions drops by roughly 5 min/h with the CRONOS strategy compared to the time-plan strategy, which occurs mostly on entry streams. The results are analyzed through the decomposition of cycles in phase sequences and recommendations are made for traffic control strategies. Copyright © 2011 Elsevier Ltd. All rights reserved.

Role of CD137 signaling in dengue virus-mediated apoptosis

International Nuclear Information System (INIS)

Nagila, Amar; Netsawang, Janjuree; Srisawat, Chatchawan; Noisakran, Sansanee; Morchang, Atthapan; Yasamut, Umpa; Puttikhunt, Chunya; Kasinrerk, Watchara

2011-01-01

Highlights: → For the first time the role of CD137 in dengue virus (DENV) infection. → Induction of DENV-mediated apoptosis by CD137 signaling. → Sensitization to CD137-mediated apoptosis by dengue virus capsid protein (DENV C). → Nuclear localization of DENV C is required for CD137-mediated apoptosis. -- Abstract: Hepatic dysfunction is a well recognized feature of dengue virus (DENV) infection. However, molecular mechanisms of hepatic injury are still poorly understood. A complex interaction between DENV and the host immune response contributes to DENV-mediated tissue injury. DENV capsid protein (DENV C) physically interacts with the human death domain-associated protein Daxx. A double substitution mutation in DENV C (R85A/K86A) abrogates Daxx interaction, nuclear localization and apoptosis. Therefore we compared the expression of cell death genes between HepG2 cells expressing DENV C and DENV C (R85A/K86A) using a real-time PCR array. Expression of CD137, which is a member of the tumor necrosis factor receptor family, increased significantly in HepG2 cells expressing DENV C compared to HepG2 cells expressing DENV C (R85A/K86A). In addition, CD137-mediated apoptotic activity in HepG2 cells expressing DENV C was significantly increased by anti-CD137 antibody compared to that of HepG2 cells expressing DENV C (R85A/K86A). In DENV-infected HepG2 cells, CD137 mRNA and CD137 positive cells significantly increased and CD137-mediated apoptotic activity was increased by anti-CD137 antibody. This work is the first to demonstrate the contribution of CD137 signaling to DENV-mediated apoptosis.

Role of CD137 signaling in dengue virus-mediated apoptosis

Energy Technology Data Exchange (ETDEWEB)

Nagila, Amar [Medical Molecular Biology Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Netsawang, Janjuree [Faculty of Medical Technology, Rangsit University, Bangkok (Thailand); Srisawat, Chatchawan [Department of Biochemistry, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Noisakran, Sansanee [Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok (Thailand); Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok (Thailand); Morchang, Atthapan; Yasamut, Umpa [Medical Molecular Biology Unit, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Department of Immunology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok (Thailand); Puttikhunt, Chunya [Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok (Thailand); Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Bangkok (Thailand); Kasinrerk, Watchara [Division of Clinical Immunology, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai (Thailand); Biomedical Technology Research Center, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency at Chiang Mai University, Chiang Mai (Thailand); and others

2011-07-08

Highlights: {yields} For the first time the role of CD137 in dengue virus (DENV) infection. {yields} Induction of DENV-mediated apoptosis by CD137 signaling. {yields} Sensitization to CD137-mediated apoptosis by dengue virus capsid protein (DENV C). {yields} Nuclear localization of DENV C is required for CD137-mediated apoptosis. -- Abstract: Hepatic dysfunction is a well recognized feature of dengue virus (DENV) infection. However, molecular mechanisms of hepatic injury are still poorly understood. A complex interaction between DENV and the host immune response contributes to DENV-mediated tissue injury. DENV capsid protein (DENV C) physically interacts with the human death domain-associated protein Daxx. A double substitution mutation in DENV C (R85A/K86A) abrogates Daxx interaction, nuclear localization and apoptosis. Therefore we compared the expression of cell death genes between HepG2 cells expressing DENV C and DENV C (R85A/K86A) using a real-time PCR array. Expression of CD137, which is a member of the tumor necrosis factor receptor family, increased significantly in HepG2 cells expressing DENV C compared to HepG2 cells expressing DENV C (R85A/K86A). In addition, CD137-mediated apoptotic activity in HepG2 cells expressing DENV C was significantly increased by anti-CD137 antibody compared to that of HepG2 cells expressing DENV C (R85A/K86A). In DENV-infected HepG2 cells, CD137 mRNA and CD137 positive cells significantly increased and CD137-mediated apoptotic activity was increased by anti-CD137 antibody. This work is the first to demonstrate the contribution of CD137 signaling to DENV-mediated apoptosis.

Methamphetamine exposure triggers apoptosis and autophagy in neuronal cells by activating the C/EBPβ-related signaling pathway.

Science.gov (United States)

Xu, Xiang; Huang, Enping; Luo, Baoying; Cai, Dunpeng; Zhao, Xu; Luo, Qin; Jin, Yili; Chen, Ling; Wang, Qi; Liu, Chao; Lin, Zhoumeng; Xie, Wei-Bing; Wang, Huijun

2018-06-25

Methamphetamine (Meth) is a widely abused psychoactive drug that primarily damages the nervous system, notably causing dopaminergic neuronal apoptosis. CCAAT-enhancer binding protein (C/EBPβ) is a transcription factor and an important regulator of cell apoptosis and autophagy. Insulin-like growth factor binding protein (IGFBP5) is a proapoptotic factor that mediates Meth-induced neuronal apoptosis, and Trib3 (tribbles pseudokinase 3) is an endoplasmic reticulum (ER) stress-inducible gene involved in autophagic cell death through the mammalian target of rapamycin (mTOR) signaling pathway. To test the hypothesis that C/EBPβ is involved in Meth-induced IGFBP5-mediated neuronal apoptosis and Trib3-mediated neuronal autophagy, we measured the protein expression of C/EBPβ after Meth exposure and evaluated the effects of silencing C/EBPβ, IGFBP5, or Trib3 on Meth-induced apoptosis and autophagy in neuronal cells and in the rat striatum after intrastriatal Meth injection. We found that, at relatively high doses, Meth exposure increased C/EBPβ protein expression, which was accompanied by increased neuronal apoptosis and autophagy; triggered the IGFBP5-mediated, p53-up-regulated modulator of apoptosis (PUMA)-related mitochondrial apoptotic signaling pathway; and stimulated the Trib3-mediated ER stress signaling pathway through the Akt-mTOR signaling axis. We also found that autophagy is an early response to Meth-induced stress upstream of apoptosis and plays a detrimental role in Meth-induced neuronal cell death. These results suggest that Meth exposure induces C/EBPβ expression, which plays an essential role in the neuronal apoptosis and autophagy induced by relatively high doses of Meth; however, relatively low concentrations of Meth did not change the expression of C/EBPβ in vitro. Further studies are needed to elucidate the role of C/EBPβ in low-dose Meth-induced neurotoxicity.-Xu, X., Huang, E., Luo, B., Cai, D., Zhao, X., Luo, Q., Jin, Y., Chen, L., Wang, Q

Exploring stop-go decision zones at rural high-speed intersections with flashing green signal and insufficient yellow time in China.

Science.gov (United States)

Tang, Keshuang; Xu, Yanqing; Wang, Fen; Oguchi, Takashi

2016-10-01

The objective of this study is to empirically analyze and model the stop-go decision behavior of drivers at rural high-speed intersections in China, where a flashing green signal of 3s followed by a yellow signal of 3s is commonly applied to end a green phase. 1, 186 high-resolution vehicle trajectories were collected at four typical high-speed intersection approaches in Shanghai and used for the identification of actual stop-go decision zones and the modeling of stop-go decision behavior. Results indicate that the presence of flashing green significantly changed the theoretical decision zones based on the conventional Dilemma Zone theory. The actual stop-go decision zones at the study intersections were thus formulated and identified based on the empirical data. Binary Logistic model and Fuzzy Logic model were then developed to further explore the impacts of flashing green on the stop-go behavior of drivers. It was found that the Fuzzy Logic model could produce comparably good estimation results as compared to the traditional Binary Logistic models. The findings of this study could contribute the development of effective dilemma zone protection strategies, the improvement of stop-go decision model embedded in the microscopic traffic simulation software and the proper design of signal change and clearance intervals at high-speed intersections in China. Copyright © 2016 Elsevier Ltd. All rights reserved.

Metabolic syndrome impairs notch signaling and promotes apoptosis in chronically ischemic myocardium.

Science.gov (United States)

Elmadhun, Nassrene Y; Sabe, Ashraf A; Lassaletta, Antonio D; Chu, Louis M; Kondra, Katelyn; Sturek, Michael; Sellke, Frank W

2014-09-01

Impaired angiogenesis is a known consequence of metabolic syndrome (MetS); however, the mechanism is not fully understood. Recent studies have shown that the notch signaling pathway is an integral component of cardiac angiogenesis. We tested, in a clinically relevant swine model, the effects of MetS on notch and apoptosis signaling in chronically ischemic myocardium. Ossabaw swine were fed either a regular diet (control [CTL], n = 8) or a high-cholesterol diet (MetS, n = 8) to induce MetS. An ameroid constrictor was placed to induce chronic myocardial ischemia. Eleven weeks later, the wine underwent cardiac harvest of the ischemic myocardium. Downregulation of pro-angiogenesis proteins notch2, notch4, jagged2, angiopoietin 1, and endothelial nitric oxide synthase were found in the MetS group compared with the CTL group. Also, upregulation of pro-apoptosis protein caspase 8 and downregulation of anti-angiogenesis protein phosphorylated forkhead box transcription factor 03 and pro-survival proteins phosphorylated P38 and heat shock protein 90 were present in the MetS group. Cell death was increased in the MetS group compared with the CTL group. Both CTL and MetS groups had a similar arteriolar count and capillary density, and notch3 and jagged1 were both similarly concentrated in the smooth muscle wall. MetS in chronic myocardial ischemia significantly impairs notch signaling by downregulating notch receptors, ligands, and pro-angiogenesis proteins. MetS also increases apoptosis signaling, decreases survival signaling, and increases cell death in chronically ischemic myocardium. Although short-term angiogenesis appears unaffected in this model of early MetS, the molecular signals for angiogenesis are impaired, suggesting that inhibition of notch signaling might underlie the decreased angiogenesis in later stages of MetS. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Differences in passenger car and large truck involved crash frequencies at urban signalized intersections: an exploratory analysis.

Science.gov (United States)

Dong, Chunjiao; Clarke, David B; Richards, Stephen H; Huang, Baoshan

2014-01-01

The influence of intersection features on safety has been examined extensively because intersections experience a relatively large proportion of motor vehicle conflicts and crashes. Although there are distinct differences between passenger cars and large trucks-size, operating characteristics, dimensions, and weight-modeling crash counts across vehicle types is rarely addressed. This paper develops and presents a multivariate regression model of crash frequencies by collision vehicle type using crash data for urban signalized intersections in Tennessee. In addition, the performance of univariate Poisson-lognormal (UVPLN), multivariate Poisson (MVP), and multivariate Poisson-lognormal (MVPLN) regression models in establishing the relationship between crashes, traffic factors, and geometric design of roadway intersections is investigated. Bayesian methods are used to estimate the unknown parameters of these models. The evaluation results suggest that the MVPLN model possesses most of the desirable statistical properties in developing the relationships. Compared to the UVPLN and MVP models, the MVPLN model better identifies significant factors and predicts crash frequencies. The findings suggest that traffic volume, truck percentage, lighting condition, and intersection angle significantly affect intersection safety. Important differences in car, car-truck, and truck crash frequencies with respect to various risk factors were found to exist between models. The paper provides some new or more comprehensive observations that have not been covered in previous studies. Copyright © 2013 Elsevier Ltd. All rights reserved.

Silver Nanoparticles Induce HePG-2 Cells Apoptosis Through ROS-Mediated Signaling Pathways

Science.gov (United States)

Zhu, Bing; Li, Yinghua; Lin, Zhengfang; Zhao, Mingqi; Xu, Tiantian; Wang, Changbing; Deng, Ning

2016-04-01

Recently, silver nanoparticles (AgNPs) have been shown to provide a novel approach to overcome tumors, especially those of hepatocarcinoma. However, the anticancer mechanism of silver nanoparticles is unclear. Thus, the purpose of this study was to estimate the effect of AgNPs on proliferation and activation of ROS-mediated signaling pathway on human hepatocellular carcinoma HePG-2 cells. A simple chemical method for preparing AgNPs with superior anticancer activity has been showed in this study. AgNPs were detected by transmission electronic microscopy (TEM) and energy dispersive X-ray (EDX). The size distribution and zeta potential of silver nanoparticles were detected by Zetasizer Nano. The average size of AgNPs (2 nm) observably increased the cellular uptake by endocytosis. AgNPs markedly inhibited the proliferation of HePG-2 cells through induction of apoptosis with caspase-3 activation and PARP cleavage. AgNPs with dose-dependent manner significantly increased the apoptotic cell population (sub-G1). Furthermore, AgNP-induced apoptosis was found dependent on the overproduction of reactive oxygen species (ROS) and affecting of MAPKs and AKT signaling and DNA damage-mediated p53 phosphorylation to advance HePG-2 cells apoptosis. Therefore, our results show that the mechanism of ROS-mediated signaling pathways may provide useful information in AgNP-induced HePG-2 cell apoptosis.

Pannexin 1 channels mediate 'find-me' signal release and membrane permeability during apoptosis.

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Chekeni, Faraaz B; Elliott, Michael R; Sandilos, Joanna K; Walk, Scott F; Kinchen, Jason M; Lazarowski, Eduardo R; Armstrong, Allison J; Penuela, Silvia; Laird, Dale W; Salvesen, Guy S; Isakson, Brant E; Bayliss, Douglas A; Ravichandran, Kodi S

2010-10-14

Apoptotic cells release 'find-me' signals at the earliest stages of death to recruit phagocytes. The nucleotides ATP and UTP represent one class of find-me signals, but their mechanism of release is not known. Here, we identify the plasma membrane channel pannexin 1 (PANX1) as a mediator of find-me signal/nucleotide release from apoptotic cells. Pharmacological inhibition and siRNA-mediated knockdown of PANX1 led to decreased nucleotide release and monocyte recruitment by apoptotic cells. Conversely, PANX1 overexpression enhanced nucleotide release from apoptotic cells and phagocyte recruitment. Patch-clamp recordings showed that PANX1 was basally inactive, and that induction of PANX1 currents occurred only during apoptosis. Mechanistically, PANX1 itself was a target of effector caspases (caspases 3 and 7), and a specific caspase-cleavage site within PANX1 was essential for PANX1 function during apoptosis. Expression of truncated PANX1 (at the putative caspase cleavage site) resulted in a constitutively open channel. PANX1 was also important for the 'selective' plasma membrane permeability of early apoptotic cells to specific dyes. Collectively, these data identify PANX1 as a plasma membrane channel mediating the regulated release of find-me signals and selective plasma membrane permeability during apoptosis, and a new mechanism of PANX1 activation by caspases.

Requirement for aspartate-cleaved bid in apoptosis signaling by DNA-damaging anti-cancer regimens

NARCIS (Netherlands)

Werner, Arlette B.; Tait, Stephen W. G.; de Vries, Evert; Eldering, Eric; Borst, Jannie

2004-01-01

Lymphoid malignancies can escape from DNA-damaging anti-cancer drugs and gamma-radiation by blocking apoptosis-signaling pathways. How these regimens induce apoptosis is incompletely defined, especially in cells with nonfunctional p53. We report here that the BH3-only Bcl-2 family member Bid is

The roles of DNA damage-dependent signals and MAPK cascades in tributyltin-induced germline apoptosis in Caenorhabditis elegans.

Science.gov (United States)

Wang, Yun; Wang, Shunchang; Luo, Xun; Yang, Yanan; Jian, Fenglei; Wang, Xuemin; Xie, Lucheng

2014-08-01

The induction of apoptosis is recognized to be a major mechanism of tributyltin (TBT) toxicity. However, the underlying signaling pathways for TBT-induced apoptosis remain unclear. In this study, using the nematode Caenorhabditis elegans, we examined whether DNA damage response (DDR) pathway and mitogen-activated protein kinase (MAPK) signaling cascades are involved in TBT-induced germline apoptosis and cell cycle arrest. Our results demonstrated that exposing worms to TBT at the dose of 10nM for 6h significantly increased germline apoptosis in N2 strain. Germline apoptosis was absent in strains that carried ced-3 or ced-4 loss-of-function alleles, indicating that both caspase protein CED-3 and Apaf-1 protein CED-4 were required for TBT-induced apoptosis. TBT-induced apoptosis was blocked in the Bcl-2 gain-of-function strain ced-9(n1950), whereas TBT induced a minor increase in the BH3-only protein EGL-1 mutated strain egl-1(n1084n3082). Checkpoint proteins HUS-1 and CLK-2 exerted proapoptotic effects, and the null mutation of cep-1, the homologue of tumor suppressor gene p53, significantly inhibited TBT-induced apoptosis. Apoptosis in the loss-of-function strains of ERK, JNK and p38 MAPK signaling pathways were completely or mildly suppressed under TBT stress. These results were supported by the results of mRNA expression levels of corresponding genes. The present study indicated that TBT-induced apoptosis required the core apoptotic machinery, and that DDR genes and MAPK pathways played essential roles in signaling the processes. Copyright © 2014 Elsevier Ltd. All rights reserved.

Safety impacts of red light cameras at signalized intersections based on cellular automata models.

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Chai, C; Wong, Y D; Lum, K M

2015-01-01

This study applies a simulation technique to evaluate the hypothesis that red light cameras (RLCs) exert important effects on accident risks. Conflict occurrences are generated by simulation and compared at intersections with and without RLCs to assess the impact of RLCs on several conflict types under various traffic conditions. Conflict occurrences are generated through simulating vehicular interactions based on an improved cellular automata (CA) model. The CA model is calibrated and validated against field observations at approaches with and without RLCs. Simulation experiments are conducted for RLC and non-RLC intersections with different geometric layouts and traffic demands to generate conflict occurrences that are analyzed to evaluate the hypothesis that RLCs exert important effects on road safety. The comparison of simulated conflict occurrences show favorable safety impacts of RLCs on crossing conflicts and unfavorable impacts for rear-end conflicts during red/amber phases. Corroborative results are found from broad analysis of accident occurrence. RLCs are found to have a mixed effect on accident risk at signalized intersections: crossing collisions are reduced, whereas rear-end collisions may increase. The specially developed CA model is found to be a feasible safety assessment tool.

The Signaling Cascades of Ginkgolide B-Induced Apoptosis in MCF-7 Breast Cancer Cells

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Wen-Hsiung Chan

2007-11-01

Full Text Available Ginkgolide B, the major active component of Ginkgo biloba extracts, can bothstimulate and inhibit apoptotic signaling. Here, we demonstrate that ginkgolide B caninduce the production of reactive oxygen species in MCF-7 breast cancer cells, leading toan increase in the intracellular concentrations of cytoplasmic free Ca2+ and nitric oxide(NO, loss of mitochondrial membrane potential (MMP, activation of caspase-9 and -3,and increase the mRNA expression levels of p53 and p21, which are known to be involvedin apoptotic signaling. In addition, prevention of ROS generation by pretreatment withN-acetyl cysteine (NAC could effectively block intracellular Ca2+ concentrationsincreases and apoptosis in ginkgolide B-treated MCF-7 cells. Moreover, pretreatment withnitric oxide (NO scavengers could inhibit ginkgolide B-induced MMP change andsequent apoptotic processes. Overall, our results signify that both ROS and NO playedimportant roles in ginkgolide B-induced apoptosis of MCF-7 cells. Based on these studyresults, we propose a model for ginkgolide B-induced cell apoptosis signaling cascades inMCF-7 cells.

The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis

International Nuclear Information System (INIS)

Verheij, M.; Ruiter, G.A.; Zerp, S.F.; Bartelink, H.; Blitterswijk, W.J. van; Fuks, Z.; Haimovitz-Friedman, A.

1998-01-01

Ionizing radiation, like a variety of other cellular stress factors, initiates apoptosis, or programmed cell death, in many cell systems. This mode of radiation-induced cell kill should be distinguished from clonogenic cell death due to unrepaired DNA damage. Ionizing radiation not only exerts its effect on the nuclear DNA, but also at the plasma membrane level where it may activate multiple signal transduction pathways. One of these pathways is the stress-activated protein kinase (SAPK) cascade which transduces death signals from the cell membrane to the nucleus. This review discusses recent evidence on the critical role of this signaling system in radiation- and stress-induced apoptosis. An improved understanding of the mechanisms involved in radiation-induced apoptosis may ultimately provide novel strategies of intervention in specific signal transduction pathways to favorably alter the therapeutic ratio in the treatment of human malignancies. (Copyright (c) 1998 Elsevier Science B.V., Amsterdam. All rights reserved.)

Effect of Pedestrians on the Saturation Flow Rate of Right Turn Movements at Signalized Intersection - Case Study from Rasht City

Science.gov (United States)

Roshani, Mostafa; Bargegol, Iraj

2017-10-01

Saturation flow rate is one of the important items in the analysis of the capacity of signalized intersections that are affected by some factors. Pedestrian crossing on signalized intersection is one of the factors which influence the vehicles flow. In addition, the released researches determined that the greatest impact of pedestrian on the saturation flow occurred in the Conflict zone where the highest chance of the encounter of pedestrians and vehicles has in turning movements. The purpose of this paper is to estimate the saturation flow rate considering the effect of a pedestrian on right turn movements of the signalized intersections in Rasht city. For this goal, 6 signalized intersections with 90 cycles of reviews were selected for the estimation of saturation flow rate by the microscopic method and also 3 right turn lanes containing radius differences with 70 cycles of reviews were collected for the investigation of the pedestrians’ effects. Each phase of right turn lanes cycle was divided in the pieces of 10-second period which was totally 476 sample volumes of considered pedestrians and vehicles at that period. Only 101 samples of those were ranged as saturated conditions. Finally, using different regression models, the best relationship between pedestrian’s volume and right turning vehicles flow parameters was evaluated. The results indicate that there is a primarily linear relationship between pedestrian volume and right turning vehicles flow with R2=0.6261. According to this regression model with the increase in pedestrians, saturation flow rate will be reduced. In addition, by comparing the adjustment factor obtained in the present study and other studies, it was found that the effect of pedestrians on the right-turn movements in Rasht city is less than the rest of the world.

Multiobjective optimization model of intersection signal timing considering emissions based on field data: A case study of Beijing.

Science.gov (United States)

Kou, Weibin; Chen, Xumei; Yu, Lei; Gong, Huibo

2018-04-18

Most existing signal timing models are aimed to minimize the total delay and stops at intersections, without considering environmental factors. This paper analyzes the trade-off between vehicle emissions and traffic efficiencies on the basis of field data. First, considering the different operating modes of cruising, acceleration, deceleration, and idling, field data of emissions and Global Positioning System (GPS) are collected to estimate emission rates for heavy-duty and light-duty vehicles. Second, multiobjective signal timing optimization model is established based on a genetic algorithm to minimize delay, stops, and emissions. Finally, a case study is conducted in Beijing. Nine scenarios are designed considering different weights of emission and traffic efficiency. The results compared with those using Highway Capacity Manual (HCM) 2010 show that signal timing optimized by the model proposed in this paper can decrease vehicles delay and emissions more significantly. The optimization model can be applied in different cities, which provides supports for eco-signal design and development. Vehicle emissions are heavily at signal intersections in urban area. The multiobjective signal timing optimization model is proposed considering the trade-off between vehicle emissions and traffic efficiencies on the basis of field data. The results indicate that signal timing optimized by the model proposed in this paper can decrease vehicle emissions and delays more significantly. The optimization model can be applied in different cities, which provides supports for eco-signal design and development.

Impact of the p53 status of tumor cells on extrinsic and intrinsic apoptosis signaling.

Science.gov (United States)

Wachter, Franziska; Grunert, Michaela; Blaj, Cristina; Weinstock, David M; Jeremias, Irmela; Ehrhardt, Harald

2013-04-17

The p53 protein is the best studied target in human cancer. For decades, p53 has been believed to act mainly as a tumor suppressor and by transcriptional regulation. Only recently, the complex and diverse function of p53 has attracted more attention. Using several molecular approaches, we studied the impact of different p53 variants on extrinsic and intrinsic apoptosis signaling. We reproduced the previously published results within intrinsic apoptosis induction: while wild-type p53 promoted cell death, different p53 mutations reduced apoptosis sensitivity. The prediction of the impact of the p53 status on the extrinsic cell death induction was much more complex. The presence of p53 in tumor cell lines and primary xenograft tumor cells resulted in either augmented, unchanged or reduced cell death. The substitution of wild-type p53 by mutant p53 did not affect the extrinsic apoptosis inducing capacity. In summary, we have identified a non-expected impact of p53 on extrinsic cell death induction. We suggest that the impact of the p53 status of tumor cells on extrinsic apoptosis signaling should be studied in detail especially in the context of therapeutic approaches that aim to restore p53 function to facilitate cell death via the extrinsic apoptosis pathway.

A Signal Coordination Control Based on Traversing Empty between Mid-Block Street Crossing and Intersection

Directory of Open Access Journals (Sweden)

Changjiang Zheng

2012-01-01

Full Text Available To solve the problem in pedestrian Mid-Block street crossing, the method of signal coordination control between mid-block street crossing and intersection is researched in this paper. The paper proposes to use “distance-flow rate-time” graph as the tool for building coordination control system model which is for different situations of traffic control. Through alternating the linear optimization model, the system outputs the distribution of signal timing and system operational factors (delays in vehicles and mid-block street crossing. Finally, taking one section on the Taiping North Road in Nanjing as an example, the signal coordination control is carried out. And the results which are delays in the vehicles and mid-block street crossing are compared to those in the current distribution of signal timing.

Blocking Ihh signaling pathway inhibits the proliferation and promotes the apoptosis of PSCs.

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Xu, Kai; Guo, Fengjing; Zhang, Shuwei; Liu, Cheng; Wang, Feixiong; Zhou, Zhiguo; Chen, Anmin

2009-02-01

The roles of Indian hedgehog (Ihh) signaling pathway in the proliferation and apoptosis of precartilaginous stem cells (PSCs) were investigated. PSCs, labeled with fibroblast growth factor receptor 3 (FGFR-3), were isolated from neonatal rats by immunomagnetic separation. After identification with FGFR-3 and Col II, the cells were incubated with different concentrations of cyclopamine (cyclo), the specific inhibitor of Ihh signaling pathway. The morphologic changes of the cells were observed under the inverted phase contrast microscope. The mRNA expression levels of Ihh, parathyroid hormonerelated peptide (PTHrP), protein Patched (Ptch), Bcl-2 and p21 were detected by RT-PCR. The protein expression levels of Ihh and Ptch were measured by Western blot. MTT assay was used to examine the effects of cyclo on proliferation of PSCs. Apoptosis rate of PSCs was examined by Annexin V/PI assay of flow cytometric analyses. After PSCs were incubated with cyclo, obvious morphologic changes were observed as compared with the control group. The mRNA expression levels of PTHrP, Ptch and Bcl-2 were decreased to varying degrees in a cyclo dose-dependent manner. However, the expression levels of Ihh and p21 mRNA were increased. The protein expression of Ptch and Ihh had the same change as the mRNA expression. Meanwhile, cyclo could obviously inhibit the proliferation and promote the apoptosis of PSCs. The results indicated that Ihh signaling pathway plays an important role in regulating the proliferation and apoptosis of PSCs, which is probably mediated by Bcl-2 and p21.

Interferon beta induces apoptosis in nasopharyngeal carcinoma cells via the TRAIL-signaling pathway.

Science.gov (United States)

Makowska, Anna; Wahab, Lora; Braunschweig, Till; Kapetanakis, Nikiforos-Ioannis; Vokuhl, Christian; Denecke, Bernd; Shen, Lian; Busson, Pierre; Kontny, Udo

2018-03-06

The combination of neoadjuvant chemotherapy, radiochemotherapy, and maintenance therapy with interferon beta (IFNβ) has led to superior results in the treatment of children and adolescents with nasopharyngeal carcinoma (NPC). However, nothing is known about the mechanism of the antitumor activity of IFNβ in NPC. Here, we investigate the role of IFNβ on apoptosis in NPC cells. Six NPC cell lines, one patient-derived NPC xenograft (PDX) and one SV40-transformed nasoepithelial cell line were used. Induction of apoptosis by IFNβ was measured by flow cytometric analysis of subG1-DNA-content, Hoechst 33258 staining and activation of caspase-3. Dissection of death ligand signaling pathways included measuring surface expression of its components by flow cytometry, activation by death ligands and neutralization with specific antibodies and siRNA. IFNβ induced apoptosis at concentrations achievable in humans in five of six NPC cell lines and in PDX cells but not in nasoepithelial cells. Inhibition of caspases-3 and -8 abrogated this effect suggesting IFNβ promoted apoptosis through the extrinsic pathway. IFNβ induced surface expression of TRAIL and TRAIL-R2 and the addition of an anti-TRAIL-antibody or transfection with TRAIL-siRNA blocked IFNβ-induced apoptosis. No induction of TRAIL-expression was noted in the IFNβ-resistant cell line. In conclusion, IFNβ leads to apoptosis in NPC cells in an autocrine way via the induction of TRAIL expression and subsequent activation of the TRAIL-signaling pathway. The mechanism described could at least partly explain the clinical benefit of IFNβ in the treatment of NPC. Further studies in a mouse-xenograft model are warranted to substantiate this effect in vivo .

Statistical modeling of total crash frequency at highway intersections

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Arash M. Roshandeh

2016-04-01

Full Text Available Intersection-related crashes are associated with high proportion of accidents involving drivers, occupants, pedestrians, and cyclists. In general, the purpose of intersection safety analysis is to determine the impact of safety-related variables on pedestrians, cyclists and vehicles, so as to facilitate the design of effective and efficient countermeasure strategies to improve safety at intersections. This study investigates the effects of traffic, environmental, intersection geometric and pavement-related characteristics on total crash frequencies at intersections. A random-parameter Poisson model was used with crash data from 357 signalized intersections in Chicago from 2004 to 2010. The results indicate that out of the identified factors, evening peak period traffic volume, pavement condition, and unlighted intersections have the greatest effects on crash frequencies. Overall, the results seek to suggest that, in order to improve effective highway-related safety countermeasures at intersections, significant attention must be focused on ensuring that pavements are adequately maintained and intersections should be well lighted. It needs to be mentioned that, projects could be implemented at and around the study intersections during the study period (7 years, which could affect the crash frequency over the time. This is an important variable which could be a part of the future studies to investigate the impacts of safety-related works at intersections and their marginal effects on crash frequency at signalized intersections.

EGF signalling pathway regulates colon cancer stem cell proliferation and apoptosis.

Science.gov (United States)

Feng, Y; Dai, X; Li, X; Wang, H; Liu, J; Zhang, J; Du, Y; Xia, L

2012-10-01

Cancer stem cells (CSCs) compose a subpopulation of cells within a tumour that can self-renew and proliferate. Growth factors such as epidermal growth factor (EGF) and basic fibroblast growth factor (b-FGF) promote cancer stem cell proliferation in many solid tumours. This study assesses whether EGF, bFGF and IGF signalling pathways are essential for colon CSC proliferation and self-renewal. Colon CSCs were cultured in serum-free medium (SFM) with one of the following growth factors: EGF, bFGF or IGF. Characteristics of CSC gene expression were evaluated by real time PCR. Tumourigenicity of CSCs was determined using a xenograft model in vivo. Effects of EGF receptor inhibitors, Gefitinib and PD153035, on CSC proliferation, apoptosis and signalling were evaluated using fluorescence-activated cell sorting and western blotting. Colon cancer cell HCT116 transformed to CSCs in SFM. Compared to other growth factors, EGF was essential to support proliferation of CSCs that expressed higher levels of progenitor genes (Musashi-1, LGR5) and lower levels of differential genes (CK20). CSCs promoted more rapid tumour growth than regular cancer cells in xenografts. EGFR inhibitors suppressed proliferation and induced apoptosis of CSCs by inhibiting autophosphorylation of EGFR and downstream signalling proteins, such as Akt kinase, extracellular signal-regulated kinase 1/2 (ERK 1/2). This study indicates that EGF signalling was essential for formation and maintenance of colon CSCs. Inhibition of the EGF signalling pathway may provide a useful strategy for treatment of colon cancer. © 2012 Blackwell Publishing Ltd.

[TRPM8 mediates PC-12 neuronal cell apoptosis induced by oxygen-glucose deprivation through cAMP-PKA/UCP4 signaling].

Science.gov (United States)

Li, Hong-Wei; Zhou, Bin; Zhang, Hai-Hong

2016-08-20

To explore the molecular mechanism responsible for apoptosis of PC-12 neuronal cells induced by oxygen-glucose deprivation (OGD). PC12 cells were exposed to OGD for 24 h to simulate ischemia-reperfusion injury. Flow cytometry was employed detect the cell apoptosis, and the expresions of TRPM8, UCP4, cAMP and PKA in the exposed cells were detected with RT-PCR and Western blotting. The changes in the expressions of Bax, Bcl-2, cAMP, PKA and UCP4 proteins were detected in the exposed cells in resposne to inhibition of TRPM8 and cAMP-PKA signal or over-expression of UCP4. OGD for 24 induced obvious apoptosis in PC-12 cells and caused TRPM8 over-expression and inhibition of UCP4 and cAMP-PKA signaling. Inhibiting TRPM8 expression reduced the cell apoptosis and up-regulated cAMP, p-PKA and UCP4 in the cells exposed to OGD. In cells exposed to OGD, inhibition of TRPM8 and cAMP-PKA signaling suppressed the expressio of UCP4 and increased the cell apoptosis. TRPM8 mediates OGD-induced PC12 cell apoptosis through cAMP-PKA/UCP4 signaling.

Extended MRI findings of intersection syndrome

International Nuclear Information System (INIS)

Lee, Roger P.; Hatem, Stephen F.; Recht, Michael P.

2009-01-01

The symptoms and physical findings of intersection syndrome have been well described in the clinical medical literature. However, the magnetic resonance imaging (MRI) findings in patients with intersection syndrome of the forearm have only recently been described in a small number of patients. We review our experience with imaging of intersection syndrome, describe previously unreported MRI findings, and emphasize modifications to MRI protocols for its evaluation. Institutional review board approval was obtained for this retrospective review of patients with MRI findings consistent with intersection syndrome of the forearm during the period from January 2004 to September 2006. Six patients were identified, three males and three females, with an average age of 39.3 years. The MRI examinations were reviewed to assess signal abnormalities within and adjacent to the first and second dorsal extensor tendon compartments (DETC): tendinosis, peritendinous edema or fluid, muscle edema, subcutaneous edema, and juxtacortical edema. The overall longitudinal extent of signal alterations was measured as well as the distance from Lister's tubercle to the crossover of the first and second DETC. Review of the MRIs showed increased intrasubstance tendon signal suggesting tendinosis in two of the six patients, peritendinous edema or fluid in all six patients, muscle edema in five of the six patients, and subcutaneous edema in three of the six patients. Juxtacortical edema was seen in one patient. Peritendinous edema or fluid extended distally beyond the radiocarpal joint in three of the six patients. The average distance from Lister's tubercle to the crossover of the first and second DETC was 3.95 cm, in keeping with recently published data. Intersection syndrome is an uncommon MRI diagnosis. In addition to the previously described MRI findings of edema adjacent to the first or second DETC, possibly with proximal extension and subcutaneous edema, we have identified additional

Advances in cell proliferation and apoptosis signal pathway and therapies of polycystic kidney disease

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Xiao-ying LIAN

2016-12-01

Full Text Available Polycystic kidney disease (PKD is one of the monogenic inherited diseases. In PKD, excessive cell proliferation and fluid secretion, and disruption of the mechanisms controlling tubular diameter may all lead to cyst formation. Current evidence has demonstrated that intracellular calcium ion and cAMP imbalance drive both abnormal cell proliferation and apoptosis signal pathway. The present paper summarized the evidence implicating calcium ion and cAMP as central players in the signaling pathway of cell proliferation and apoptosis in PKD, and considered the potential therapeutic approaches targeted to slow cyst growth in PKD. DOI: 10.11855/j.issn.0577-7402.2016.11.13

Calcium signals and caspase-12 participated in paraoxon-induced apoptosis in EL4 cells.

Science.gov (United States)

Li, Lan; Cao, Zhiheng; Jia, Pengfei; Wang, Ziren

2010-04-01

In order to investigate whether calcium signals participate in paraoxon (POX)-induced apoptosis in EL4 cells, real-time laser scanning confocal microscopy (LSCM) was used to detect Ca(2+) changes during the POX application. Apoptotic rates of EL4 cells and caspase-12 expression were also evaluated. POX (1-10nM) increased intracellular calcium concentration ([Ca(2+)]i) in EL4 cells in a dose-dependent manner at early stage (0-2h) of POX application, and apoptotic rates of EL4 cells after treatment with POX for 16h were also increased in a dose-dependent manner. Pre-treatment with EGTA, heparin or procaine attenuated POX-induced [Ca(2+)]i elevation and apoptosis. Additionally, POX up-regulated caspase-12 expression in a dose-dependent manner, and pre-treatment with EGTA, heparin or procaine significantly inhibited POX-induced increase of caspase-12 expression. Our results suggested that POX induced [Ca(2+)]i elevation in EL4 cells at the early stage of POX-induced apoptosis, which might involve Ca(2+) efflux from the endoplasmic reticulum (ER) and Ca(2+) influx from extracellular medium. Calcium signals and caspase-12 were important upstream messengers in POX-induced apoptosis in EL4 cells. The ER-associated pathway possibly operated in this apoptosis. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

Notch signaling protects retina from nuclear factor-kB- and poly-ADP-ribosepolymerase-mediated apoptosis under high-glucose stimulation

Institute of Scientific and Technical Information of China (English)

Xiuhong Qin1; Zhenzhen Zhang2; Haitao Xu1; and Yazhen Wu1

2011-01-01

Proliferative diabetic retinopathy,the primary cause of vision loss in adults,is one of serious microvascular complications caused by diabetes.Both poly-ADP-ribosepolymerase (PARP) and nuclear factor (NF)-kB signaling are involved in the injury process.Injury activates PARP,which in turn potentiates NF-kB activation and causes cell apoptosis.Like the NF-kB pathway,Notch1 signaling plays a key role in the regulation of cell proliferation,differentiation,and apoptosis.However,the connections between these signaling pathways are not well understood.In this study,we used both streptozotocin (STZ)-induced diabetic mice and human retinal vascular endothelial cells (HRVECs) cultured in high glucose to detect these relationships.We found that apoptosis was increased in both STZinduced diabetic mice and high-glucose-treated HRVECs,which was due to increased activation of PARP,cleaved caspase3,and reduced expression of Notch1 and p-Akt.The results of Notch1 overexpression and knockdown indicated that Notch1 signaling participated in the interaction of PARP and p50,and inhibited PARP- and p50-mediated apoptosis directly.These phenomena could be blocked by pretreatment with the PI3K inhibitor wortmannin via reducing p-Akt levels.Thus,our study demonstrated that Notch1 signaling protects cells from PARP- and NF-kB-induced apoptosis under high glucose through the activation of Akt.

Optimization of Signal Timing of Intersections by Internal Metering of Queue Time Ratio of Vehicles in Network Scale

Directory of Open Access Journals (Sweden)

Mina Ghanbarikarekani

2016-06-01

Full Text Available Optimization of signal timing in urban network is usually done by minimizing the delay times or queue lengths. Sincethe effect of each intersection on the whole network is not considered in the mentioned methods, traffic congestion may occur in network links. Therefore, this paper has aimed to provide a timing optimization algorithm for traffic signals using internal timing policy based on balancing queue time ratio of vehicles in network links. In the proposed algorithm, the difference between the real queue time ratio and the optimum one for each link of intersection was minimized. To evaluate the efficiency of the proposed algorithm on traffic performance, the proposed algorithm was applied in a hypothetical network. By comparing the simulating software outputs, before and after implementing the algorithm, it was concluded that the queue time ratio algorithm has improved the traffic parameters by increasing the flow as well as reducing the delay time and density of the network.

Signal treatments to reduce heavy vehicle crash-risk at metropolitan highway intersections.

Science.gov (United States)

Archer, Jeffery; Young, William

2009-05-01

Heavy vehicle red-light running at intersections is a common safety problem that has severe consequences. This paper investigates alternative signal treatments that address this issue. A micro-simulation analysis approach was adopted as a precursor to a field trial. The simulation model emulated traffic conditions at a known problem intersection and provided a baseline measure to compare the effects of: an extension of amber time; an extension of green for heavy vehicles detected in the dilemma zone at the onset of amber; an extension of the all-red safety-clearance time based on the detection of vehicles considered likely to run the red light at two detector locations during amber; an extension of the all-red safety-clearance time based on the detection of potential red-light runners during amber or red; and a combination of the second and fourth alternatives. Results suggested safety improvements for all treatments. An extension of amber provided the best safety effect but is known to be prone to behavioural adaptation effects and wastes traffic movement time unnecessarily. A green extension for heavy vehicles detected in the dilemma zone and an all-red extension for potential red-light runners were deemed to provide a sustainable safety improvement and operational efficiency.

Fractalkine is a "find-me" signal released by neurons undergoing ethanol-induced apoptosis.

Science.gov (United States)

Sokolowski, Jennifer D; Chabanon-Hicks, Chloe N; Han, Claudia Z; Heffron, Daniel S; Mandell, James W

2014-01-01

Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal-microglial signaling. Quantification of apoptotic debris in fractalkine-knockout (KO) and CX3CR1-KO mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a "find-me" signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-KO and CX3CR1-KO mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these KOs by 6 h after ethanol treatment. Collectively, this suggests that fractalkine acts as a "find me" signal released by apoptotic neurons, and subsequently plays a critical role in modulating both clearance and inflammatory cytokine gene expression after ethanol-induced apoptosis.

Fractalkine is a "find-me" signal released by neurons undergoing ethanol-induced apoptosis

Directory of Open Access Journals (Sweden)

Jennifer D Sokolowski

2014-11-01

Full Text Available Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal-microglial signaling. Quantification of apoptotic debris in fractalkine-knockout and CX3CR1-knockout mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a ‘find-me’ signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-knockout and CX3CR1-knockout mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these knockouts by 6 hours after ethanol treatment. Collectively, this suggests that fractalkine acts as a ‘find me’ signal released by apoptotic neurons, and subsequently plays a critical role in modulating both phagocytic clearance and inflammatory cytokine gene expression after

Role of Notch-1 signaling in ethanol induced PC12 apoptosis | Li ...

African Journals Online (AJOL)

Chronic alcoholic dementia has crucial role in progress of neurodegenerative disease and affects a large portion of our aging population. Neuronal cell apoptosis may be a contributing factor of neurodegenerative disease (ND) and Alzheimer's disease (AD). Previous researches have indicated that Notch-1 signaling ...

TGEV nucleocapsid protein induces cell cycle arrest and apoptosis through activation of p53 signaling

International Nuclear Information System (INIS)

Ding, Li; Huang, Yong; Du, Qian; Dong, Feng; Zhao, Xiaomin; Zhang, Wenlong; Xu, Xingang; Tong, Dewen

2014-01-01

Highlights: • TGEV N protein reduces cell viability by inducing cell cycle arrest and apoptosis. • TGEV N protein induces cell cycle arrest and apoptosis by regulating p53 signaling. • TGEV N protein plays important roles in TGEV-induced cell cycle arrest and apoptosis. - Abstract: Our previous studies showed that TGEV infection could induce cell cycle arrest and apoptosis via activation of p53 signaling in cultured host cells. However, it is unclear which viral gene causes these effects. In this study, we investigated the effects of TGEV nucleocapsid (N) protein on PK-15 cells. We found that TGEV N protein suppressed cell proliferation by causing cell cycle arrest at the S and G2/M phases and apoptosis. Characterization of various cellular proteins that are involved in regulating cell cycle progression demonstrated that the expression of N gene resulted in an accumulation of p53 and p21, which suppressed cyclin B1, cdc2 and cdk2 expression. Moreover, the expression of TGEV N gene promoted translocation of Bax to mitochondria, which in turn caused the release of cytochrome c, followed by activation of caspase-3, resulting in cell apoptosis in the transfected PK-15 cells following cell cycle arrest. Further studies showed that p53 inhibitor attenuated TGEV N protein induced cell cycle arrest at S and G2/M phases and apoptosis through reversing the expression changes of cdc2, cdk2 and cyclin B1 and the translocation changes of Bax and cytochrome c induced by TGEV N protein. Taken together, these results demonstrated that TGEV N protein might play an important role in TGEV infection-induced p53 activation and cell cycle arrest at the S and G2/M phases and apoptosis occurrence

Abscisic-acid-induced cellular apoptosis and differentiation in glioma via the retinoid acid signaling pathway.

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Zhou, Nan; Yao, Yu; Ye, Hongxing; Zhu, Wei; Chen, Liang; Mao, Ying

2016-04-15

Retinoid acid (RA) plays critical roles in regulating differentiation and apoptosis in a variety of cancer cells. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share structural similarities. Here we proposed that ABA may also play a role in cellular differentiation and apoptosis by sharing a similar signaling pathway with RA that may be involved in glioma pathogenesis. We reported for the first time that the ABA levels were twofold higher in low-grade gliomas compared with high-grade gliomas. In glioma tissues, there was a positive correlation between the ABA levels and the transcription of cellular retinoic acid-binding protein 2 (CRABP2) and a negative correlation between the ABA levels and transcription of fatty acid-binding protein 5 (FABP5). ABA treatment induced a significant increase in the expression of CRABP2 and a decrease in the expression of peroxisome proliferator-activated receptor (PPAR) in glioblastoma cells. Remarkably, both cellular apoptosis and differentiation were increased in the glioblastoma cells after ABA treatment. ABA-induced cellular apoptosis and differentiation were significantly reduced by selectively silencing RAR-α, while RAR-α overexpression exaggerated the ABA-induced effects. These results suggest that ABA may play a role in the pathogenesis of glioma by promoting cellular apoptosis and differentiation through the RA signaling pathway. © 2015 UICC.

Modeling pedestrian crossing speed profiles considering speed change behavior for the safety assessment of signalized intersections.

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Iryo-Asano, Miho; Alhajyaseen, Wael K M

2017-11-01

Pedestrian safety is one of the most challenging issues in road networks. Understanding how pedestrians maneuver across an intersection is the key to applying countermeasures against traffic crashes. It is known that the behaviors of pedestrians at signalized crosswalks are significantly different from those in ordinary walking spaces, and they are highly influenced by signal indication, potential conflicts with vehicles, and intersection geometries. One of the most important characteristics of pedestrian behavior at crosswalks is the possible sudden speed change while crossing. Such sudden behavioral change may not be expected by conflicting vehicles, which may lead to hazardous situations. This study aims to quantitatively model the sudden speed changes of pedestrians as they cross signalized crosswalks under uncongested conditions. Pedestrian speed profiles are collected from empirical data and speed change events are extracted assuming that the speed profiles are stepwise functions. The occurrence of speed change events is described by a discrete choice model as a function of the necessary walking speed to complete crossing before the red interval ends, current speed, and the presence of turning vehicles in the conflict area. The amount of speed change before and after the event is modeled using regression analysis. A Monte Carlo simulation is applied for the entire speed profile of the pedestrians. The results show that the model can represent the pedestrian travel time distribution more accurately than the constant speed model. Copyright © 2017 Elsevier Ltd. All rights reserved.

Arctigenin promotes apoptosis in ovarian cancer cells via the iNOS/NO/STAT3/survivin signalling.

Science.gov (United States)

Huang, Ke; Li, Li-an; Meng, Yuan-guang; You, Yan-qin; Fu, Xiao-yu; Song, Lei

2014-12-01

Arctigenin is a biologically active lignan extracted from the seeds of Arctium lappa and shows anticancer activity against a variety of human cancers. The aim of this study was to determine the effects of arctigenin on ovarian cancer cell proliferation and survival and associated molecular mechanisms. Human ovarian cancer OVCAR3 and SKOV3 cells were treated with arctigenin, and cell proliferation and apoptosis were assessed. Western blot analysis was used to examine signal transducer and activator of transcription-3 (STAT3) phosphorylation and survivin and inducible nitric oxide synthase (iNOS) expression. The involvement of STAT3/survivin/iNOS/NO signalling in arctigenin action was checked. Arctigenin treatment resulted in a significant and dose-dependent inhibition of cell proliferation. Arctigenin-treated cells showed a 4-6 times increase in the percentage of apoptosis, compared with control cells. Pre-treatment with Ac-DEVD-CHO, a specific inhibitor of caspase-3, counteracted the induction of apoptosis by arctigenin. Arctigenin treatment significantly inhibited STAT3 phosphorylation and survivin and iNOS expression. Arctigenin-induced apoptosis was impaired by pre-transfection with survivin-expressing plasmid or addition of chemical nitric oxide (NO) donors. Additionally, exogenous NO prevented the suppression of STAT3 phosphorylation and survivin expression by arctigenin. Arctigenin treatment inhibits the proliferation and induces caspase-3-dependent apoptosis of ovarian cancer cells. Suppression of iNOS/NO/STAT3/survivin signalling is causally linked to the anticancer activity of arctigenin. Therefore, arctigenin may be applicable to anticancer therapy for ovarian cancer. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Platelet-derived growth factor (PDGF)-signaling mediates radiation-induced apoptosis in human prostate cancer cells with loss of p53 function

International Nuclear Information System (INIS)

Kim, Harold E.; Han, Sue J.; Kasza, Thomas; Han, Richard; Choi, Hyeong-Seon; Palmer, Kenneth C.; Kim, Hyeong-Reh C.

1997-01-01

Platelet-derived growth factor (PDGF) signals a diversity of cellular responses in vitro, including cell proliferation, survival, transformation, and chemotaxis. PDGF functions as a 'competence factor' to induce a set of early response genes expressed in G 1 including p21 WAF1/CIP1 , a functional mediator of the tumor suppressor gene p53 in G 1 /S checkpoint. For PDGF-stimulated cells to progress beyond G 1 and transit the cell cycle completely, progression factors in serum such as insulin and IGF-1 are required. We have recently shown a novel role of PDGF in inducing apoptosis in growth-arrested murine fibroblasts. The PDGF-induced apoptosis is rescued by insulin, suggesting that G 1 /S checkpoint is a critical determinant for PDGF-induced apoptosis. Because recent studies suggest that radiation-induced signal transduction pathways interact with growth factor-mediated signaling pathways, we have investigated whether activation of the PDGF-signaling facilitates the radiation-induced apoptosis in the absence of functional p53. For this study we have used the 125-IL cell line, a mutant p53-containing, highly metastatic, and hormone-unresponsive human prostate carcinoma cell line. PDGF signaling is constitutively activated by transfection with a p28 v-sis expression vector, which was previously shown to activate PDGF α- and β- receptors. Although the basal level of p21 WAF1/CIP1 expression and radiation-induced apoptosis were not detectable in control 125-IL cells as would be predicted in mutant p53-containing cells, activation of PDGF-signaling induced expression of p21 WAF1/CIP1 and radiation-induced apoptosis. Our study suggests that the level of 'competence' growth factors including PDGF may be one of the critical determinants for radiation-induced apoptosis, especially in cells with loss of p53 function at the site of radiotherapy in vivo

Identification of ASK1, MKK4, JNK, c-Jun, and caspase-3 as a signaling cascade involved in cadmium-induced neuronal cell apoptosis

International Nuclear Information System (INIS)

Kim, Sun Don; Moon, Chang Kyu; Eun, Su-Yong; Ryu, Pan Dong; Jo, Sangmee Ahn

2005-01-01

Cd induces oxidative stress and apoptosis in various cells by activating mitogen-activated protein kinases (MAPKs), but the precise signaling components of the MAPK cascade and their role in neuronal apoptosis are still unclear. Here, we report that Cd treatment of SH-SY5Y cells caused apoptosis through sequential phosphorylation of the apoptosis signal regulating kinase 1, MAPK kinase 4, c-Jun N-terminal kinase (JNK), and c-Jun as determined by overexpression of dominant negative (DN) constructs of these genes or using a specific JNK inhibitor SP600125. Both Cd-induced JNK and c-Jun phosphorylation and apoptosis were inhibited dramatically by N-acetyl-L-cysteine, a free radical scavenger. In addition, caspase inhibitors, zDEVD and zVAD, reduced apoptosis but not JNK and c-Jun phosphorylation induced by Cd, while overexpression of DN JNK1 inhibited caspase-3 activity. Taken together, our data suggested that the JNK/c-Jun signaling cascade plays a crucial role in Cd-induced neuronal cell apoptosis and provides a molecular linkage between oxidative stress and neuronal apoptosis

Signal Control for Reducing Vehicle NOx and CO2 Emissions Based on Prediction of Arrival Traffic Flows at Intersections

Science.gov (United States)

Oda, Toshihiko

Nitrogen oxide (NOx) and carbon dioxide (CO2) emissions from vehicles have been increasing every year because of the growing number of vehicles, and they cause serious environmental problems such as air pollution and global warming. To alleviate these problems, this paper proposes a new traffic signal control method for reducing vehicle NOx and CO2 emissions on arterial roads. To this end, we first model the amount of vehicle emissions as a function of the traffic delay and the number of stops at intersections. This step is necessary because it is difficult to obtain the amount of emissions directly using traffic control systems. Second, we introduce a signal control model in which the control parameters are continuously updated on the basis of predictions of arrival traffic flows at intersections. The signal timings are calculated in such a manner so as to minimize the weighted sum of the two emissions, which depend on the traffic flow. To evaluate the validity of this method, simulation experiments are carried out on an arterial road. The experiments show that the proposed method significantly outperforms existing methods in reducing both the emissions and travel time.

Determining of the Parking Manoeuvre and the Taxi Blockage Adjustment Factor for the Saturation Flow Rate at the Outlet Legs of Signalized Intersections: Case Study from Rasht City (Iran)

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Behbahani, Hamid; Jahangir Samet, Mehdi; Najafi Moghaddam Gilani, Vahid; Amini, Amir

2017-10-01

The presence of taxi stops within the area of signalized intersections at the outlet legs due to unnatural behaviour of the taxis, sudden change of lanes, parking manoeuvres activities and stopping the vehicle to discharge or pick up the passengers have led to reduction of saturation flow rate at the outlet leg of signalized intersections and increased delay as well as affecting the performance of a crossing lane. So far, in term of evaluating effective adjustment factors on saturation flow rate at the inlet legs of the signalized intersections, various studies have been carried out, however; there has not been any studies on effective adjustment factors on saturation flow rate at the inlet legs. Hence, the evaluating of the traffic effects of unique behaviours on the saturation flow rate of the outlet leg is very important. In this research the parking manoeuvre time and taxi blockage time were evaluated and analyzed based on the available lane width as well as determining the effective adjustment factors on the saturation flow rate using recording related data at four signalized intersections in Rasht city. The results show that the average parking manoeuvre time is a function of the lane width and is increased as the lane width is reduced. Also, it is suggested to use the values of 7.37 and 11.31 seconds, respectively for the average parking manoeuvre time and the average blockage time of taxies at the outlet legs of signalized intersections for the traffic designing in Rasht city.

Simulation of queue length and vehicle delays on signal-controlled intersection

Directory of Open Access Journals (Sweden)

Leverents Evgeny

2018-01-01

Full Text Available The extensive use of information technology in the field of traffic control will increase the traffic capacity of intersection points and transports. To assess the efficacy of changing options for the road traffic organization or the reorganization of intersection points, you need to know the average delay in vehicles and the length of the queue. The adaptive traffic light control is one of such tools. Simulation modeling of traffic flows use for the definition of its work. The aim of this work is to create a simulation model of controlled intersection, which can evaluate the efficiency of the application the adaptive regulation in various traffic situations, including the availability or deficiency of pedestrian traffic through the intersection. The numerical experiment in in the model pass with using of the Monte Carlo method, which can to draw a conclusion about the calculated parameter on the basis of the result of the reproduction of the calculation model.

Signaling mechanisms of apoptosis-like programmed cell death in unicellular eukaryotes.

Science.gov (United States)

Shemarova, Irina V

2010-04-01

In unicellular eukaryotes, apoptosis-like cell death occurs during development, aging and reproduction, and can be induced by environmental stresses and exposure to toxic agents. The essence of the apoptotic machinery in unicellular organisms is similar to that in mammals, but the apoptotic signal network is less complex and of more ancient origin. The review summarizes current data about key apoptotic proteins and mechanisms of the transduction of apoptotic signals by caspase-like proteases and mitochondrial apoptogenic proteins in unicellular eukaryotes. The roles of receptor-dependent and receptor-independent caspase cascades are reviewed. 2010 Elsevier Inc. All rights reserved.

Signal pathway of hippocampal apoptosis and cognitive impairment of mice caused by cerium chloride.

Science.gov (United States)

Cheng, Zhe; Li, Na; Cheng, Jie; Hu, Renping; Gao, Guodong; Cui, Yaling; Gong, Xiaolan; Wang, Ling; Hong, Fashui

2012-12-01

Experimental studies have demonstrated that lanthanides could impair cognitive functions of children and animals, but very little is known about the hippocampal apoptosis and its molecular mechanism. The study investigated the signal pathway of hippocampal apoptosis induced by intragastric administration of CeCl(3) for 60 consecutive days. It showed that cerium had been significantly accumulated in the mouse hippocampus, and CeCl(3) caused hippocampal apoptosis and impairment of spatial recognition memory of mice. CeCl(3) effectively activated caspase-3 and -9, inhibited Bcl-2, and increased the levels of Bax and cytochrome c, promoted accumulation of reactive oxygen species in the mouse hippocampus. It implied that CeCl(3)-induced apoptosis in the mouse hippocampus could be triggered via mitochondrion-mediated pathway. Our findings suggest the need for great caution to handle the lanthanides for workers and consumers. 2011 Wiley Periodicals, Inc

Star-PAP Control of BIK Expression and Apoptosis Is Regulated by Nuclear PIPKIα and PKCδ Signaling

Science.gov (United States)

Li, Weimin; Laishram, Rakesh S.; Ji, Zhe; Barlow, Christy A.; Tian, Bin; Anderson, Richard A.

2012-01-01

SUMMARY BIK protein is an initiator of mitochondrial apoptosis and BIK expression is induced by pro-apoptotic signals including DNA damage. Here we demonstrate that 3′-end processing and expression of BIK mRNA are controlled by the nuclear PI4,5P2-regulated poly(A) polymerase Star-PAP downstream of DNA damage. Nuclear PKCδ is a key mediator of apoptosis and DNA damage stimulates PKCδ association with the Star-PAP complex where PKCδ is required for Star-PAP-dependent BIK expression. PKCδ binds the PI4,5P2-generating enzyme PIPKIα, which is essential for PKCδ interaction with the Star-PAP complex and PKCδ activity is directly stimulated by PI4,5P2. Features in the BIK 3′-UTR uniquely define Star-PAP specificity and may block canonical PAP activity toward BIK mRNA. This reveals a nuclear phosphoinositide signaling nexus where PIPKIα, PI4,5P2 and PKCδ regulate Star-PAP control of BIK expression and induction of apoptosis. This pathway is distinct from the Star-PAP-mediated oxidative stress pathway indicating signal-specific regulation of mRNA 3′-end processing. PMID:22244330

Fas-Induced Apoptosis of Renal Cell Carcinoma is Mediated by Apoptosis Signal-Regulating Kinase 1 via Mitochondrial Damage-Dependent Caspase-8 Activation

Directory of Open Access Journals (Sweden)

Mohamed Hassan

2009-01-01

Full Text Available Renal cell carcinoma (RCC is a prototype of a chemo refractory tumour. It remains the most lethal of the common urologic cancers and is highly resistant to conventional therapy. Here, we confirmed the efficiency of anti-Fas monoclonal antibody (CH11 as alternative therapeutic approach for the treatment of RCC and investigated the molecular mechanism(s, whereby CH11 induces apoptosis of RCC cells. The present study shows an essential role for apoptosis signal-regulating kinase 1 (ASK1, together with both c-jun-N-terminal kinase (JNK and p38 pathways, and caspase-8 in this process. Furthermore, CH11-dependent induction of the ASK1–JNK/p38 pathways was found to activate the transcription factors AP-1 and ATF-2, and FADD-caspase-8-Bid signalling, resulting in the translocation of both Bax and Bak proteins, and subsequently mitochondrial dysregulation that is characterized by the loss of mitochondrial membrane potential (ΔΨm, cytochrome c release and cleavage of caspase-9, caspase-3 and PARP. Thus, the described molecular mechanisms of CH11-induced apoptosis suggest the reliability of Fas activation as an alternative therapeutic approach for the treatment of patients with advanced renal cell carcinoma.

[Role of Rac1 signaling pathway of azathioprine and peptidoglycan in the regulation of monocyte-macrophage apoptosis in Crohn's disease].

Science.gov (United States)

Zhou, Z; Jing, Y; Ran, Y; Zhao, J; Zhou, L; Wang, B M

2018-04-01

Objective: To evaluate the changes of macrophages and expression of Rac1 in the inflammatory site of Crohn's disease, and to investigate the effects of 6-thioguanine (6-TG) and peptidoglycan on apoptosis of human peripheral blood monocyte-macrophage by regulating Rac1 signaling pathway. Methods: Ten patients with Crohn's disease and eight healthy controls diagnosed were enrolled at Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital from January 2013 to January 2014. The number of macrophages, apoptosis and expression of Rac1 in the inflammation sites and non-inflammation sites of intestinal mucosa were detected in both patients and controls. Peripheral blood mononuclear cells (PBMCs) were sorted by CD 14 immunomagnetic beads. The apoptosis of monocytes, expression of Rac1 and related apoptosis signaling molecules were detected in patients treated with peptidoglycan, 6-TG and Rac1 inhibitor NSC23766 and another 15 healthy donors. Results: The number of macrophages and apoptotic cells significantly increased in the inflammatory group of Crohn's disease patients compared with the non-inflammatory group. The expression of PAK1, downstream molecular of Rac1 signaling pathway of macrophages was also significantly higher in the inflammatory group of Crohn's disease patients than that in healthy controls and non-inflammatory group. Compared with control group, anti-apoptotic signals (NF-κB, Bcl-xL and STAT-3) in PBMCs increased in the peptidoglycan group, while slightly decreased in 6-TG group. 6-TG and NSC23766 significantly promoted peptidoglycan-related anti-apoptosis [peptidoglycan group (8.6±3.7)%, peptidoglycan+ 6-TG group (42.0±2.7)%, peptidoglycan+ NSC23766 group (58.5±6.9)%, PRac1 signaling pathway leading to macrophage apoptosis.

Dynamic Eco-Driving Speed Guidance at Signalized Intersections: Multivehicle Driving Simulator Based Experimental Study

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Peng Chen

2018-01-01

Full Text Available Variations in vehicle fuel consumption and gas emissions are usually associated with changes in cruise speed and the aggressiveness of drivers’ acceleration/deceleration, especially at traffic signals. In an attempt to enhance vehicle fuel efficiency on arterials, this study developed a dynamic eco-driving speed guidance strategy (DESGS using real-time signal timing and vehicle positioning information in a connected vehicle (CV environment. DESGS mainly aims to optimize the fuel/emission speed profiles for vehicles approaching signalized intersections. An optimization-based rolling horizon and a dynamic programming approach were proposed to track the optimal guided velocity for individual vehicles along the travel segment. In addition, a vehicle specific power (VSP based approach was integrated into DESGS to estimate the fuel consumption and CO2 emissions. To evaluate the effectiveness of the overall strategy, 15 experienced drivers were recruited to participate in interactive speed guidance experiments using multivehicle driving simulators. It was found that compared to vehicles without speed guidance, those with DESGS had a significantly reduced number of stops and approximately 25% less fuel consumption and CO2 emissions.

Interference of silibinin with IGF-1R signalling pathways protects human epidermoid carcinoma A431 cells from UVB-induced apoptosis

International Nuclear Information System (INIS)

Liu, Weiwei; Otkur, Wuxiyar; Li, Lingzhi; Wang, Qiong; He, Hao; Zang, Linghe; Hayashi, Toshihiko; Tashiro, Shin-ichi; Onodera, Satoshi; Xia, Mingyu; Ikejima, Takashi

2013-01-01

Highlights: ► Silibinin protects A431 cells from UVB irradiation-induced apoptosis. ► Up-regulation of the IGF-1R-JNK/ERK pathways by UVB induces cell apoptosis. ► Silibinin inhibits IGF-1R pathways to repress caspase-8-mediated apoptosis. -- Abstract: Ultraviolet B (UVB) from sunlight is a major cause of cutaneous lesion. Silibinin, a traditional hepatic protectant, elicits protective effects against UVB-induced cellular damage. In A431 cells, the insulin-like growth factor-1 receptor (IGF-1R) was markedly up-regulated by UVB irradiation. The activation of the IGF-1R signalling pathways contributed to apoptosis of the cells rather than rescuing the cells from death. Up-regulated IGF-1R stimulated downstream mitogen-activated protein kinases (MAPKs), such as c-Jun N-terminal kinases (JNK) and extracellular signal-regulated protein kinases 1/2 (ERK1/2). The subsequent activation of caspase-8 and caspase-3 led to apoptosis. The activation of IGF-1R signalling pathways is the cause of A431 cell death. The pharmacological inhibitors and the small interfering RNA (siRNA) targeting IGF-1R suppressed the downstream activation of JNK/ERK-caspases to help the survival of the UVB-irradiated A431 cells. Indeed, silibinin treatment suppressed the IGF-1R-JNK/ERK pathways and thus protected the cells from UVB-induced apoptosis

Albumin-induced apoptosis of glomerular parietal epithelial cells is modulated by extracellular signal-regulated kinase 1/2

Science.gov (United States)

Ohse, Takamoto; Krofft, Ron D.; Wu, Jimmy S.; Eddy, Allison A.; Pippin, Jeffrey W.; Shankland, Stuart J.

2012-01-01

Background. The biological role(s) of glomerular parietal epithelial cells (PECs) is not fully understood in health or disease. Given its location, PECs are constantly exposed to low levels of filtered albumin, which is increased in nephrotic states. We tested the hypothesis that PECs internalize albumin and increased uptake results in apoptosis. Methods. Confocal microscopy of immunofluorescent staining and immunohistochemistry were used to demonstrate albumin internalization in PECs and to quantitate albumin uptake in normal mice and rats as well as experimental models of membranous nephropathy, minimal change disease/focal segmental glomerulosclerosis and protein overload nephropathy. Fluorescence-activated cell sorting analysis was performed on immortalized cultured PECs exposed to fluorescein isothiocyanate (FITC)-labeled albumin in the presence of an endosomal inhibitor or vehicle. Apoptosis was measured by Hoechst staining in cultured PECs exposed to bovine serum albumin. Levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) were restored by retroviral infection of mitogen-activated protein kinase (MEK) 1/2 and reduced by U0126 in PECs exposed to high albumin levels in culture and apoptosis measured by Hoechst staining. Results. PECs internalized albumin normally, and this was markedly increased in all of the experimental disease models (P PECs also internalize FITC-labeled albumin, which was reduced by endosomal inhibition. A consequence of increased albumin internalization was PEC apoptosis in vitro and in vivo. Candidate signaling pathways underlying these events were examined. Data showed markedly reduced levels of phosphorylated extracellular signal-regulated kinase 1 and 2 (ERK1/2) in PECs exposed to high albumin levels in nephropathy and in culture. A role for ERK1/2 in limiting albumin-induced apoptosis was shown by restoring p-ERK1/2 by retroviral infection, which reduced apoptosis in cultured PECs, while a forced

Chromium picolinate induced apoptosis of lymphocytes and the signaling mechanisms thereof

International Nuclear Information System (INIS)

Jana, Mahadevan; Rajaram, Anantanarayanan; Rajaram, Rama

2009-01-01

Cr(III)(picolinate) 3 [Cr(III)(pic) 3 ] is currently used as a nutritional supplement and for treating Type-2 diabetes. The effect of Cr(III)(pic) 3 uptake in peripheral blood lymphocytes is investigated in this study. From the cytotoxicity data, DNA fragmentation pattern, Annexin V staining, TUNEL positivity and the ultrastructural characteristics such as chromatin condensation and formation of apoptotic bodies, it is clear that Cr(III)(pic) 3 induces a concentration dependent apoptosis. It is shown that reactive oxygen species (ROS) produced by treatment with Cr(III)(pic) 3 leads to apoptosis, since we find that pretreatment with N-acetyl cysteine inhibits the process. Using Western blotting technique and fluorescence measurements, the downstream signaling molecules have also been identified. Cr(III)(pic) 3 treatment leads to collapse of the mitochondrial membrane potential, Bax expression, increase in cytosolic cytochrome c content and active caspase-3 and DNA fragmentation and all these manifestations are reduced by pretreating the lymphocytes with N-acetyl cysteine. Thus, it is shown that Cr(III)(pic) 3 is cytotoxic to lymphocytes with ROS and mitochondrial events playing a role in bringing about apoptosis.

Low Emissions and Delay Optimization for an Isolated Signalized Intersection Based on Vehicular Trajectories.

Science.gov (United States)

Lin, Ciyun; Gong, Bowen; Qu, Xin

2015-01-01

A traditional traffic signal control system is established based on vehicular delay, queue length, saturation and other indicators. However, due to the increasing severity of urban environmental pollution issues and the development of a resource-saving and environmentally friendly social philosophy, the development of low-carbon and energy-efficient urban transport is required. This paper first defines vehicular trajectories and the calculation of vehicular emissions based on VSP. Next, a regression analysis method is used to quantify the relationship between vehicular emissions and delay, and a traffic signal control model is established to reduce emissions and delay using the enumeration method combined with saturation constraints. Finally, one typical intersection of Changchun is selected to verify the model proposed in this paper; its performance efficiency is also compared using simulations in VISSIM. The results of this study show that the proposed model can significantly reduce vehicle delay and traffic emissions simultaneously.

Antimony trioxide-induced apoptosis is dependent on SEK1/JNK signaling.

Science.gov (United States)

Mann, Koren K; Davison, Kelly; Colombo, Myrian; Colosimo, April L; Diaz, Zuanel; Padovani, Alessandra M S; Guo, Qi; Scrivens, P James; Gao, Wenli; Mader, Sylvie; Miller, Wilson H

2006-01-05

Very little is known concerning the toxicity of antimony, despite its commercial use as a flame retardant and medical use as a treatment for parasitic infections. Our previous studies show that antimony trioxide (Sb(2)O(3)) induces growth inhibition in patient-derived acute promyelocytic leukemia (APL) cell lines, a disease in which a related metal, arsenic trioxide (As(2)O(3)), is used clinically. However, signaling pathways initiated by Sb(2)O(3) treatment remain undefined. Here, we show that Sb(2)O(3) treatment of APL cells is associated with increased apoptosis as well as differentiation markers. Sb(2)O(3)-induced reactive oxygen species (ROS) correlated with increased apoptosis. In addition, when we decreased the buffering capacity of the cell by depleting glutathione, ROS production and apoptosis was enhanced. Arsenic-resistant APL cells with increased glutathione levels exhibited increased cross-resistance to Sb(2)O(3). Based on studies implicating c-jun kinase (JNK) in the mediation of the response to As(2)O(3), we investigated the role for JNK in Sb(2)O(3)-induced apoptosis. Sb(2)O(3) activates JNK and its downstream target, AP-1. In fibroblasts with a genetic deletion in SEK1, an upstream regulator of JNK, Sb(2)O(3)-induced growth inhibition as well as JNK activation was decreased. These data suggest roles for ROS and the SEK1/JNK pathway in the cytotoxicity associated with Sb(2)O(3) exposure.

Molecular mechanism of apoptosis and characterization of apoptosis induced by radiation

International Nuclear Information System (INIS)

Li Yumin; Zhang Yuguang; Li Yukun

1999-01-01

The major discoveries of apoptosis research in recent years were reviewed briefly. The mechanisms of caspases/ICE gene family and bcl-2 gene family on apoptosis were analyzed. And the signal transduction pathway of apoptosis found currently has been summarized. The characterizations of apoptosis induced by radiation such as time-effects, dose-effects and the radiosensibility were summed up

TNF-α- Mediated-p38-Dependent Signaling Pathway Contributes to Myocyte Apoptosis in Rats Subjected to Surgical Trauma

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Huaxing Wu

2015-03-01

Full Text Available Background: The accumulation of cytokines in the plasma after trauma can induce myocyte apoptosis. We aimed to identify which cytokine(s present in the plasma responsible for myocyte apoptosis, and delineated the signal transduction mechanism in rats subjected to surgical trauma. Methods: Rats were randomized into two groups: control and trauma groups, which was divided into five subgroups: posttraumatic 0, 3, 6, 12, and 24 h subgroups. Cardiomyocytes isolated from traumatized rats were incubated with one of the factors for 12 h (normal plasma; Cytomix; TNF-α; IL-1β; IFN-γ; trauma plasma; anti-TNF-α antibody; SB203580. Myocyte apoptosis, cytokine levels, and MAPKs activation, as the primary experimental outcomes, were measured by TUNEL, flow cytometry, ELISA and Western blot, respectively. Results: Myocyte apoptosis was induced by surgical trauma during the early stage after trauma. Accompanying this change, plasma TNF-α, IL-1β, and IFN-γ levels were elevated in traumatized rats. Incubation of traumatized cardiomyocytes with cytomix or TNF-α alone induced myocyte apoptosis, and increased the activation of p38 and ERK1/2. Myocyte apoptosis and p38 activation were elevated in traumatized cardiomyocytes with trauma plasma, and these increases were partly abolished by anti-TNF-α antibody or SB203580. Conclusion: Our study demonstrated that there exists the TNF-α-mediated-p38-dependent signaling pathway that contributed to posttraumatic myocyte apoptosis of rats undergoing surgical trauma.

Intersection carbon monoxide modeling

International Nuclear Information System (INIS)

Zamurs, J.

1990-01-01

In this note the author discusses the need for better air quality mobile source models near roadways and intersections. To develop the improved models, a better understanding of emissions and their relation to ambient concentrations is necessary. The database for the modal model indicates that vehicles do have different emission levels for different engine operating modes. If the modal approach is used information is needed on traffic signal phasing, queue lengths, delay times, acceleration rates, deceleration rates, capacity, etc. Dispersion estimates using current air quality models may be inaccurate because the models do not take into account intersecting traffic streams, multiple buildings of varying setbacks, height, and spacing

Salidroside protects against foam cell formation and apoptosis, possibly via the MAPK and AKT signaling pathways.

Science.gov (United States)

Ni, Jing; Li, Yuanmin; Li, Weiming; Guo, Rong

2017-10-10

Foam cell formation and apoptosis are closely associated with atherosclerosis pathogenesis. We determined the effect of salidroside on oxidized low-density lipoprotein (ox-LDL)-induced foam cell formation and apoptosis in THP1 human acute monocytic leukemia cells and investigated the associated molecular mechanisms. THP1-derived macrophages were incubated with salidroside for 5 h and then exposed to ox-LDL for 24 h to induce foam cell formation. Cytotoxicity, lipid deposition, apoptosis, and the expression of various proteins were tested using the CCK8 kit, Oil Red O staining, flow cytometry, and western blotting, respectively. Ox-LDL treatment alone promoted macrophage-derived foam cell formation, while salidroside treatment alone inhibited it (p foam cell formation and apoptosis, partly by regulating the MAPK and Akt signaling pathways.

Stimulated Raman signals at conical intersections: Ab initio surface hopping simulation protocol with direct propagation of the nuclear wave function

International Nuclear Information System (INIS)

Kowalewski, Markus; Mukamel, Shaul

2015-01-01

Femtosecond Stimulated Raman Spectroscopy (FSRS) signals that monitor the excited state conical intersections dynamics of acrolein are simulated. An effective time dependent Hamiltonian for two C—H vibrational marker bands is constructed on the fly using a local mode expansion combined with a semi-classical surface hopping simulation protocol. The signals are obtained by a direct forward and backward propagation of the vibrational wave function on a numerical grid. Earlier work is extended to fully incorporate the anharmonicities and intermode couplings

Stimulated Raman signals at conical intersections: Ab initio surface hopping simulation protocol with direct propagation of the nuclear wave function

Energy Technology Data Exchange (ETDEWEB)

Kowalewski, Markus, E-mail: mkowalew@uci.edu; Mukamel, Shaul, E-mail: smukamel@uci.edu [Department of Chemistry, University of California, Irvine, California 92697-2025 (United States)

2015-07-28

Femtosecond Stimulated Raman Spectroscopy (FSRS) signals that monitor the excited state conical intersections dynamics of acrolein are simulated. An effective time dependent Hamiltonian for two C—H vibrational marker bands is constructed on the fly using a local mode expansion combined with a semi-classical surface hopping simulation protocol. The signals are obtained by a direct forward and backward propagation of the vibrational wave function on a numerical grid. Earlier work is extended to fully incorporate the anharmonicities and intermode couplings.

Low Emissions and Delay Optimization for an Isolated Signalized Intersection Based on Vehicular Trajectories.

Directory of Open Access Journals (Sweden)

Ciyun Lin

Full Text Available A traditional traffic signal control system is established based on vehicular delay, queue length, saturation and other indicators. However, due to the increasing severity of urban environmental pollution issues and the development of a resource-saving and environmentally friendly social philosophy, the development of low-carbon and energy-efficient urban transport is required. This paper first defines vehicular trajectories and the calculation of vehicular emissions based on VSP. Next, a regression analysis method is used to quantify the relationship between vehicular emissions and delay, and a traffic signal control model is established to reduce emissions and delay using the enumeration method combined with saturation constraints. Finally, one typical intersection of Changchun is selected to verify the model proposed in this paper; its performance efficiency is also compared using simulations in VISSIM. The results of this study show that the proposed model can significantly reduce vehicle delay and traffic emissions simultaneously.

Pedestrian Safety Treatments for Signalized Intersections : Training Course Development

Science.gov (United States)

2017-11-01

When drivers make left turns during a permissive turn phase, they must yield to pedestrians as well as oncoming through vehicles. Left-turning drivers sometimes overlook pedestrians in the crosswalk while watching the opposing intersection approach. ...

Endoplasmic reticulum stress and IRE-1 signaling cause apoptosis in colon cancer cells in response to andrographolide treatment.

Science.gov (United States)

Banerjee, Aditi; Ahmed, Hafiz; Yang, Peixin; Czinn, Steven J; Blanchard, Thomas G

2016-07-05

The plant metabolite andrographolide induces cell cycle arrest and apoptosis in cancer cells. The mechanism(s) by which andrographolide induces apoptosis however, have not been elucidated. The present study was performed to determine the molecular events that promote apoptosis in andrographolide treated cells using T84, HCT116 and COLO 205 colon cancer cell lines. Andrographolide was determined to limit colony formation and Ki67 expression, alter nuclear morphology, increase cytoplasmic histone-associated-DNA-fragments, and increase cleaved caspase-3 levels. Andrographolide also induced significantly higher expression of endoplasmic reticulum (ER) stress proteins GRP-78 and IRE-1 by 48 h but not PERK or ATF6. Apoptosis signaling molecules BAX, spliced XBP-1 and CHOP were also significantly increased. Moreover, chemical inhibition of ER stress or IRE-1 depletion with siRNA in andrographolide treated cells significantly limited expression of IRE-1 and CHOP as determined by immunofluorescence staining, real time PCR, or immunobloting. This was accompanied by a decreased BAX/Bcl-2 ratio. Andrographolide significantly promotes cancer cell death compared to normal cells. These data demonstrate that andrographolide associated ER stress contributes to apoptosis through the activation of a pro-apoptotic GRP-78/IRE-1/XBP-1/CHOP signaling pathway.

Self-Localization at Street Intersections.

Science.gov (United States)

Fusco, Giovanni; Shen, Huiying; Coughlan, James M

2014-05-01

There is growing interest among smartphone users in the ability to determine their precise location in their environment for a variety of applications related to wayfinding, travel and shopping. While GPS provides valuable self-localization estimates, its accuracy is limited to approximately 10 meters in most urban locations. This paper focuses on the self-localization needs of blind or visually impaired travelers, who are faced with the challenge of negotiating street intersections. These travelers need more precise self-localization to help them align themselves properly to crosswalks, signal lights and other features such as walk light pushbuttons. We demonstrate a novel computer vision-based localization approach that is tailored to the street intersection domain. Unlike most work on computer vision-based localization techniques, which typically assume the presence of detailed, high-quality 3D models of urban environments, our technique harnesses the availability of simple, ubiquitous satellite imagery (e.g., Google Maps) to create simple maps of each intersection. Not only does this technique scale naturally to the great majority of street intersections in urban areas, but it has the added advantage of incorporating the specific metric information that blind or visually impaired travelers need, namely, the locations of intersection features such as crosswalks. Key to our approach is the integration of IMU (inertial measurement unit) information with geometric information obtained from image panorama stitchings. Finally, we evaluate the localization performance of our algorithm on a dataset of intersection panoramas, demonstrating the feasibility of our approach.

CONTROLLING TRAFFIC FLOW IN MULTILANE-ISOLATED INTERSECTION USING ANFIS APPROACH TECHNIQUES

Directory of Open Access Journals (Sweden)

G. R. LAI

2015-08-01

Full Text Available Many controllers have applied the Adaptive Neural-Fuzzy Inference System (ANFIS concept for optimizing the controller performance. However, there are less traffic signal controllers developed using the ANFIS concept. ANFIS traffic signal controller with its fuzzy rule base and its ability to learn from a set of sample data could improve the performance of Existing traffic signal controlling system to reduce traffic congestions at most of the busy traffic intersections in city such as Kuala Lumpur, Malaysia. The aim of this research is to develop an ANFIS traffic signals controller for multilane-isolated four approaches intersections in order to ease traffic congestions at traffic intersections. The new concept to generate sample data for ANFIS training is introduced in this research. The sample data is generated based on fuzzy rules and can be analysed using tree diagram. This controller is simulated on multilane-isolated traffic intersection model developed using M/M/1 queuing theory and its performance in terms of average waiting time, queue length and delay time are compared with traditional controllers and fuzzy controller. Simulation result shows that the average waiting time, queue length, and delay time of ANFIS traffic signal controller are the lowest as compared to the other three controllers. In conclusion, the efficiency and performance of ANFIS controller are much better than that of fuzzy and traditional controllers in different traffic volumes.

Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-κB-mediated survival signaling

International Nuclear Information System (INIS)

Leskinen, Markus J.; Heikkilae, Hanna M.; Speer, Mei Y.; Hakala, Jukka K.; Laine, Mika; Kovanen, Petri T.; Lindstedt, Ken A.

2006-01-01

Chymase released from activated mast cells induces apoptosis of vascular smooth muscle cells (SMCs) in vitro by degrading the pericellular matrix component fibronectin, so causing disruption of focal adhesion complexes and Akt dephosphorylation, which are necessary for cell adhesion and survival. However, the molecular mechanisms of chymase-mediated apoptosis downstream of Akt have remained elusive. Here, we show by means of RT-PCR, Western blotting, EMSA, immunocytochemistry and confocal microscopy, that chymase induces SMC apoptosis by disrupting NF-κB-mediated survival signaling. Following chymase treatment, the translocation of active NF-κB/p65 to the nucleus was partly abolished and the amount of nuclear p65 was reduced. Pretreatment of SMCs with chymase also inhibited LPS- and IL-1β-induced nuclear translocation of p65. The chymase-induced degradation of p65 was mediated by active caspases. Loss of NF-κB-mediated transactivation resulted in downregulation of bcl-2 mRNA and protein expression, leading to mitochondrial swelling and release of cytochrome c. The apoptotic process involved activation of both caspase 9 and caspase 8. The results reveal that, by disrupting the NF-κB-mediated survival-signaling pathway, activated chymase-secreting mast cells can mediate apoptosis of cultured arterial SMCs. Since activated mast cells colocalize with apoptotic SMCs in vulnerable areas of human atherosclerotic plaques, they may participate in the weakening and rupture of atherosclerotic plaques

miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis in osteosarcoma cells

Energy Technology Data Exchange (ETDEWEB)

Li, Zhi [Department of Human Anatomy and Histoembryology, College of Basic Medical Sciences, Jilin University (China); Li, Youjun, E-mail: liyoujunn@126.com [Department of Human Anatomy and Histoembryology, College of Basic Medical Sciences, Jilin University (China); Wang, Nan; Yang, Lifeng; Zhao, Wei; Zeng, Xiandong [Central Hospital Affiliated to Shenyang Medical College (China)

2016-03-18

miR-130b was significantly up-regulated in osteosarcoma (OS) cells. Naked cuticle homolog 2 (NKD2) inhibited tumor growth and metastasis in OS by suppressing Wnt signaling. We used three miRNA target analysis tools to identify potential targets of miR-130b, and found that NKD2 is a potential target of miR-130b. Based on these findings, we hypothesize that miR-130b might target NKD2 and regulate the Wnt signaling to promote OS growth. We detected the expression of miR-130b and NKD2 mRNA and protein by quantitative Real-Time PCR (qRT-PCR) and western blot assays, respectively, and found up-regulation of miR-130b and down-regulation of NKD2 mRNA and protein exist in OS cell lines. MTT and flow cytometry assays showed that miR-130b inhibitors inhibit proliferation and promote apoptosis in OS cells. Furthermore, we showed that NKD2 is a direct target of miR-130b, and miR-130b regulated proliferation and apoptosis of OS cells by targeting NKD2. We further investigated whether miR-130b and NKD2 regulate OS cell proliferation and apoptosis by inhibiting Wnt signaling, and the results confirmed our speculation that miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis of OS cells. These findings will offer new clues for OS development and progression, and novel potential therapeutic targets for OS. - Highlights: • miR-130b is up-regulated and NKD2 is down-regulated in osteosarcoma cell lines. • Down-regulation of miR-130b inhibits proliferation of osteosarcoma cells. • Down-regulation of miR-130b promotes apoptosis of osteosarcoma cells. • miR-130b directly targets NKD2. • NKD2 regulates OS cell proliferation and apoptosis by inhibiting the Wnt signaling.

miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis in osteosarcoma cells

International Nuclear Information System (INIS)

Li, Zhi; Li, Youjun; Wang, Nan; Yang, Lifeng; Zhao, Wei; Zeng, Xiandong

2016-01-01

miR-130b was significantly up-regulated in osteosarcoma (OS) cells. Naked cuticle homolog 2 (NKD2) inhibited tumor growth and metastasis in OS by suppressing Wnt signaling. We used three miRNA target analysis tools to identify potential targets of miR-130b, and found that NKD2 is a potential target of miR-130b. Based on these findings, we hypothesize that miR-130b might target NKD2 and regulate the Wnt signaling to promote OS growth. We detected the expression of miR-130b and NKD2 mRNA and protein by quantitative Real-Time PCR (qRT-PCR) and western blot assays, respectively, and found up-regulation of miR-130b and down-regulation of NKD2 mRNA and protein exist in OS cell lines. MTT and flow cytometry assays showed that miR-130b inhibitors inhibit proliferation and promote apoptosis in OS cells. Furthermore, we showed that NKD2 is a direct target of miR-130b, and miR-130b regulated proliferation and apoptosis of OS cells by targeting NKD2. We further investigated whether miR-130b and NKD2 regulate OS cell proliferation and apoptosis by inhibiting Wnt signaling, and the results confirmed our speculation that miR-130b targets NKD2 and regulates the Wnt signaling to promote proliferation and inhibit apoptosis of OS cells. These findings will offer new clues for OS development and progression, and novel potential therapeutic targets for OS. - Highlights: • miR-130b is up-regulated and NKD2 is down-regulated in osteosarcoma cell lines. • Down-regulation of miR-130b inhibits proliferation of osteosarcoma cells. • Down-regulation of miR-130b promotes apoptosis of osteosarcoma cells. • miR-130b directly targets NKD2. • NKD2 regulates OS cell proliferation and apoptosis by inhibiting the Wnt signaling.

Nur77 inhibits oxLDL induced apoptosis of macrophages via the p38 MAPK signaling pathway

International Nuclear Information System (INIS)

Shao, Qin; Han, Fei; Peng, Shi; He, Ben

2016-01-01

The interaction between macrophages and oxLDL plays a crucial role in the initiation and progression of atherosclerosis. As a key initiator in a number of plaque promoting processes, oxLDL induces variable effects such as cell apoptosis or proliferation. Orphan nuclear receptor Nur77 is potently induced in macrophages by diverse stimuli, suggesting that it is of importance in vascular inflammation resulting in atherosclerosis, but whether Nur77 induction is detrimental or protective is unclear. In our study, we explore the role of Nur77 in the regulation of oxLDL-induced macrophage apoptosis and the signaling pathways that are involved. We found that oxLDL induced Nur77 expression in a dose and time dependent fashion, and cell viability was decreased in parallel. To determine whether Nur77 induction contributes to the loss of cell viability or is a protective mechanism, the effect of Nur77 overexpression was examined. Importantly, Nur77 overexpression inhibited the oxLDL-induced decrease of cell viability, inhibited the production of apoptotic bodies and restored DNA synthesis following oxLDL exposure. Furthermore, we found that Nur77 induction is mediated through the p38 MAPK signaling pathway. After pretreatment with SB203580, cell viability was decreased, the expression of CyclinA2 and PCNA was attenuated and the percentage of cell apoptosis was enhanced. Likewise, Nur77 overexpression increased the expression of the cell cycle genes PCNA and p21, and attenuated the increase in caspase-3. On the other hand, knockdown of Nur77 expression by specific siRNA resulted in the increased expression of caspase 3. The results demonstrate that Nur77 is induced by oxLDL via the p38 MAPK signaling pathway, which is involved in the regulation of cell survival. Nur77 enhanced cell survival via suppressing apoptosis, without affecting cell proliferation of activated macrophages, which may be beneficial in patients with atherosclerosis. - Highlights: • oxLDL could induce Nur77

Nur77 inhibits oxLDL induced apoptosis of macrophages via the p38 MAPK signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Shao, Qin; Han, Fei; Peng, Shi; He, Ben, E-mail: heben@medmail.com.cn

2016-03-18

The interaction between macrophages and oxLDL plays a crucial role in the initiation and progression of atherosclerosis. As a key initiator in a number of plaque promoting processes, oxLDL induces variable effects such as cell apoptosis or proliferation. Orphan nuclear receptor Nur77 is potently induced in macrophages by diverse stimuli, suggesting that it is of importance in vascular inflammation resulting in atherosclerosis, but whether Nur77 induction is detrimental or protective is unclear. In our study, we explore the role of Nur77 in the regulation of oxLDL-induced macrophage apoptosis and the signaling pathways that are involved. We found that oxLDL induced Nur77 expression in a dose and time dependent fashion, and cell viability was decreased in parallel. To determine whether Nur77 induction contributes to the loss of cell viability or is a protective mechanism, the effect of Nur77 overexpression was examined. Importantly, Nur77 overexpression inhibited the oxLDL-induced decrease of cell viability, inhibited the production of apoptotic bodies and restored DNA synthesis following oxLDL exposure. Furthermore, we found that Nur77 induction is mediated through the p38 MAPK signaling pathway. After pretreatment with SB203580, cell viability was decreased, the expression of CyclinA2 and PCNA was attenuated and the percentage of cell apoptosis was enhanced. Likewise, Nur77 overexpression increased the expression of the cell cycle genes PCNA and p21, and attenuated the increase in caspase-3. On the other hand, knockdown of Nur77 expression by specific siRNA resulted in the increased expression of caspase 3. The results demonstrate that Nur77 is induced by oxLDL via the p38 MAPK signaling pathway, which is involved in the regulation of cell survival. Nur77 enhanced cell survival via suppressing apoptosis, without affecting cell proliferation of activated macrophages, which may be beneficial in patients with atherosclerosis. - Highlights: • oxLDL could induce Nur77

Multiple signal transduction pathways in okadaic acid induced apoptosis in HeLa cells

International Nuclear Information System (INIS)

Jayaraj, R.; Gupta, Nimesh; Rao, P.V. Lakshmana

2009-01-01

Okadaic acid (OA) is the major component of diarrhetic shell fish poisoning toxins and a potent inhibitor of protein phosphatase 1 and 2A. We investigated the signal transduction pathways involved in OA induced cell death in HeLa cells. OA induced cytotoxicity and apoptosis at IC50 of 100 nM. OA treatment resulted in time dependent increase in reactive oxygen species and depleted intracellular glutathione levels. Loss of mitochondrial membrane permeability led to translocation of bax, cytochrome-c and AIF from mitochondria to cytosol. The cells under fluorescence microscope showed typical apoptotic morphology with condensed chromatin, and nuclear fragmentation. We investigated the mitochondrial-mediated caspase cascade. The time dependent activation and cleavage of of bax, caspases-8, 10, 9, 3 and 7 was observed in Western blot analysis. In addition to caspase-dependent pathway AIF mediated caspase-independent pathway was involved in OA mediated cell death. OA also caused time dependent inhibition of protein phosphatase 2A activity and phosphorylation of p38 and p42/44 MAP kinases. Inhibitor studies with Ac-DEVO-CHO and Z-VAD-FMK could not prevent the phosphorylation of p38 and p42/44 MAP kinases. Our experiments with caspase inhibitors Ac-DEVD-CHO, Z-IETD-FMK and Z-VAD-FMK inhibited capsase-3, 8 cleavages but did not prevent OA-induced apoptosis and DNA fragmentation. Similarly, pretreatment with cyclosporin-A and N-acetylcysteine could not prevent the DNA fragmentation. In summary, the results of our study show that OA induces multiple signal transduction pathways acting either independently or simultaneously leading to apoptosis

Membrane type 1-matrix metalloproteinase/Akt signaling axis modulates TNF-α-induced procoagulant activity and apoptosis in endothelial cells.

Directory of Open Access Journals (Sweden)

Hiroshi Ohkawara

Full Text Available Membrane type 1-matrix metalloproteinase (MT1-MMP functions as a signaling molecule in addition to a proteolytic enzyme. Our hypothesis was that MT1-MMP cooperates with protein kinase B (Akt in tumor necrosis factor (TNF-α-induced signaling pathways of vascular responses, including tissue factor (TF procoagulant activity and endothelial apoptosis, in cultured human aortic endothelial cells (ECs. TNF-α (10 ng/mL induced a decrease in Akt phosphorylation within 60 minutes in ECs. A chemical inhibitor of MMP, TIMP-2 and selective small interfering RNA (siRNA-mediated suppression of MT1-MMP reversed TNF-α-triggered transient decrease of Akt phosphorylation within 60 minutes, suggesting that MT1-MMP may be a key regulator of Akt phosphorylation in TNF-α-stimulated ECs. In the downstream events, TNF-α increased TF antigen and activity, and suppressed the expression of thrombomodulin (TM antigen. Inhibition of Akt markedly enhanced TNF-α-induced expression of TF antigen and activity, and further reduced the expression of TM antigen. Silencing of MT1-MMP by siRNA also reversed the changed expression of TF and TM induced by TNF-α. Moreover, TNF-α induced apoptosis of ECs through Akt- and forkhead box protein O1 (FoxO1-dependent signaling pathway and nuclear factor-kB (NF-kB activation. Knockdown of MT1-MMP by siRNA reversed apoptosis of ECs by inhibiting TNF-α-induced Akt-dependent regulation of FoxO1 in TNF-α-stimulated ECs. Immunoprecipitation demonstrated that TNF-α induced the changes in the associations between the cytoplasmic fraction of MT1-MMP and Akt in ECs. In conclusion, we show new evidence that MT1-MMP/Akt signaling axis is a key modifier for TNF-α-induced signaling pathways for modulation of procoagulant activity and apoptosis of ECs.

Agmatine protects against intracerebroventricular streptozotocin-induced water maze memory deficit, hippocampal apoptosis and Akt/GSK3β signaling disruption.

Science.gov (United States)

Moosavi, Maryam; Zarifkar, Amir Hossein; Farbood, Yaghoub; Dianat, Mahin; Sarkaki, Alireza; Ghasemi, Rasoul

2014-08-05

Centrally administered streptozotocin (STZ), is known to cause Alzheimer׳s like memory deterioration. It mainly affects insulin signaling pathways such as PI3/Akt and GSK-3β which are involved in cell survival. Previous studies indicate that STZ increases the ratio of Bax/Bcl-2 and thereby induces caspase-3 activation and apoptosis. Agmatine, a polyamine derived from l-arginine decarboxylation, is recently shown to exert some neuroprotective effects. This study aimed to assess if agmatine reverses STZ-induced memory deficits, hippocampal Akt/GSK-3β signaling disruption and caspase-3 activation. Adult male Sprague-Dawely rats weighing 200-250 g were used. The canules were implanted bilaterally into lateral ventricles. STZ was administered on days 1 and 3 (3 mg/kg) and agmatine treatment (40 or 80 mg/kg) was started from day 4 and continued in an every other day manner till day 14. The animal׳s learning and memory capability was assessed on days 15-18 using Morris water maze. After complement of behavioral studies the hippocampi was isolated and the amounts of hippocampal cleaved caspase-3 (the landmark of apoptosis), Bax/Bcl-2 ratio, total and phosphorylated forms of GSK-3β and Akt were analyzed by western blot. The results showed that agmatine in 80 but not 40 mg/kg reversed the memory deterioration induced by STZ. Western blot analysis revealed that STZ prompted elevation of caspase-3; Bax/Bcl-2 ratio and disrupted Akt/GSK-3β signaling in the hippocampus. Agmatine treatment prevented apoptosis and Akt/GSK-3β signaling impairment induced by STZ. This study disclosed that agmatine treatment averts not only STZ-induced memory deterioration but also hippocampal apoptosis and Akt/GSK-3β signaling disruption. Copyright © 2014 Elsevier B.V. All rights reserved.

Increasing Capacity of Intersections with Transit Priority

Directory of Open Access Journals (Sweden)

Yanxi Hao

2016-12-01

Full Text Available Dedicated bus lane (DBL and transit signal priority (TSP are two effective and low-cost ways of improving the reliability of transits. However, these strategies reduce the capacity of general traffic. This paper presents an integrated optimization (IO model to improve the performance of intersections with dedicated bus lanes. The IO model integrated geometry layout, main-signal timing, pre-signal timing and transit priority. The optimization problem is formulated as a Mix-Integer-Non-Linear-Program (MINLP that can be transformed into a Mix-Integer-Linear-Program (MILP and then solved by the standard branch-and-bound technique. The applicability of the IO model is tested through numerical experiment under different intersection layouts and traffic demands. A VISSIM micro simulation model was developed and used to evaluate the performance of the proposed IO model. The test results indicate that the proposed model can increase the capacity and reduce the delay of general traffic when providing priority to buses.

Development of an in-vehicle intersection collision countermeasure

Science.gov (United States)

Pierowicz, John A.

1997-02-01

Intersection collisions constitute approximately twenty-six percent of all accidents in the United States. Because of their complexity, and demands on the perceptual and decision making abilities of the driver, intersections present an increased risk of collisions between automobiles. This situation provides an opportunity to apply advanced sensor and processing capabilities to prevent these collisions. A program to determine the characteristics of intersection collisions and identify potential countermeasures will be described. This program, sponsored by the National Highway Traffic Safety Administration, utilized accident data to develop a taxonomy of intersection crashes. This taxonomy was used to develop a concept for an intersection collision avoidance countermeasure. The concept utilizes in-vehicle position, dynamic status, and millimeter wave radar system and an in-vehicle computer system to provide inputs to an intersection collision avoidance algorithm. Detection of potential violation of traffic control device, or proceeding into the intersection with inadequate gap will lead to the presentation of a warning to the driver. These warnings are presented to the driver primarily via a head-up display and haptic feedback. Roadside to vehicle communication provides information regarding phased traffic signal information. Active control of the vehicle's brake and steering systems are described. Progress in the development of the systems will be presented along with the schedule of future activities.

Apoptosis of bone marrow mesenchymal stem cells caused by homocysteine via activating JNK signal.

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Benzhi Cai

Full Text Available Bone marrow mesenchymal stem cells (BMSCs are capable of homing to and repair damaged myocardial tissues. Apoptosis of BMSCs in response to various pathological stimuli leads to the attenuation of healing ability of BMSCs. Plenty of evidence has shown that elevated homocysteine level is a novel independent risk factor of cardiovascular diseases. The present study was aimed to investigate whether homocysteine may induce apoptosis of BMSCs and its underlying mechanisms. Here we uncovered that homocysteine significantly inhibited the cellular viability of BMSCs. Furthermore, TUNEL, AO/EB, Hoechst 333342 and Live/Death staining demonstrated the apoptotic morphological appearance of BMSCs after homocysteine treatment. A distinct increase of ROS level was also observed in homocysteine-treated BMSCs. The blockage of ROS by DMTU and NAC prevented the apoptosis of BMSCs induced by homocysteine, indicating ROS was involved in the apoptosis of BMSCs. Moreover, homocysteine also caused the depolarization of mitochondrial membrane potential of BMSCs. Furthermore, apoptotic appearance and mitochondrial membrane potential depolarization in homocysteine-treated BMSCs was significantly reversed by JNK inhibitor but not p38 MAPK and ERK inhibitors. Western blot also confirmed that p-JNK was significantly activated after exposing BMSCs to homocysteine. Homocysteine treatment caused a significant reduction of BMSCs-secreted VEGF and IGF-1 in the culture medium. Collectively, elevated homocysteine induced the apoptosis of BMSCs via ROS-induced the activation of JNK signal, which provides more insight into the molecular mechanisms of hyperhomocysteinemia-related cardiovascular diseases.

Increasing the endogenous NO level causes catalase inactivation and reactivation of intercellular apoptosis signaling specifically in tumor cells.

Science.gov (United States)

Bauer, Georg

2015-12-01

Tumor cells generate extracellular superoxide anions and are protected against intercellular apoptosis-inducing HOCl- and NO/peroxynitrite signaling through the expression of membrane-associated catalase. This enzyme decomposes H2O2 and thus prevents HOCl synthesis. It efficiently interferes with NO/peroxynitrite signaling through oxidation of NO and decomposition of peroxynitrite. The regulatory potential of catalase at the crosspoint of ROS and RNS chemical biology, as well as its high local concentration on the outside of the cell membrane of tumor cells, establish tight control of intercellular signaling and thus prevent tumor cell apoptosis. Therefore, inhibition of catalase or its inactivation by singlet oxygen reactivate intercellular apoptosis-inducing signaling. Nitric oxide and peroxynitrite are connected with catalase in multiple and meaningful ways, as (i) NO can be oxidated by compound I of catalase, (ii) NO can reversibly inhibit catalase, (iii) peroxynitrite can be decomposed by catalase and (iv) the interaction between peroxynitrite and H2O2 leads to the generation of singlet oxygen that inactivates catalase. Therefore, modulation of the concentration of free NO through addition of arginine, inhibition of arginase, induction of NOS expression or inhibition of NO dioxygenase triggers an autoamplificatory biochemical cascade that is based on initial formation of singlet oxygen, amplification of superoxide anion/H2O2 and NO generation through singlet oxygen dependent stimulation of the FAS receptor and caspase-8. Finally, singlet oxygen is generated at sufficiently high concentration to inactivate protective catalase and to reactivate intercellular apoptosis-inducing ROS signaling. This regulatory network allows to establish several pathways for synergistic interactions, like the combination of modulators of NO metabolism with enhancers of superoxide anion generation, modulators of NO metabolism that act at different targets and between modulators of

Increasing the endogenous NO level causes catalase inactivation and reactivation of intercellular apoptosis signaling specifically in tumor cells

Science.gov (United States)

Bauer, Georg

2015-01-01

Tumor cells generate extracellular superoxide anions and are protected against intercellular apoptosis-inducing HOCl- and NO/peroxynitrite signaling through the expression of membrane-associated catalase. This enzyme decomposes H2O2 and thus prevents HOCl synthesis. It efficiently interferes with NO/peroxynitrite signaling through oxidation of NO and decomposition of peroxynitrite. The regulatory potential of catalase at the crosspoint of ROS and RNS chemical biology, as well as its high local concentration on the outside of the cell membrane of tumor cells, establish tight control of intercellular signaling and thus prevent tumor cell apoptosis. Therefore, inhibition of catalase or its inactivation by singlet oxygen reactivate intercellular apoptosis-inducing signaling. Nitric oxide and peroxynitrite are connected with catalase in multiple and meaningful ways, as (i) NO can be oxidated by compound I of catalase, (ii) NO can reversibly inhibit catalase, (iii) peroxynitrite can be decomposed by catalase and (iv) the interaction between peroxynitrite and H2O2 leads to the generation of singlet oxygen that inactivates catalase. Therefore, modulation of the concentration of free NO through addition of arginine, inhibition of arginase, induction of NOS expression or inhibition of NO dioxygenase triggers an autoamplificatory biochemical cascade that is based on initial formation of singlet oxygen, amplification of superoxide anion/H2O2 and NO generation through singlet oxygen dependent stimulation of the FAS receptor and caspase-8. Finally, singlet oxygen is generated at sufficiently high concentration to inactivate protective catalase and to reactivate intercellular apoptosis-inducing ROS signaling. This regulatory network allows to establish several pathways for synergistic interactions, like the combination of modulators of NO metabolism with enhancers of superoxide anion generation, modulators of NO metabolism that act at different targets and between modulators of

Polydatin inhibits cell proliferation and induces apoptosis in laryngeal cancer and HeLa cells via suppression of the PDGF/AKT signaling pathway.

Science.gov (United States)

Li, Haixia; Shi, Baoyuan; Li, Yanyun; Yin, Fengfang

2017-07-01

Polydatin (PD), a stilbene compound extracted from Polygonum cuspidatum, is suggested to possess anti-cancer activities, including inhibition of cell proliferation, cell cycle arrest, and induction of apoptosis. The platelet-derived growth factor (PDGF)/AKT signaling pathway plays complex roles in tumor suppression. However, the effect of PD on the PDGF/AKT signaling pathway in laryngeal cancer and HeLa cells has not been explored. MTT assay and flow cytometry showed that PD inhibited cell proliferation and induced apoptosis in Hep-2 and AMC-HN-8 cells. Western blot analysis indicated that PD inhibited the expression levels of PDGF-B and phosphorylated AKT (p-AKT) in both cells. Treatment of PDGF-B siRNA or PDGFR inhibitor found that after the PDGF signaling was inactivated, p-AKT expression was significantly decreased in Hep-2 cells. Tumor xenograft experiment in nude mice indicated PD significantly inhibited the growth of Hep-2 cells in vivo. In conclusion, PD inhibited cell proliferation and induced apoptosis in laryngeal cancer and HeLa cells via inactivation of the PDGF/AKT signaling pathway. © 2017 Wiley Periodicals, Inc.

Piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways.

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Wang, Hongfei; Wang, Yongqiang; Gao, Hongmei; Wang, Bing; Dou, Lin; Li, Yin

2018-02-01

Piperlongumine is an alkaloid compound extracted from Piper longum L. It is a chemical substance with various pharmacological effects and medicinal value, including anti-tumor, lipid metabolism regulatory, antiplatelet aggregation and analgesic properties. The present study aimed to understand whether piperlongumine induces the apoptosis and autophagy of leukemic cells, and to identify the mechanism involved. Cell viability and autophagy were detected using MTT, phenazine methyl sulfate and trypan blue exclusion assays. The apoptosis rate was calculated using flow cytometry. The protein expression levels of microtubule-associated protein 1A/1B-light chain 3, Akt and mechanistic target of rapamycin (mTOR) were measured using western blotting. The cell growth of leukemic cells was completely inhibited following treatment with piperlongumine, and marked apoptosis was also induced. Dead cells as a result of autophagy were stained using immunofluorescence and observed under a light microscope. Phosphoinositide 3-kinase (PI3K)/Akt/mTOR signaling was suppressed by treatment with piperlongumine, while p38 signaling and caspase-3 activity were induced by treatment with piperlongumine. It was concluded that piperlongumine induces apoptosis and autophagy in leukemic cells through targeting the PI3K/Akt/mTOR and p38 signaling pathways.

2,5-hexanedione induces bone marrow mesenchymal stem cell apoptosis via inhibition of Akt/Bad signal pathway.

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Sun, Jingsong; Shi, Xiaoxia; Li, Shuangyue; Piao, Fengyuan

2018-04-01

2,5-Hexanedione (HD) is an important bioactive metabolite of n-hexane and mediates the neurotoxicity of parent compound. Studies show that HD induces apoptotic death of neural progenitor cells. However, its underlying mechanism remains unknown. Mesenchymal stem cells (MSCs) are multipotential stem cells with the ability to differentiate into various cell types and have been used as cell model for studying the toxic effects of chemicals on stem cells. In this study, we exposed rat bone marrow MSCs to 0, 10, 20, and 40 mM HD in vitro. Apoptosis and disruption of mitochondrial transmembrane potential were estimated by immunochemistry staining. The expression of Akt, Bad, phosphorylated Akt (p-Akt), and Bad (p-Bad) as well as cytochrome c in mitochondria and cytosol were examined by Western blot. Moreover, caspase 3 activity, viability, and death of cells were measured by spectrophotometry. Our results showed that HD induced cell apoptosis and increased caspase 3 activity. HD down-regulated the expression levels of p-Akt, p-Bad and induced MMP depolarization, followed by cytochrome c release. Moreover, HD led to a concentration-dependent increase in the MSCs death, which was relative to MSCs apoptosis. However, these toxic effects of HD on the MSCs were significantly mitigated in the presence of IGF, which could activate PI3 K/Akt pathway. These results indicated that HD induced mitochondria-mediated apoptosis in the MSCs via inhibiting Akt/Bad signaling pathway and apoptotic death of MSCs via the signaling pathway. These results might provide some clues for studying further the mechanisms of HD-induced stem cell apoptosis and adverse effect on neurogenesis. © 2017 Wiley Periodicals, Inc.

Effect of LIPUS on inflammatory factors, cell apoptosis and integrin signaling pathway in osteoarthritis animal models

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Li-Cai Zhang

2017-05-01

Full Text Available Objective: To study the effect of low-intensity pulsed ultrasound (LIPUS on inflammatory factors, cell apoptosis and integrin signaling pathway in osteoarthritis animal models. Methods: Male New Zealand white rabbits were selected as the experimental animals and randomly divided into sham group, osteoarthritis model group (OA group and LIPUS intervention group (LIPUS group, animal models with osteoarthritis in hind limb knee joint were established and then given LIPUS intervention. 6 weeks after the intervention, the articular cartilage was separated to detect the expression of inflammatory factors, cell apoptosis molecules and integrin signaling pathway molecules. Results: OPN, NO, IL-1β, TNF-α, Fas, FasL, LC3-II, Beclin-1, Integrinβ1, FAK, ERK1/2, JNK, p38MAPK, MMP-1 and MMP-3 protein expression in articular cartilage of OA group were significantly higher than those of Sham group while Col-I and Col-II protein expression were significantly lower than those of Sham group; OPN, NO, IL-1β, TNF-α, Fas, FasL, LC3-II, Beclin-1, Integrinβ1, FAK, ERK1/2, JNK, p38MAPK, MMP-1 and MMP-3 protein expression in articular cartilage of LIPUS group were significantly lower than those of OA group while Col-I and Col-II protein expression were significantly higher than those of OA group. Conclusion: LIPUS has inhibiting effect on the inflammation, apoptosis and integrin signaling pathway in articular cartilage of osteoarthritis animal models, and it can promote the repair of articular cartilage.

Membrane Type 1–Matrix Metalloproteinase/Akt Signaling Axis Modulates TNF-α-Induced Procoagulant Activity and Apoptosis in Endothelial Cells

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Ohkawara, Hiroshi; Ishibashi, Toshiyuki; Sugimoto, Koichi; Ikeda, Kazuhiko; Ogawa, Kazuei; Takeishi, Yasuchika

2014-01-01

Membrane type 1–matrix metalloproteinase (MT1-MMP) functions as a signaling molecule in addition to a proteolytic enzyme. Our hypothesis was that MT1-MMP cooperates with protein kinase B (Akt) in tumor necrosis factor (TNF)-α-induced signaling pathways of vascular responses, including tissue factor (TF) procoagulant activity and endothelial apoptosis, in cultured human aortic endothelial cells (ECs). TNF-α (10 ng/mL) induced a decrease in Akt phosphorylation within 60 minutes in ECs. A chemical inhibitor of MMP, TIMP-2 and selective small interfering RNA (siRNA)-mediated suppression of MT1-MMP reversed TNF-α-triggered transient decrease of Akt phosphorylation within 60 minutes, suggesting that MT1-MMP may be a key regulator of Akt phosphorylation in TNF-α-stimulated ECs. In the downstream events, TNF-α increased TF antigen and activity, and suppressed the expression of thrombomodulin (TM) antigen. Inhibition of Akt markedly enhanced TNF-α-induced expression of TF antigen and activity, and further reduced the expression of TM antigen. Silencing of MT1-MMP by siRNA also reversed the changed expression of TF and TM induced by TNF-α. Moreover, TNF-α induced apoptosis of ECs through Akt- and forkhead box protein O1 (FoxO1)-dependent signaling pathway and nuclear factor-kB (NF-kB) activation. Knockdown of MT1-MMP by siRNA reversed apoptosis of ECs by inhibiting TNF-α-induced Akt-dependent regulation of FoxO1 in TNF-α-stimulated ECs. Immunoprecipitation demonstrated that TNF-α induced the changes in the associations between the cytoplasmic fraction of MT1-MMP and Akt in ECs. In conclusion, we show new evidence that MT1-MMP/Akt signaling axis is a key modifier for TNF-α-induced signaling pathways for modulation of procoagulant activity and apoptosis of ECs. PMID:25162582

Mixed Vehicle Flow At Signalized Intersection: Markov Chain Analysis

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Gertsbakh Ilya B.

2015-09-01

Full Text Available We assume that a Poisson flow of vehicles arrives at isolated signalized intersection, and each vehicle, independently of others, represents a random number X of passenger car units (PCU’s. We analyze numerically the stationary distribution of the queue process {Zn}, where Zn is the number of PCU’s in a queue at the beginning of the n-th red phase, n → ∞. We approximate the number Yn of PCU’s arriving during one red-green cycle by a two-parameter Negative Binomial Distribution (NBD. The well-known fact is that {Zn} follow an infinite-state Markov chain. We approximate its stationary distribution using a finite-state Markov chain. We show numerically that there is a strong dependence of the mean queue length E[Zn] in equilibrium on the input distribution of Yn and, in particular, on the ”over dispersion” parameter γ= Var[Yn]/E[Yn]. For Poisson input, γ = 1. γ > 1 indicates presence of heavy-tailed input. In reality it means that a relatively large ”portion” of PCU’s, considerably exceeding the average, may arrive with high probability during one red-green cycle. Empirical formulas are presented for an accurate estimation of mean queue length as a function of load and g of the input flow. Using the Markov chain technique, we analyze the mean ”virtual” delay time for a car which always arrives at the beginning of the red phase.

Edaravone attenuates neuronal apoptosis in hypoxic-ischemic brain damage rat model via suppression of TRAIL signaling pathway.

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Li, Chunyi; Mo, Zhihuai; Lei, Junjie; Li, Huiqing; Fu, Ruying; Huang, Yanxia; Luo, Shijian; Zhang, Lei

2018-06-01

Edaravone is a new type of oxygen free radical scavenger and able to attenuate various brain damage including hypoxic-ischemic brain damage (HIBD). This study was aimed at investigating the neuroprotective mechanism of edaravone in rat hypoxic-ischemic brain damage model and its correlation with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway. 75 seven-day-old Sprague-Dawley neonatal rats were equally divided into three groups: sham-operated group (sham), HIBD group and HIBD rats injected with edaravone (HIBD + EDA) group. Neurological severity and space cognitive ability of rats in each group were evaluated using Longa neurological severity score and Morris water maze testing. TUNEL assay and flow cytometry were used to determine brain cell apoptosis. Western blot was used to estimate the expression level of death receptor-5 (DR5), Fas-associated protein with death domain (FADD), caspase 8, B-cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein (Bax). In addition, immunofluorescence was performed to detect caspase 3. Edaravone reduced neurofunctional damage caused by HIBD and improved the cognitive capability of rats. The above experiment results suggested that edaravone could down-regulate the expression of active caspase 3 protein, thereby relieving neuronal apoptosis. Taken together, edaravone could attenuate neuronal apoptosis in rat hypoxic-ischemic brain damage model via suppression of TRAIL signaling pathway, which also suggested that edaravone might be an effective therapeutic strategy for HIBD clinical treatment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Eco-Approach and Departure System for Left-Turn Vehicles at a Fixed-Time Signalized Intersection

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Huifu Jiang

2018-01-01

Full Text Available This research proposed an eco-approach and departure system for left-turn vehicles at a fixed-time signalized intersection. This system gives higher priority to enhancing traffic safety than improving mobility and fuel efficiency, and optimizes the entire traffic consisted of connected and automated vehicles (CAVs and conventional human-driven vehicles by providing ecological speed trajectories for left-turn CAVs. All the ecological speed trajectories are offline optimized before the implementation of system. The speed trajectory optimization is constructed in Pontryagin’s Minimum Principle structure. The before and after evaluation of the proposed system shows the percentage of vehicles that drive pass the intersection at safe speed increases by 2.14% to 45.65%, fuel consumption benefits range 0.53% to 18.44%, emission benefits range from 0.57% to 15.69%, no significant throughput benefits is observed. The proposed system significantly enhances the traffic safety and improves the fuel efficiency and emission reduction of left-turn vehicles with no adverse effect on mobility, and has a good robustness against the randomness of traffic. The investigation also indicates that the computation time of proposed system is greatly reduced compared to previous eco-driving system with online speed optimization. The computation time is up to 0.01 s. The proposed system is ready for real-time application.

Ranking the types of intersections for assessing the safety of pedestrians using TOPSIS method

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Călin ŞERBU

2014-11-01

Full Text Available Every year, more than 1500 accidents with pedestrian occur in the intersections in Romania. The number of accidents involving pedestrians in roundabouts intersections type increased approximately three times in 2013 compared to 2009 in Romania. This alarming increase led to the need of assessing the safety of pedestrians in intersections with or without safety systems. The safety systems for pedestrians and drivers include: the road marking, the pedestrian crossings marking, signal intersections with road signs, traffic lights or pedestrian safety barriers. We propose to assess the types of intersections with TOPSIS method.

Apoptosis and Molecular Targeting Therapy in Cancer

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Hassan, Mohamed; Watari, Hidemichi; AbuAlmaaty, Ali; Ohba, Yusuke; Sakuragi, Noriaki

2014-01-01

Apoptosis is the programmed cell death which maintains the healthy survival/death balance in metazoan cells. Defect in apoptosis can cause cancer or autoimmunity, while enhanced apoptosis may cause degenerative diseases. The apoptotic signals contribute into safeguarding the genomic integrity while defective apoptosis may promote carcinogenesis. The apoptotic signals are complicated and they are regulated at several levels. The signals of carcinogenesis modulate the central control points of the apoptotic pathways, including inhibitor of apoptosis (IAP) proteins and FLICE-inhibitory protein (c-FLIP). The tumor cells may use some of several molecular mechanisms to suppress apoptosis and acquire resistance to apoptotic agents, for example, by the expression of antiapoptotic proteins such as Bcl-2 or by the downregulation or mutation of proapoptotic proteins such as BAX. In this review, we provide the main regulatory molecules that govern the main basic mechanisms, extrinsic and intrinsic, of apoptosis in normal cells. We discuss how carcinogenesis could be developed via defective apoptotic pathways or their convergence. We listed some molecules which could be targeted to stimulate apoptosis in different cancers. Together, we briefly discuss the development of some promising cancer treatment strategies which target apoptotic inhibitors including Bcl-2 family proteins, IAPs, and c-FLIP for apoptosis induction. PMID:25013758

Ultraviolet (UV and Hydrogen Peroxide Activate Ceramide-ER Stress-AMPK Signaling Axis to Promote Retinal Pigment Epithelium (RPE Cell Apoptosis

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Jin Yao

2013-05-01

Full Text Available Ultraviolet (UV radiation and reactive oxygen species (ROS impair the physiological functions of retinal pigment epithelium (RPE cells by inducing cell apoptosis, which is the main cause of age-related macular degeneration (AMD. The mechanism by which UV/ROS induces RPE cell death is not fully addressed. Here, we observed the activation of a ceramide-endoplasmic reticulum (ER stress-AMP activated protein kinase (AMPK signaling axis in UV and hydrogen peroxide (H2O2-treated RPE cells. UV and H2O2 induced an early ceramide production, profound ER stress and AMPK activation. Pharmacological inhibitors against ER stress (salubrinal, ceramide production (fumonisin B1 and AMPK activation (compound C suppressed UV- and H2O2-induced RPE cell apoptosis. Conversely, cell permeable short-chain C6 ceramide and AMPK activator AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide mimicked UV and H2O2’s effects and promoted RPE cell apoptosis. Together, these results suggest that UV/H2O2 activates the ceramide-ER stress-AMPK signaling axis to promote RPE cell apoptosis.

Intersection Group Dynamic Subdivision and Coordination at Intraregional Boundaries in Sudden Disaster

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Ciyun Lin

2015-01-01

Full Text Available This paper aims at the traffic flow agglomeration effect characteristics and rapid evacuation requirement in sudden disaster; operation time of intraregional boundaries traffic signal coordination was presented firstly. Then intraregional boundaries intersection group dynamic subdivision and consolidation method based on relative similarity degree and similarity coefficient of adjacent intersections was put forward. As to make the traffic control strategy adapt to traffic condition of different intraregional boundaries intersection groups, this paper proposes an intraregional boundaries traffic signal coordination and optimization technology based on organic computing theory. Finally, this paper uses Delphi 7.0, MapX, and Oracle developing a software package, combined with Paramics V6 Simulator to validate the methods of this paper. The result shows that it can obviously improve disaster affected regional traffic signal control efficiency which reduces average traffic delay by 30–35%, decreases vehicle queue by more than 20% and reduces evacuation time more than 13.06%.

Curcumin Induced Human Gastric Cancer BGC-823 Cells Apoptosis by ROS-Mediated ASK1-MKK4-JNK Stress Signaling Pathway

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Tao Liang

2014-09-01

Full Text Available The signaling mediated by stress-activated MAP kinases (MAPK, c-Jun N-terminal kinase (JNK has well-established importance in cancer. In the present report, we investigated the effects of curcumin on the signaling pathway in human gastric cancer BGC-823 cells. Curcumin induced reactive oxygen species (ROS production and BGC-823 cells apoptosis. Inhibition of ROS generation by antioxidant (NAC or Trion significantly prevented curcumin-mediated apoptosis. Notably, we observed that curcumin activated ASK1, a MAPKKK that is oxidative stress sensitive and responsible to phosphorylation of JNK via triggering cascades, up-regulated an upstream effector of the JNK, MKK4, and phosphorylated JNK protein expression in BGC-823 cells. However, curcumin induced ASK1-MKK4-JNK signaling was attenuated by NAC. All the findings confirm the possibility that oxidative stress-activated ASK1-MKK4-JNK signaling cascade promotes the apoptotic response in curcumin-treated BGC-823 cells.

Xingshentongqiao Decoction Mediates Proliferation, Apoptosis, Orexin-A Receptor and Orexin-B Receptor Messenger Ribonucleic Acid Expression and Represses Mitogen-activated Protein Kinase Signaling

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Yuanli Dong

2015-01-01

Full Text Available Background: Hypocretin (HCRT signaling plays an important role in the pathogenesis of narcolepsy and can be significantly influenced by Chinese herbal therapy. Our previous study showed that xingshentongqiao decoction (XSTQ is clinically effective for the treatment of narcolepsy. To determine whether XSTQ improves narcolepsy by modulating HCRT signaling, we investigated its effects on SH-SY5Y cell proliferation, apoptosis, and HCRT receptor 1/2 (orexin receptor 1 [OX1R] and orexin receptor 2 [OX2R] expression. The signaling pathways involved in these processes were also assessed. Methods: The effects of XSTQ on proliferation and apoptosis in SH-SY5Y cells were assessed using cell counting kit-8 and annexin V-fluorescein isothiocyanate assays. OX1R and OX2R expression was assessed by quantitative real-time polymerase chain reaction analysis. Western blotting for mitogen-activated protein kinase (MAPK pathway activation was performed to further assess the signaling mechanism of XSTQ. Results: XSTQ reduced the proliferation and induced apoptosis of SH-SY5Y cells. This effect was accompanied by the upregulation of OX1R and OX2R expression and the reduced phosphorylation of extracellular signal-regulated kinase (Erk 1/2, p38 MAPK and c-Jun N-terminal kinase (JNK. Conclusions: XSTQ inhibits proliferation and induces apoptosis in SH-SY5Y cells. XSTQ also promotes OX1R and OX2R expression. These effects are associated with the repression of the Erk1/2, p38 MAPK, and JNK signaling pathways. These results define a molecular mechanism for XSTQ in regulating HCRT and MAPK activation, which may explain its ability to treat narcolepsy.

Shifting the balance of mitochondrial apoptosis: therapeutic perspectives

International Nuclear Information System (INIS)

Fulda, Simone

2012-01-01

Signaling via the intrinsic (mitochondrial) pathway of apoptosis represents one of the critical signal transduction cascades that control the regulation of cell death. This pathway is typically altered in human cancers, thereby providing a suitable target for therapeutic intervention. Members of the Bcl-2 family of proteins as well as cell survival signaling cascades such as the PI3K/Akt/mTOR pathway are involved in the regulation of mitochondria-mediated apoptosis. Therefore, further insights into the molecular mechanisms that form the basis for the control of mitochondria-mediated apoptosis will likely open new perspectives to bypass evasion of apoptosis and treatment resistance in human cancers.

Shifting the balance of mitochondrial apoptosis: therapeutic perspectives

Energy Technology Data Exchange (ETDEWEB)

Fulda, Simone, E-mail: simone.fulda@kgu.de [Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt (Germany)

2012-10-08

Signaling via the intrinsic (mitochondrial) pathway of apoptosis represents one of the critical signal transduction cascades that control the regulation of cell death. This pathway is typically altered in human cancers, thereby providing a suitable target for therapeutic intervention. Members of the Bcl-2 family of proteins as well as cell survival signaling cascades such as the PI3K/Akt/mTOR pathway are involved in the regulation of mitochondria-mediated apoptosis. Therefore, further insights into the molecular mechanisms that form the basis for the control of mitochondria-mediated apoptosis will likely open new perspectives to bypass evasion of apoptosis and treatment resistance in human cancers.

Shifting the balance of mitochondrial apoptosis: therapeutic perspectives

Directory of Open Access Journals (Sweden)

Simone eFulda

2012-10-01

Full Text Available Signaling via the intrinsic (mitochondrial pathway of apoptosis represents one of the critical signal transduction cascades that control the regulation of cell death. This pathway is typically altered in human cancers, thereby providing a suitable target for therapeutic intervention. Members of the Bcl-2 family of proteins as well as cell survival signaling cascades such as the PI3K/Akt/mTOR pathway are involved in the regulation of mitochondria-mediated apoptosis. Therefore, further insights into the molecular mechanisms that form the basis for the control of mitochondria-mediated apoptosis will likely open new perspectives to bypass evasion of apoptosis and treatment resistance in human cancers.

Cantharidin Induced Oral Squamous Cell Carcinoma Cell Apoptosis via the JNK-Regulated Mitochondria and Endoplasmic Reticulum Stress-Related Signaling Pathways.

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Chin-Chuan Su

Full Text Available Oral cancer is a subtype of head and neck cancer which represents 2.65% of all human malignancies. Most of oral cancer is histopathologically diagnosed as oral squamous cell carcinoma (OSCC. OSCC is characterized by a high degree of local invasion and a high rate of metastasis to the cervical lymph nodes. How to prevention and treatment of OSCC is important and imperative. Here, we investigated the therapeutic effect and molecular mechanism of cantharidin, an active compound isolated from blister beetles, on OSCC in vitro. Results showed that cantharidin significantly decreased cell viability in human tongue squamous carcinoma-derived SAS, CAL-27, and SCC-4 cell lines. The further mechanistic studies were carried out in SAS cells. Cantharidin also significantly increased apoptosis-related signals, including caspase-9, caspase-7 and caspase-3 proteins. Besides, cantharidin decreased mitochondrial transmembrane potential (MMP and induced cytochrome c and apoptosis inducing factor (AIF release. Cantharidin also increased Bax, Bid, and Bak protein expressions and decreased Bcl-2 protein expression. Cantharidin could also increase the endoplasmic reticulum (ER stress signals, including the expressions of phosphorylated eIF-2α and CHOP, but not Grp78 and Grp94. Furthermore, cantharidin reduced pro-caspase-12 protein expression. In signals of mitogen-activated protein kinases, cantharidin increased the phosphorylation of JNK, but not ERK and p38. Transfection of shRNA-JNK to OSCC cells effectively reversed the cantharidin-induced cell apoptotic signals, including the mitochondrial and ER stress-related signaling molecules. Taken together, these findings suggest that cantharidin induces apoptosis in OSCC cells via the JNK-regulated mitochondria and ER stress-related signaling pathways.

Growth and apoptosis of human natural killer cell neoplasms: role of interleukin-2/15 signaling.

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Yamasaki, Satoshi; Maeda, Motoi; Ohshima, Koichi; Kikuchi, Masahiro; Otsuka, Teruhisa; Harada, Mine

2004-10-01

Interleukin (IL)-15 plays an important role in the survival of human natural killer (NK) cells. We investigated IL-2/15 signaling in NK cell neoplasms from five patients and in five cell lines (NK-92, KHYG-1, SNK-6, HANK1 and MOTN-1) compared to mature peripheral NK cells from 10 healthy subjects. Apoptosis of NK cell lines was prevented by addition of IL-15 in vitro. Blocking IL-2/15Rbeta on IL-2-stimulated NK-92 cells resulted in reduced expression of Bcl-X(L) and phosphorylated Stat5, which paralleled early apoptosis without altering Bcl-2 expression. These data add IL-2/15Rbeta to the list of factors important for the survival of NK cell neoplasms.

Cell shrinkage as a signal to apoptosis in NIH 3T3 fibroblasts

DEFF Research Database (Denmark)

Friis, Martin B; Friborg, Christel R; Schneider, Linda

2005-01-01

Cell shrinkage is a hallmark of the apoptotic mode of programmed cell death, but it is as yet unclear whether a reduction in cell volume is a primary activation signal of apoptosis. Here we studied the effect of an acute elevation of osmolarity (NaCl or sucrose additions, final osmolarity 687...... accelerated in fibroblasts overexpressing Rac. Conversely, the activation of the extracellular signal-regulated kinase (Erk1/2) was initially significantly decreased. Subsequent to activation of p38, p53 was activated through serine-15 phosphorylation, and active p53 was translocated from the cytosol......: cellular shrinkage activates Rac, with activation of p38, followed by phosphorylation and nuclear translocation of p53, resulting in permeability increases and caspase-3 activation....

Distributed traffic signal control using fuzzy logic

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Chiu, Stephen

1992-01-01

We present a distributed approach to traffic signal control, where the signal timing parameters at a given intersection are adjusted as functions of the local traffic condition and of the signal timing parameters at adjacent intersections. Thus, the signal timing parameters evolve dynamically using only local information to improve traffic flow. This distributed approach provides for a fault-tolerant, highly responsive traffic management system. The signal timing at an intersection is defined by three parameters: cycle time, phase split, and offset. We use fuzzy decision rules to adjust these three parameters based only on local information. The amount of change in the timing parameters during each cycle is limited to a small fraction of the current parameters to ensure smooth transition. We show the effectiveness of this method through simulation of the traffic flow in a network of controlled intersections.

Iron overload promotes erythroid apoptosis through regulating HIF-1a/ROS signaling pathway in patients with myelodysplastic syndrome.

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Zheng, Qing-Qing; Zhao, You-Shan; Guo, Juan; Zhao, Si-da; Song, Lu-Xi; Fei, Cheng-Ming; Zhang, Zheng; Li, Xiao; Chang, Chun-Kang

2017-07-01

Erythroid apoptosis increases significantly in myelodysplastic syndrome (MDS) patients with iron overload, but the underlying mechanism is not fully clear. In this study, we aim to explore the effect of HIF-1a/ROS on erythroid apoptosis in MDS patients with iron overload. We found that iron overload injured cellular functions through up-regulating ROS levels in MDS/AML cells, including inhibited cell viability, increased cell apoptosis and blocked cell cycle at G0/G1 phase. Interestingly, overexpression of hypoxia inducible factor-1a (HIF-1a), which was under-expressed in iron overload models, reduced ROS levels and attenuated cell damage caused by iron overload in MDS/AML cells. And gene knockdown of HIF-1a got the similar results as iron overload in MDS/AML cells. Furthermore, iron overload caused high erythroid apoptosis was closely related with ROS in MDS patients. Importantly, the HIF-1a protein levels of erythrocytes elevated obviously after incubation with desferrioxamine (DFO) from MDS patients with iron overload, accompanied by ROS levels inhibited and erythroid apoptosis reduced. Taken together, our findings determine that the HIF-1a/ROS signaling pathway plays a key role in promoting erythroid apoptosis in MDS patients with iron overload. Copyright © 2017 Elsevier Ltd. All rights reserved.

EGFR-dependent signalling reduced and p38 dependent apoptosis required by Gallic acid in Malignant Mesothelioma cells.

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Demiroglu-Zergeroglu, Asuman; Candemir, Gulsife; Turhanlar, Ebru; Sagir, Fatma; Ayvali, Nurettin

2016-12-01

The unrestrained EGFR signalling contributes to malignant phenotype in a number of cancers including Malignant Mesotheliomas. Present study was designed to evaluate EGFR-dependent anti-proliferative and apoptotic effects of Gallic acid in transformed Mesothelial (MeT-5A) and Malignant Mesothelioma (SPC212) cells. Gallic acid reduced the viability of Malignant Mesothelioma cells in a concentration and time-dependent manner. However, viability of mesothelial cells reduced only at high concentration and longer time periods. Gallic acid restrained the activation of EGFR, ERK1/2 and AKT proteins and down regulated expression of Cyclin D and Bcl-2 genes, but upregulated the expression of p21 gene in EGF-induced SPC212 cells. GA-induced transitory G1 arrest and triggered mitochondrial and death receptor mediated apoptosis, which requires p38MAPK activation. The data provided here indicate that GA is able to inhibit EGFR dependent proliferation and survival signals and induces p38 pathway dependent apoptosis in Malignant Mesothelioma cells. On the basis of these experimental findings it is worthwhile to investigate further the biological activity of Gallic acid on other Mesothelioma cell lines harbouring aberrant EGFR signals. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Subretinal Fluid Levels of Signal-Transduction Proteins and Apoptosis Molecules in Macula-Off Retinal Detachment Undergoing Scleral Buckle Surgery.

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Carpineto, Paolo; Aharrh-Gnama, Agbeanda; Ciciarelli, Vincenzo; Borrelli, Enrico; Petti, Francesco; Aloia, Raffaella; Lamolinara, Alessia; Di Nicola, Marta; Mastropasqua, Leonardo

2016-12-01

To evaluate signal transduction and early apoptosis protein levels in subretinal fluid collected during scleral buckling surgery for macula-off rhegmatogenous retinal detachment (RRD). Our aim was to assess both their relation with RRD features and their influence on the posttreatment outcome. Thirty-three eyes of 33 RRD patients scheduled for scleral buckle surgery were enrolled in the study. Undiluted subretinal fluid samples were collected during surgery and analyzed via magnetic bead-based immunoassay. All patients underwent a complete ophthalmologic evaluation at baseline and at each follow-up visit (months 1, 3, and 6). Moreover, both at baseline and at the postsurgery month 6 visit, the patients were tested by means of spectral-domain optical coherence tomography (SD-OCT) in order to evaluate the average ganglion cell-inner plexiform complex thickness, as well as the photoreceptor inner segment/outer segment junction status. Patients' clinical features (retinal detachment size, detachment duration, and occurrence of proliferative vitreoretinopathy) were associated with several early apoptotic factors (caspase-8, caspase-9, and B-cell lymphoma 2 [Bcl-2]-associated death promoter [BAD]). Furthermore, both early apoptosis factors (caspase-8, Bcl-2, and p53) and signal-transduction proteins (ERK 1/2) were found to influence the postsurgery month 3 OCT characteristics. Signal-transduction proteins and early apoptosis proteins are associated with different clinical features and postsurgery outcomes.

Types of intersections.

NARCIS (Netherlands)

2015-01-01

There are many types of intersections in the Netherlands. In an inherently safe road traffic system, however, the number of intersection types needs to be limited, depending on the road types that intersect. The desired types of intersections do not always correspond with the recommendations in the

Effects of countdown timers on driver behavior after the yellow onset at Chinese intersections.

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Long, Kejun; Han, Lee D; Yang, Qiang

2011-10-01

Few studies have focused on the effect of countdown timers at signalized intersections in China, where such timers are widely deployed for their perceived benefits of increased safety and capacity. This study examines the effect of countdown timers on driver behavior during the yellow interval. Signal phasing and traffic operations were videotaped at 4 comparable signalized intersections under normal conditions. Microscopic details were extracted manually at 25 Hz to yield 24 h of data on onset time of the yellow, onset time of the red, driver location and actions after the onset of the yellow, red light-running violations, etc. For comparable intersections with and without countdown timers, driver behavior measured by driver decision (stop or go) and vehicle entry time (when the vehicle crosses the stop line) were analyzed using binary logistical regression (BLR) and a nonparametric test, respectively. The results suggest that countdown timers can indeed influence driver behaviors, in terms of decisions to stop or cross the intersection as well as the distribution of vehicle entry times. There was a strong correlation between the presence of countdown timers and an increase in red light violations. Countdown timers may lead to increased entrance into the intersection during the later portions of the yellow and even the red. This alarming finding calls for further research as well as for serious consideration before the field deployment of countdown timers.

“Bus Lane Within The Area Of Intersection” Method For Buses Priority On The Intersections

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Vikovych Ihor

2015-12-01

Full Text Available The primary objective of this article is to formalize the “special bus lanes within the area of intersection” method that allows providing buses with space-time priority at signalized intersections (mostly of the isolated type, including those with no more than two traffic lanes in each direction at the approaches to the intersection. The article establishes the limits for efficient application of this method, and describes the results of a simulation experiment conducted in the VISSIM environment to investigate the functioning of the method on an actual intersection. The most critical phase of implementation of this method is to determine the optimum length of the special bus lane at the approach to the intersection. The optimum length of special bus lanes at the approaches to isolated or coordinated intersections is determined based on the maximum length of queued vehicles which is computed using the simulation models developed in the Objective-C language. The article covers the basic characteristics of those models, their structure and building principles, and also provides the model validation results. Simulation models can be used both for determination of the optimum length of special bus lanes at the approaches to signalized intersections and for analysis of intersection performance based on the maximum length of queued vehicles.

Grounded Intersectionality

DEFF Research Database (Denmark)

Marfelt, Mikkel Mouritz

2016-01-01

associated with intersectional research. The findings assist in positioning the proposed methodological framework within recent intersectional debates. Findings – The review shows a rise in intersectional publications since the birth of the “intersectionality” term in 1989. Moreover, the paper points to four...... oriented but still emphasizes stable concepts. Moreover, it does not give primacy to oppression. Finally, it adopts a critical stance on the nature of the macro, meso, and micro levels as dominant analytical perspectives. As a result, this paper focusses on the importance of intersectionality...

Choice of the control variables of an isolated intersection by graph colouring

Directory of Open Access Journals (Sweden)

Batanović Vladan

2015-01-01

Full Text Available This paper deals with the problem of grouping the traffic streams into some groups - signal groups on a signalized intersection. The fact that more traffic streams, which are not in a conflict, can be controlled by one sequence of traffic lights means that one control variable can be assigned to one signal group. Determination of the complete sets of signal groups, i.e. the groups of traffic streams on one intersection, controlled by one control variable is defined in this paper as a graphcoloring problem. The complete sets of signal groups are obtained by coloring the complement of the graph of identical indications. It is shown that the minimal number of signal groups in the complete set of signal groups is equal to the chromatic number of the complement of the graph with identical indications. The problem of finding all complete sets of signal groups with minimal cardinality, which is equal to the chromatic number, is formulated as a linear programming problem where the values of variables belong to set {0,1}.

Sustainable intersection control to accommodate urban freight mobility.

Science.gov (United States)

2009-08-01

In this research, we studied green extension of a two-phased vehicleactuated signal at an isolated : intersection between two one-way streets. The green phase is extended by a preset time interval, referred to : as critical gap, from the time of a...

Mitigating gas emissions at signalised intersections using wireless vehicle detectors

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Moses Kwasi Torkudzor

2015-09-01

Full Text Available Traffic congestion on roads wastes travel times and increases fuel consumption as well as gas emissions which are dangerous to human health. This has led to growing concern about environmental protection and energy conservation and a number of studies to increase fuel economy and reduce gas emissions. To increase travel times so as to reduce fuel consumption and gas emissions, traffic signals at intersections must be well implemented. It is therefore necessary to employ the current technology of wireless sensor networks to enhance the optimisation of the signalised intersections so as to address such a concern. In this study, a vehicular traffic control model was developed to optimise a signalised intersection, using wireless vehicle detectors. Real-time traffic volume gathered were analysed to obtain the peak hour traffic volume causing congestion. The intersection was modelled and simulated in Synchro7 as an actuated signalised model using results from the analysed data. The model for morning peak and evening peak periods gave optimal cycle lengths which result in the reduction of gas emissions, fuel consumption and delay at the intersection.

Cell responses to FGFR3 signalling: growth, differentiation and apoptosis

International Nuclear Information System (INIS)

L'Hote, Corine G.M.; Knowles, Margaret A.

2005-01-01

FGFR3 is a receptor tyrosine kinase (RTK) of the FGF receptor family, known to have a negative regulatory effect on long bone growth. Fgfr3 knockout mice display longer bones and, accordingly, most germline-activating mutations in man are associated with dwarfism. Somatically, some of the same activating mutations are associated with the human cancers multiple myeloma, cervical carcinoma and carcinoma of the bladder. How signalling through FGFR3 can lead to either chondrocyte apoptosis or cancer cell proliferation is not fully understood. Although FGFR3 can be expressed as two main splice isoforms (IIIb or IIIc), there is no apparent link with specific cell responses, which may rather be associated with the cell type or its differentiation status. Depending on cell type, differential activation of STAT proteins has been observed. STAT1 phosphorylation seems to be involved in inhibition of chondrocyte proliferation while activation of the ERK pathway inhibits chondrocyte differentiation and B-cell proliferation (as in multiple myeloma). The role of FGFR3 in epithelial cancers (bladder and cervix) is not known. Some of the cell specificity may arise via modulation of signalling by crosstalk with other signalling pathways. Recently, inhibition of the ERK pathway in achondroplastic mice has provided hope for an approach to the treatment of dwarfism. Further understanding of the ability of FGFR3 to trigger different responses depending on cell type and cellular context may lead to treatments for both skeletal dysplasias and cancer

Dynamic all-red extension at signalized intersection : probabilistic modeling and algorithm.

Science.gov (United States)

2011-01-01

Red light running has been a major cause of intersection injuries and fatalities in the United : States. In 2004 alone, there were 8,619 fatal crashes and 848,000 crashes with people injured, all : caused by RLR. Under the U.S. Department of Transpor...

Study of cellular signaling of apoptosis induced by different types of ionizing radiations in lymphoblastoid cells differing in their P53 status

International Nuclear Information System (INIS)

Fischer, Barbara

2004-01-01

The general objective of this thesis was to identify the cellular mechanisms that govern the induction of apoptosis by ionizing radiations with high linear energy transfer (LET), particularly fast neutrons and carbon ions. It was also attempted to determine the role in these mechanisms of the p53 tumor suppressor protein. For this, lymphoblastoid lines differing by their p53 status have been used: TK6 (p53 + / +), WTK1 (p53 mute) and NH32 (p53 - / -). At first, the study concerned the induction of apoptosis by fast neutrons, and the effects of these radiations have been compared with those of X-rays on cell lines. Results show that for the same irradiation dose, fast neutrons are more efficient than X-rays in terms of inducing apoptosis. This induction of apoptosis also varies according to the p53 status of the cells. These data suggest that fast neutrons activate apoptosis in two distinct ways: a p53-dependent pathway that occurs in the first hours after irradiation, and an independent pathway of p53, which is slower, but also involves caspases. The author then tried to characterize the two active apoptotic signaling pathways in lymphoblastoid lines by fast neutrons, in order to identify the different mechanisms involved in triggering the apoptotic process as a function of p53. Results show that the p53 status not only affects the kinetics of induction of apoptosis but also the nature of active caspases. The p53-dependent apoptosis is associated with the activation of caspases-3, 7, 8 and 9, the cleavage of BID by caspase-8, the fall of Δψm and the release of cytochrome c from mitochondria to cytoplasm. On the other hand, caspase-7 seems to be activated by an independent p53 signaling pathway. In the following experiments, the mechanisms leading to the initiation of apoptotic pathways induced by fast neutrons were explored, and more particularly the activation of caspase-8 in p53-dependent apoptosis. The involvement of the Fas necrosis receptor in the activation

3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway.

Science.gov (United States)

Liu, Zhe; Zhang, Yuan-Yuan; Zhang, Qian-Wen; Zhao, Su-Rong; Wu, Cheng-Zhu; Cheng, Xiu; Jiang, Chen-Chen; Jiang, Zhi-Wen; Liu, Hao

2014-04-01

The hexokinase inhibitor 3-bromopyruvate (3-BrPA) can inhibit glycolysis in tumor cells to reduce ATP production, resulting in apoptosis. However, as 3-BrPA is an alkylating agent, its cytotoxic action may be induced by other molecular mechanisms. The results presented here reveal that 3-BrPA-induced apoptosis is caspase independent. Further, 3-BrPA induces the generation of reactive oxygen species in MDA-MB-231 cells, leading to mitochondria-mediated apoptosis. These results suggest that caspase-independent apoptosis may be induced by the generation of reactive oxygen species. In this study, we also demonstrated that 3-BrPA induces apoptosis through the downregulation of myeloid cell leukemia-1 (Mcl-1) in MDA-MB-231 breast cancer cells. The results of Mcl-1 knockdown indicate that Mcl-1 plays an important role in 3-BrPA-induced apoptosis. Further, the upregulation of Mcl-1 expression in 3-BrPA-treated MDA-MB-231 cells significantly increases cell viability. In addition, 3-BrPA treatment resulted in the downregulation of p-Akt, suggesting that 3-BrPA may downregulate Mcl-1 through the phosphoinositide-3-kinase/Akt pathway. These findings indicate that 3-BrPA induces apoptosis in breast cancer cells by downregulating Mcl-1 through the phosphoinositide-3-kinase/Akt signaling pathway.

Vitamin E and Lycopene Reduce Coal Burning Fluorosis-induced Spermatogenic Cell Apoptosis via Oxidative Stress-mediated JNK and ERK Signaling Pathways.

Science.gov (United States)

Tian, Yuan; Xiao, Yuehai; Wang, Bolin; Sun, Chao; Tang, Kaifa; Sun, Fa

2017-12-22

Although fluoride has been widely used in toothpaste, mouthwash, and drinking water to prevent dental caries, the excessive intake of fluoride can cause fluorosis which is associated with dental, skeletal, and soft tissue fluorosis. Recent evidences have drawn the attention to its adverse effects on male reproductive system that include spermatogenesis defect, sperm count loss, and sperm maturation impairment. Fluoride induces oxidative stress through the activation of mitogen activated protein kinase (MAPK) cascade which can lead to cell apoptosis. Vitamin E (VE) and lycopene are two common anti-oxidants, being protective to reactive oxygen species (ROS)-induced toxic effects. However, whether and how these two anti-oxidants prevent fluoride-induced spermatogenic cell apoptosis are largely unknown. In the present study, a male rat model for coal burning fluorosis was established and the histological lesions and spermatogenic cell apoptosis in rat testes were observed. The decreased expression of clusterin, a heterodimeric glycoprotein reported to regulate spermatogenic cell apoptosis, is detected in fluoride-treated rat testes. Interestingly, the co-administration with VE or lycopene reduced fluorosis-mediated testicular toxicity and rescued clusterin expression. Further, fluoride caused the enhanced Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) phosphorylation, which was reduced by VE or lycopene. Thus, VE and lycopene prevent coal burning fluorosis-induced spermatogenic cell apoptosis through the suppression of oxidative stress-mediated JNK and ERK signaling pathway, which could be an alternative therapeutic strategy for the treatment of fluorosis. ©2017 The Author(s).

E2/ER β Enhances Calcineurin Protein Degradation and PI3K/Akt/MDM2 Signal Transduction to Inhibit ISO-Induced Myocardial Cell Apoptosis

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Kuan-Ho Lin

2017-04-01

Full Text Available Secretion of multifunctional estrogen and its receptor has been widely considered as the reason for markedly higher frequency of heart disease in men than in women. 17β-Estradiol (E2, for instance, has been reported to prevent development of cardiac apoptosis via activation of estrogen receptors (ERs. In addition, protein phosphatase such as protein phosphatase 1 (PP1 and calcineurin (PP2B are also involved in cardiac hypertrophy and cell apoptosis signaling. However, the mechanism by which E2/ERβ suppresses apoptosis is not fully understood, and the role of protein phosphatase in E2/ERβ action also needs further investigation. In this study, we observed that E2/ERβ inhibited isoproterenol (ISO-induced myocardial cell apoptosis, cytochrome c release and downstream apoptotic markers. Moreover, we found that E2/ERβ blocks ISO-induced apoptosis in H9c2 cells through the enhancement of calcineurin protein degradation through PI3K/Akt/MDM2 signaling pathway. Our results suggest that supplementation with estrogen and/or overexpression of estrogen receptor β gene may prove to be effective means to treat stress-induced myocardial damage.

Study on the relationship between PI3K/AKT signaling pathway and apoptosis in cartilage tissue of rats with osteoarthritis

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Xiao-Yan Li

2017-05-01

Full Text Available Objective: To study the relationship between PI3K/AKT signaling pathway and apoptosis in cartilage tissue of rats with osteoarthritis (OA. Methods: The clean male Wistar rats were selected as experimental animals and randomly divided into OA model group and control group. The OA model was established by intra-articular injection of papain solution and L-cysteine. Fourth weeks and eighth weeks after model establishment, the expression of PI3K/AKT signaling molecules, inflammatory mediators, apoptosis marker molecules and autophagy marker molecules in articular cartilage were determined. Results: p-PI3K and p-AKT expression in articular cartilage of OA group were significantly lower than those of control group; IL-1β, IL-6, IL-17, IL-18, eIF4E, Bax, Caspase-3, mTOR, Beclin1, Atg5 and Atg7 expression in articular cartilage of OA group were significantly higher than those of control group and negatively correlated with p-PI3K and p-AKT expression while Bcl-2 expression in articular cartilage of OA group was significantly lower than that of control group and positively correlated with p-PI3K and p-AKT expression. Conclusion: The inhibition of PI3K/AKT signaling pathway in cartilage tissue of OA rat model can promote chondrocyte apoptosis and autophagy.

At the cross-roads: an on-road examination of driving errors at intersections.

Science.gov (United States)

Young, Kristie L; Salmon, Paul M; Lenné, Michael G

2013-09-01

A significant proportion of road trauma occurs at intersections. Understanding the nature of driving errors at intersections therefore has the potential to lead to significant injury reductions. To further understand how the complexity of modern intersections shapes behaviour of these errors are compared to errors made mid-block, and the role of wider systems failures in intersection error causation is investigated in an on-road study. Twenty-five participants drove a pre-determined urban route incorporating 25 intersections. Two in-vehicle observers recorded the errors made while a range of other data was collected, including driver verbal protocols, video, driver eye glance behaviour and vehicle data (e.g., speed, braking and lane position). Participants also completed a post-trial cognitive task analysis interview. Participants were found to make 39 specific error types, with speeding violations the most common. Participants made significantly more errors at intersections compared to mid-block, with misjudgement, action and perceptual/observation errors more commonly observed at intersections. Traffic signal configuration was found to play a key role in intersection error causation, with drivers making more errors at partially signalised compared to fully signalised intersections. Copyright © 2012 Elsevier Ltd. All rights reserved.

Delays at signalised intersections with exhaustive traffic control

NARCIS (Netherlands)

Boon, M.A.A.; Adan, I.J.B.F.; Winands, E.M.M.; Down, D.G.

2010-01-01

In this paper we study a traffic intersection with vehicle-actuated traffic signal control. Traffic lights stay green until all lanes within a group are emptied. Assuming general renewal arrival processes, we derive exact limiting distributions of the delays under Heavy Traffic (HT) conditions,

Delays at signalised intersections with exhaustive traffic control

NARCIS (Netherlands)

Boon, M.A.A.; Adan, I.J.B.F.; Winands, E.M.M.; Down, D.G.

2012-01-01

In this paper, we study a traffic intersection with vehicle-actuated traffic signal control. Traffic lights stay green until all lanes within a group are emptied. Assuming general renewal arrival processes, we derive exact limiting distributions of the delays under heavy traffic (HT) conditions.

Raf-1/CK2 and RhoA/ROCK signaling promote TNF-α-mediated endothelial apoptosis via regulating vimentin cytoskeleton.

Science.gov (United States)

Yang, Lifeng; Tang, Lian; Dai, Fan; Meng, Guoliang; Yin, Runting; Xu, Xiaole; Yao, Wenjuan

2017-08-15

Both RhoA/ROCK and Raf-1/CK2 pathway play essential roles in cell proliferation, apoptosis, differentiation, and multiple other common cellular functions. We previously reported that vimentin is responsible for TNF-α-induced cell apoptosis. Herein, we investigated the regulation of RhoA/ROCK and Raf-1/CK2 signaling on vimentin filaments and endothelial apoptosis mediated by TNF-α. Treatment with TNF-α significantly induced the activation of RhoA and ROCK, and the expression of ROCK1. RhoA deficiency could obviously inhibit ROCK activation and ROCK1 expression induced by TNF-α. Both RhoA deficiency and ROCK activity inhibition (Y-27632) greatly inhibited endothelial apoptosis and preserved cell viability in TNF-α-induced human umbilical vein endothelial cells (HUVECs). Also vimentin phosphorylation and the remodeling of vimentin or phospho-vimentin induced by TNF-α were obviously attenuated by RhoA suppression and ROCK inhibition. TNF-α-mediated vimentin cleavage was significantly inhibited by RhoA suppression and ROCK inhibition through decreasing the activation of caspase3 and 8. Furthermore, TNF-α treatment greatly enhanced the activation of Raf-1. Suppression of Raf-1 or CK2 by its inhibitor (GW5074 or TBB) blocked vimentin phosphorylation, remodeling and endothelial apoptosis, and preserved cell viability in TNF-α-induced HUVECs. However, Raf-1 inhibition showed no significant effect on TNF-α-induced ROCK expression and activation, suggesting that the regulation of Raf-1/CK2 signaling on vimentin was independent of ROCK. Taken together, these results indicate that both RhoA/ROCK and Raf-1/CK2 pathway are responsible for TNF-α-mediated endothelial cytotoxicity via regulating vimentin cytoskeleton. Copyright © 2017 Elsevier B.V. All rights reserved.

TAB2 Is Essential for Prevention of Apoptosis in Fetal Liver but Not for Interleukin-1 Signaling

Science.gov (United States)

Sanjo, Hideki; Takeda, Kiyoshi; Tsujimura, Tohru; Ninomiya-Tsuji, Jun; Matsumoto, Kunihiro; Akira, Shizuo

2003-01-01

The proinflammatory cytokine interleukin-1 (IL-1) transmits a signal via several critical cytoplasmic proteins such as MyD88, IRAKs and TRAF6. Recently, serine/threonine kinase TAK1 and TAK1 binding protein 1 and 2 (TAB1/2) have been identified as molecules involved in IL-1-induced TRAF6-mediated activation of AP-1 and NF-κB via mitogen-activated protein (MAP) kinases and IκB kinases, respectively. However, their physiological functions remain to be clarified. To elucidate their roles in vivo, we generated TAB2-deficient mice. The TAB2 deficiency was embryonic lethal due to liver degeneration and apoptosis. This phenotype was similar to that of NF-κB p65-, IKKβ-, and NEMO/IKKγ-deficient mice. However, the IL-1-induced activation of NF-κB and MAP kinases was not impaired in TAB2-deficient embryonic fibroblasts. These findings demonstrate that TAB2 is essential for embryonic development through prevention of liver apoptosis but not for the IL-1 receptor-mediated signaling pathway. PMID:12556483

Bid integrates intrinsic and extrinsic signaling in apoptosis induced by alpha-tocopheryl succinate in human gastric carcinoma cells

Czech Academy of Sciences Publication Activity Database

Zhao, Y.; Li, R.; Xia, W.; Neužil, Jiří; Lu, Y.; Zhang, H.; Zhao, X.; Zhang, X.; Sun, C.; Wu, K.

2010-01-01

Roč. 288, č. 1 (2010), s. 42-49 ISSN 0304-3835 R&D Projects: GA ČR(CZ) GA204/08/0811 Institutional research plan: CEZ:AV0Z50520701 Keywords : Alpha-tocopheryl succinate * signaling * apoptosis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.864, year: 2010

Modeling the dynamics of driver's dilemma zone perception using machine learning methods for safer intersection control.

Science.gov (United States)

2014-04-01

The "dilemma zone" (DZ) is defined as the area where drivers approaching a signalized intersection must decide to either proceed or stop at the onset of the yellow indication. Drivers that might perceive themselves to be too close to an intersection ...

PI3K/Akt signaling mediated Hexokinase-2 expression inhibits cell apoptosis and promotes tumor growth in pediatric osteosarcoma

Energy Technology Data Exchange (ETDEWEB)

Zhuo, Baobiao; Li, Yuan; Li, Zhengwei; Qin, Haihui; Sun, Qingzeng; Zhang, Fengfei; Shen, Yang; Shi, Yingchun [Department of Surgery, The Children' s Hospital of Xuzhou, Xuzhou, Jiangsu Province 221006 (China); Wang, Rong, E-mail: wangrong2008163@163.com [Department of Ultrasonography, Affiliated Hospital of Xuzhou Medical College, Xuzhou, Jiangsu Province 221006 (China)

2015-08-21

Accumulating evidence has shown that PI3K/Akt pathway is frequently hyperactivated in osteosarcoma (OS) and contributes to tumor initiation and progression. Altered phenotype of glucose metabolism is a key hallmark of cancer cells including OS. However, the relationship between PI3K/Akt pathway and glucose metabolism in OS remains largely unexplored. In this study, we showed that elevated Hexokinase-2 (HK2) expression, which catalyzes the first essential step of glucose metabolism by conversion of glucose into glucose-6-phosphate, was induced by activated PI3K/Akt signaling. Immunohistochemical analysis showed that HK2 was overexpressed in 83.3% (25/30) specimens detected and was closely correlated with Ki67, a cell proliferation index. Silencing of endogenous HK2 resulted in decreased aerobic glycolysis as demonstrated by reduced glucose consumption and lactate production. Inhibition of PI3K/Akt signaling also suppressed aerobic glycolysis and this effect can be reversed by reintroduction of HK2. Furthermore, knockdown of HK2 led to increased cell apoptosis and reduced ability of colony formation; meanwhile, these effects were blocked by 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor through its actions on hexokinase, indicating that HK2 functions in cell apoptosis and growth were mediated by altered aerobic glycolysis. Taken together, our study reveals a novel relationship between PI3K/Akt signaling and aerobic glycolysis and indicates that PI3K/Akt/HK2 might be potential therapeutic approaches for OS. - Highlights: • PI3K/Akt signaling contributes to elevated expression of HK2 in osteosarcoma. • HK2 inhibits cell apoptosis and promotes tumor growth through enhanced Warburg effect. • Inhibition of glycolysis blocks the oncogenic activity of HK2.

cAMP/PKA signaling pathway contributes to neuronal apoptosis via regulating IDE expression in a mixed model of type 2 diabetes and Alzheimer's disease.

Science.gov (United States)

Li, Huajie; Yang, Song; Wu, Jian; Ji, Lei; Zhu, Linfeng; Cao, Liping; Huang, Jinzhong; Jiang, Qingqing; Wei, Jiang; Liu, Meng; Mao, Keshi; Wei, Ning; Xie, Wei; Yang, Zhilong

2018-02-01

Type 2 diabetes (T2D) may play a relevant role in the development of Alzheimer's disease (AD), however, the underlying mechanism was not clear yet. We developed an animal model presenting both AD and T2D, morris water maze (MWM) test and recognition task were performed to trace the cognitive function. Fasting plasma glucose (FPG) and oral glucose tolerance test (OGTT) were determined to trace the metabolism evolution. TUNEL assay and apoptosis-related protein levels were analyzed for the detection of neuronal apoptosis. Cyclic adenosine monophosphate (cAMP) agonist bucladesine or protein kinase (PKA) inhibitor H-89 were used to determine the effects of cAMP/PKA signaling pathway on IDE expression and neuronal apoptosis. The results showed that T2D contributes to the AD progress by accelerating and worsening spatial memory and recognition dysfunctions. Metabolic parameters and glucose tolerance were significantly changed in the presence of the AD and T2D. The significantly induced neuronal apoptosis and increased pro-apoptotic proteins in mice with AD and T2D were also observed. We showed the decreased expression level of IDE and the activating of cAMP/PKA signaling pathway in AD and T2D mice. Further studies indicated that cAMP agonist decreased the expression level of IDE and induced the neuronal apoptosis in mice with AD and T2D; whereas PKA inhibitor H-89 treatment showed the completely opposite results. Our study indicated that, in the T2D and AD mice, cAMP/PKA signaling pathway and IDE may participate in the contribute role of T2D in accelerating the pathological process of AD via causing the accumulation of Aβ and neuronal apoptosis. © 2017 Wiley Periodicals, Inc.

Role of nongenomic activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase 1/2 pathways in 1,25D3-mediated apoptosis in squamous cell carcinoma cells.

Science.gov (United States)

Ma, Yingyu; Yu, Wei-Dong; Kong, Rui-Xian; Trump, Donald L; Johnson, Candace S

2006-08-15

Vitamin D is a steroid hormone that regulates calcium homeostasis and bone metabolism. The active form of vitamin D [1 alpha,25-dihydroxyvitamin D(3) (1,25D3)] acts through both genomic and nongenomic pathways. 1,25D3 has antitumor effects in a variety of cancers, including colorectal, prostate, breast, ovarian, and skin cancers. 1,25D3 exerts growth-inhibitory effects in cancer cells through the induction of apoptosis, cell cycle arrest, and differentiation. The mechanisms regulating 1,25D3-induced apoptosis remain unclear. We investigated the role of nongenomic signaling in 1,25D3-mediated apoptosis in squamous cell carcinoma (SCC) cells. 1,25D3 induced rapid and sustained activation of phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) 1/2 pathways in SCC cells. These effects were nongenomic: they occurred rapidly and were not inhibited by cycloheximide or actinomycin D. To examine whether the nongenomic activation of Akt and ERK1/2 plays a role in 1,25D3-mediated apoptosis, the expression of Akt or ERK1/2 was reduced by small interfering RNA (siRNA). siRNA-Akt significantly enhanced 1,25D3-induced apoptosis as indicated by increased levels of Annexin V-positive cells and increased sub-G(1) population and DNA fragmentation. In contrast, siRNA-ERK1/2 had no effects on 1,25D3-induced apoptosis. In addition, siRNA-Akt transfection followed by 1,25D3 treatment induced apoptosis much sooner than 1,25D3 alone. siRNA-Akt and 1,25D3 induced caspase-10 activation, suppressed the expression of c-IAP1 and XIAP, and promoted 1,25D3-induced caspase-3 activation. These results support a link between 1,25D3-induced nongenomic signaling and apoptosis. 1,25D3 induces the activation of phosphatidylinositol 3-kinase/Akt, which suppresses 1,25D3-mediated apoptosis and prolongs the survival of SCC cells.

Hyperoxia accelerates Fas-mediated signaling and apoptosis in the lungs of Legionella pneumophila pneumonia

Directory of Open Access Journals (Sweden)

Tanabe Yoshinari

2011-04-01

Full Text Available Abstract Background Oxygen supplementation is commonly given to the patients with severe pneumonia including Legionella disease. Recent data suggested that apoptosis may play an important role, not only in the pathogenesis of Legionella pneumonia, but also in oxygen-induced tissue damage. In the present study, the lethal sensitivity to Legionella pneumonia were compared in the setting of hyperoxia between wild-type and Fas-deficient mice. Findings C57BL/6 mice and B6.MRL-Faslpr mice characterized with Fas-deficiency were used in this study. After intratracheal administration of L. pneumophila, mice were kept in hyperoxic conditions (85-90% O2 conc. in an airtight chamber for 3 days. Bone-marrow derived macrophages infected with L. pneumophila were also kept in hyperoxic conditions. Caspase activity and cytokine production were determined by using commercially available kits. Smaller increases of several apoptosis markers, such as caspase-3 and -8, were demonstrated in Fas-deficient mice, even though the bacterial burdens in Fas-deficient and wild type mice were similar. Bone-marrow derived macrophages from Fas-deficient mice were shown to be more resistant to Legionella-induced cytotoxicity than those from wild-type mice under hyperoxia. Conclusions These results demonstrated that Fas-mediated signaling and apoptosis may be a crucial factor in the pathogenesis of Legionella pneumonia in the setting of hyperoxia.

Biomarkers of Chondrocyte Apoptosis and Autophagy in Osteoarthritis

Science.gov (United States)

Musumeci, Giuseppe; Castrogiovanni, Paola; Trovato, Francesca Maria; Weinberg, Annelie Martina; Al-Wasiyah, Mohammad K.; Alqahtani, Mohammed H.; Mobasheri, Ali

2015-01-01

Cell death with morphological and molecular features of apoptosis has been detected in osteoarthritic (OA) cartilage, which suggests a key role for chondrocyte death/survival in the pathogenesis of OA. Identification of biomarkers of chondrocyte apoptosis may facilitate the development of novel therapies that may eliminate the cause or, at least, slow down the degenerative processes in OA. The aim of this review was to explore the molecular markers and signals that induce chondrocyte apoptosis in OA. A literature search was conducted in PubMed, Scopus, Web of Science and Google Scholar using the keywords chondrocyte death, apoptosis, osteoarthritis, autophagy and biomarker. Several molecules considered to be markers of chondrocyte apoptosis will be discussed in this brief review. Molecular markers and signalling pathways associated with chondroycte apoptosis may turn out to be therapeutic targets in OA and approaches aimed at neutralizing apoptosis-inducing molecules may at least delay the progression of cartilage degeneration in OA. PMID:26334269

Cell surface-bound TIMP3 induces apoptosis in mesenchymal Cal78 cells through ligand-independent activation of death receptor signaling and blockade of survival pathways.

Directory of Open Access Journals (Sweden)

Christina Koers-Wunrau

Full Text Available BACKGROUND: The matrix metalloproteinases (MMPs and their endogenous regulators, the tissue inhibitor of metalloproteinases (TIMPs 1-4 are responsible for the physiological remodeling of the extracellular matrix (ECM. Among all TIMPs, TIMP3 appears to play a unique role since TIMP3 is a secreted protein and, unlike the other TIMP family members, is tightly bound to the ECM. Moreover TIMP3 has been shown to be able to induce apoptotic cell death. As little is known about the underlying mechanisms, we set out to investigate the pro-apoptotic effect of TIMP3 in human mesenchymal cells. METHODOLOGY/PRINCIPAL FINDINGS: Lentiviral overexpression of TIMP3 in mesenchymal cells led to a strong dose-dependent induction of ligand-independent apoptosis as reflected by a five-fold increase in caspase 3 and 7 activity compared to control (pLenti6/V5-GW/lacZ or uninfected cells, whereas exogenous TIMP3 failed to induce apoptosis. Concordantly, increased cleavage of death substrate PARP and the caspases 3 and 7 was observed in TIMP3 overexpressing cultures. Notably, activation of caspase-8 but not caspase-9 was observed in TIMP3-overexpressing cells, indicating a death receptor-dependent mechanism. Moreover, overexpression of TIMP3 led to a further induction of apoptosis after stimulation with TNF-alpha, FasL and TRAIL. Most interestingly, TIMP3-overexpression was associated with a decrease in phosphorylation of cRaf, extracellular signal-regulated protein kinase (Erk1/2, ribosomal S6 kinase (RSK1 and Akt and serum deprivation of TIMP3-overexpressing cells resulted in a distinct enhancement of apoptosis, pointing to an impaired signaling of serum-derived survival factors. Finally, heparinase treatment of heparan sulfate proteoglycans led to the release of TIMP3 from the surface of overexpressing cells and to a significant decrease in apoptosis indicating that the binding of TIMP3 is necessary for apoptosis induction. CONCLUSION: The results demonstrate that

Drivers' smart advisory system improves driving performance at STOP sign intersections

Directory of Open Access Journals (Sweden)

Qing Li

2017-06-01

Full Text Available STOP signs are often physically blocked by obstacles at the corner, forming a safety threat. To enhance the safety at an un-signalized intersection like a STOP sign intersection, a radio frequency identification (RFID based drivers smart advisory system (DSAS was developed, which provides drivers with an earlier warning message when they are approaching an un-signalized intersection. In this research, a pilot field test was conducted with the DSAS alarm on an approach towards a STOP sign intersection in a residential area in Houston, Texas. The designed test route covers all turning movements, including left turn, through movement, and right turn. GPS units recorded test drivers' driving behaviors. A self-developed MATLAB program and statistically significant difference t-test were applied to analyze the impacts of the DSAS messages on drivers' driving performance, in terms of approaching speed profile, acceleration/deceleration rates, braking distance, and possible extra vehicle emissions induced by the introduction of the DSAS message. Drivers' preference on the DSAS was investigated by a designed survey questionnaire among test drivers. Results showed that the DSAS alarm was able to induce drivers to drive significantly slower to approach a STOP sign intersection, perform smaller fluctuation in acceleration/deceleration rates, and be more aware of a coming STOP sign indicated by decelerating earlier. All test drivers preferred to follow the DSAS alarm on roads for a safety concern. Further, the DSAS alarm caused the reduction in emission rates through movement. For a general observation, more road tests with more participants and different test routes were recommended.

Route-Based Signal Preemption Control of Emergency Vehicle

Directory of Open Access Journals (Sweden)

Haibo Mu

2018-01-01

Full Text Available This paper focuses on the signal preemption control of emergency vehicles (EV. A signal preemption control method based on route is proposed to reduce time delay of EV at intersections. According to the time at which EV is detected and the current phase of each intersection on the travelling route of EV, the calculation methods of the earliest start time and the latest start time of green light at each intersection are given. Consequently, the effective time range of green light at each intersection is determined in theory. A multiobjective programming model, whose objectives are the minimal residence time of EV at all intersections and the maximal passing numbers of general society vehicles, is presented. Finally, a simulation calculation is carried out. Calculation results indicate that, by adopting the signal preemption method based on route, the delay of EV is reduced and the number of society vehicles passing through the whole system is increased. The signal preemption control method of EV based on route can reduce the time delay of EV and improve the evacuation efficiency of the system.

Singlet oxygen treatment of tumor cells triggers extracellular singlet oxygen generation, catalase inactivation and reactivation of intercellular apoptosis-inducing signaling.

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Riethmüller, Michaela; Burger, Nils; Bauer, Georg

2015-12-01

Intracellular singlet oxygen generation in photofrin-loaded cells caused cell death without discrimination between nonmalignant and malignant cells. In contrast, extracellular singlet oxygen generation caused apoptosis induction selectively in tumor cells through singlet oxygen-mediated inactivation of tumor cell protective catalase and subsequent reactivation of intercellular ROS-mediated apoptosis signaling through the HOCl and the NO/peroxynitrite signaling pathway. Singlet oxygen generation by extracellular photofrin alone was, however, not sufficient for optimal direct inactivation of catalase, but needed to trigger the generation of cell-derived extracellular singlet oxygen through the interaction between H2O2 and peroxynitrite. Thereby, formation of peroxynitrous acid, generation of hydroxyl radicals and formation of perhydroxyl radicals (HO2(.)) through hydroxyl radical/H2O2 interaction seemed to be required as intermediate steps. This amplificatory mechanism led to the formation of singlet oxygen at a sufficiently high concentration for optimal inactivation of membrane-associated catalase. At low initial concentrations of singlet oxygen, an additional amplification step needed to be activated. It depended on singlet oxygen-dependent activation of the FAS receptor and caspase-8, followed by caspase-8-mediated enhancement of NOX activity. The biochemical mechanisms described here might be considered as promising principle for the development of novel approaches in tumor therapy that specifically direct membrane-associated catalase of tumor cells and thus utilize tumor cell-specific apoptosis-inducing ROS signaling. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Insulin protects against Aβ-induced spatial memory impairment, hippocampal apoptosis and MAPKs signaling disruption.

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Ghasemi, Rasoul; Zarifkar, Asadollah; Rastegar, Karim; maghsoudi, Nader; Moosavi, Maryam

2014-10-01

Alzheimer disease (AD) is a progressive neurodegenerative disease characterized by extracellular deposits of beta amyloid (Aβ) and neuronal loss particularly in the hippocampus. Accumulating evidences have implied that insulin signaling impairment plays a key role in the pathology of AD; as much as it is considered as type 3 Diabetes. MAPKs are a group of signaling molecules which are involved in pathobiology of AD. Therefore this study was designed to investigate if intrahippocampal insulin hinders Aβ-related memory deterioration, hippocampal apoptosis and MAPKs signaling alteration induced by Aβ. Adult male Sprague-Dawely rats weighing 250-300 g were used in this study. The canules were implanted bilaterally into CA1 region. Aβ25-35 was administered during first 4 days after surgery (5 μg/2.5 μL/daily). Insulin treatment (0.5 or 6 mU) was done during days 4-9. The animal's learning and memory capability was assessed on days 10-13 using Morris water maze. After finishing of behavioral studies the hippocampi was isolated and the amount of hippocampal cleaved caspase 3 (the landmark of apoptosis) and the phosphorylated (activated) forms of P38, JNK and ERK was analyzed by western blot. The results showed that insulin in 6 but not 0.5 mU reversed the memory loss induced by Aβ25-35. Western blot analysis revealed that Aβ25-35 induced elevation of caspase-3 and all 3 MAPks subfamily activity, while insulin in 6 mu restored ERK and P38 activation but has no effect on JNK. This study disclosed that intrahippocampal insulin treatment averts not only Aβ-induced memory deterioration but also hippocampal caspase-3, ERK and P38 activation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Lymphotropic Virions Affect Chemokine Receptor-Mediated Neural Signaling and Apoptosis: Implications for Human Immunodeficiency Virus Type 1-Associated Dementia

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Zheng, Jialin; Ghorpade, Anuja; Niemann, Douglas; Cotter, Robin L.; Thylin, Michael R.; Epstein, Leon; Swartz, Jennifer M.; Shepard, Robin B.; Liu, Xiaojuan; Nukuna, Adeline; Gendelman, Howard E.

1999-01-01

Chemokine receptors pivotal for human immunodeficiency virus type 1 (HIV-1) infection in lymphocytes and macrophages (CCR3, CCR5, and CXCR4) are expressed on neural cells (microglia, astrocytes, and/or neurons). It is these cells which are damaged during progressive HIV-1 infection of the central nervous system. We theorize that viral coreceptors could effect neural cell damage during HIV-1-associated dementia (HAD) without simultaneously affecting viral replication. To these ends, we studied the ability of diverse viral strains to affect intracellular signaling and apoptosis of neurons, astrocytes, and monocyte-derived macrophages. Inhibition of cyclic AMP, activation of inositol 1,4,5-trisphosphate, and apoptosis were induced by diverse HIV-1 strains, principally in neurons. Virions from T-cell-tropic (T-tropic) strains (MN, IIIB, and Lai) produced the most significant alterations in signaling of neurons and astrocytes. The HIV-1 envelope glycoprotein, gp120, induced markedly less neural damage than purified virions. Macrophage-tropic (M-tropic) strains (ADA, JR-FL, Bal, MS-CSF, and DJV) produced the least neural damage, while 89.6, a dual-tropic HIV-1 strain, elicited intermediate neural cell damage. All T-tropic strain-mediated neuronal impairments were blocked by the CXCR4 antibody, 12G5. In contrast, the M-tropic strains were only partially blocked by 12G5. CXCR4-mediated neuronal apoptosis was confirmed in pure populations of rat cerebellar granule neurons and was blocked by HA1004, an inhibitor of calcium/calmodulin-dependent protein kinase II, protein kinase A, and protein kinase C. Taken together, these results suggest that progeny HIV-1 virions can influence neuronal signal transduction and apoptosis. This process occurs, in part, through CXCR4 and is independent of CD4 binding. T-tropic viruses that traffic in and out of the brain during progressive HIV-1 disease may play an important role in HAD neuropathogenesis. PMID:10482576

Agent-based game theory modeling for driverless vehicles at intersections.

Science.gov (United States)

2013-02-01

This report presents three research efforts that were published in various journals. The first research effort presents a reactive-driving agent based algorithm for modeling driver left turn gap acceptance behavior at signalized intersections. This m...

Resolvin D1 Protects Lipopolysaccharide-induced Acute Kidney Injury by Down-regulating Nuclear Factor-kappa B Signal and Inhibiting Apoptosis

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Yu-Liang Zhao

2016-01-01

Conclusion: In LPS-induced AKI, RvD1 could decrease TNF-α level, ameliorate kidney pathological injury, protect kidney function, and improve animal survival by down-regulating NF-κB inflammatory signal as well as inhibiting renal cell apoptosis.

Shear stress induces cell apoptosis via a c-Src-phospholipase D-mTOR signaling pathway in cultured podocytes

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Huang, Chunfa, E-mail: chunfa.huang@case.edu [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States); Bruggeman, Leslie A. [Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States); Hydo, Lindsey M. [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Miller, R. Tyler [Louis Stokes Cleveland Veteran Affairs Medical Center, Case Western Reserve University (United States); Department of Medicine, Case Western Reserve University (United States); Rammelkamp Center for Research and Education, MetroHealth System Campus, Cleveland, OH 44106 (United States)

2012-06-10

The glomerular capillary wall, composed of endothelial cells, the glomerular basement membrane and the podocytes, is continually subjected to hemodynamic force arising from tractional stress due to blood pressure and shear stress due to blood flow. Exposure of glomeruli to abnormal hemodynamic force such as hyperfiltration is associated with glomerular injury and progressive renal disease, and the conversion of mechanical stimuli to chemical signals in the regulation of the process is poorly understood in podocytes. By examining DNA fragmentation, apoptotic nuclear changes and cytochrome c release, we found that shear stress induced cell apoptosis in cultured podocytes. Meanwhile, podocytes exposed to shear stress also stimulated c-Src phosphorylation, phospholipase D (PLD) activation and mammalian target of rapamycin (mTOR) signaling. Using the antibodies against c-Src, PLD{sub 1}, and PLD{sub 2} to perform reciprocal co-immunoprecipitations and in vitro PLD activity assay, our data indicated that c-Src interacted with and activated PLD{sub 1} but not PLD{sub 2}. The inhibition of shear stress-induced c-Src phosphorylation by PP{sub 2} (a specific inhibitor of c-Src kinase) resulted in reduced PLD activity. Phosphatidic acid, produced by shear stress-induced PLD activation, stimulated mTOR signaling, and caused podocyte hypertrophy and apoptosis.

Blocking Epidermal Growth Factor Receptor Signaling in HTR-8/SVneo First Trimester Trophoblast Cells Results in Dephosphorylation of PKBα/AKT and Induces Apoptosis

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J. Bolnick

2011-01-01

Full Text Available We identified a major peptide signaling target of EGF/EGFR pathway and explored the consequences of blocking or activating this pathway in the first trimester extravillous trophoblast cells, HTR-8/SVneo. A global analysis of protein phosphorylation was undertaken using novel technology (Kinexus Kinetworks that utilizes SDS-polyacrylamide minigel electrophoresis and multi-lane immunoblotting to permit specific and semiquantitative detection of multiple phosphoproteins. Forty-seven protein phosphorylation sites were queried, and the results reported based on relative phosphorylation at each site. EGF- and Iressa-(gefitinib, ZD1839, an inhibitor of EGFR treated HTR-8/SVneo cells were subjected to immunoblotting and flow cytometry to confirm the phosphoprotein screen and to assess the effects of EGF versus Iressa on cell cycle and apoptosis. EGFR mediates the phosphorylation of important signaling proteins, including PKBα/AKT. This pathway is likely to be central to EGFR-mediated trophoblast survival. Furthermore, EGF treatment induces proliferation and inhibits apoptosis, while Iressa induces apoptosis.

Leukemia-associated gene MLAA-34 reduces arsenic trioxide-induced apoptosis in HeLa cells via activation of the Wnt/β-catenin signaling pathway.

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Zhang, Pengyu; Zhao, Xuan; Zhang, Wenjuan; He, Aili; Lei, Bo; Zhang, Wanggang; Chen, Yinxia

2017-01-01

Our laboratory previously used the SEREX method in U937 cells and identified a novel leukemia-associated gene MLAA-34, a novel splice variant of CAB39L associated with acute monocytic leukemia, that exhibited anti-apoptotic activities in U937 cells. Whether MLAA-34 has an anti-apoptotic role in other tumor cells has not yet been reported. We explored whether MLAA-34 exhibited anti-apoptotic effects in HeLa cervical cancer cells and the possible mechanism of action. We generated a HeLa cell line stably expressing MLAA-34 and found that MLAA-34 overexpression had no effect on the growth, apoptosis and cell cycle of HeLa cells. However, upon treatment with arsenic trioxide (ATO) to induce apoptosis, the cell viability and colony formation ability of ATO-treated MLAA-34 stable HeLa cells were significantly higher than that of ATO-treated controls, and the apoptosis rate and proportion of G2/M cells also decreased. We found that ATO treatment of HeLa cells resulted in significant decreases in the expression of β-catenin mRNA and protein and the downstream target factors c-Myc, cyclin B1, and cyclin D1 in the Wnt signaling pathway. Notably, ATO-treated MLAA-34 stable HeLa cells showed a significant reduction in the ATO-mediated downregulation of these factors. In addition, MLAA-34 overexpression significantly increased the expression of nuclear β-catenin protein in ATO-treated cells compared with HeLa cells treated only with ATO. Thus, here we have found that the Wnt/β-catenin signaling pathway is involved in ATO-induced apoptosis in HeLa cells. MLAA-34 reduces ATO-induced apoptosis and G2/M arrest, and the anti-apoptotic effect may be achieved by activating the Wnt/β-catenin signaling pathway in HeLa cells.

Activating Nrf-2 signaling depresses unilateral ureteral obstruction-evoked mitochondrial stress-related autophagy, apoptosis and pyroptosis in kidney.

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Shue Dong Chung

Full Text Available Exacerbated oxidative stress and inflammation may induce three types of programmed cell death, autophagy, apoptosis and pyroptosis in unilateral ureteral obstruction (UUO kidney. Sulforaphane activating NF-E2-related nuclear factor erythroid-2 (Nrf-2 signaling may ameliorate UUO-induced renal damage. UUO was induced in the left kidney of female Wistar rats. The level of renal blood flow, cortical and medullary oxygen tension and reactive oxygen species (ROS was evaluated. Fibrosis, ED-1 (macrophage/monocyte infiltration, oxidative stress, autophagy, apoptosis and pyroptosis were evaluated by immunohistochemistry and Western blot in UUO kidneys. Effects of sulforaphane, an Nrf-2 activator, on Nrf-2- and mitochondrial stress-related proteins and renal injury were examined. UUO decreased renal blood flow and oxygen tension and increased renal ROS, 3-nitrotyrosine stain, ED-1 infiltration and fibrosis. Enhanced renal tubular Beclin-1 expression started at 4 h UUO and further enhanced at 3d UUO, whereas increased Atg-5-Atg12 and LC3-II expression were found at 3d UUO. Increased renal Bax/Bcl-2 ratio, caspase 3 and PARP fragments, apoptosis formation associated with increased caspase 1 and IL-1β expression for pyroptosis formation were started from 3d UUO. UUO reduced nuclear Nrf-2 translocation, increased cytosolic and inhibitory Nrf-2 expression, increased cytosolic Bax translocation to mitochondrial and enhanced mitochondrial Cytochrome c release into cytosol of the UUO kidneys. Sulforaphane significantly increased nuclear Nrf-2 translocation and decreased mitochondrial Bax translocation and Cytochrome c release into cytosol resulting in decreased renal injury. In conclusion, sulforaphane via activating Nrf-2 signaling preserved mitochondrial function and suppressed UUO-induced renal oxidative stress, inflammation, fibrosis, autophagy, apoptosis and pyroptosis.

PASSENGER CAR EQUIVALENT (PCE OF THROUGH VEHICLES AT SIGNALIZED INTERSECTIONS IN DHAKA METROPOLITAN CITY, BANGLADESH

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Partha SAHA

2009-01-01

PCE currently used in Bangladesh is based on the values given in Geometric Design of Highways (MoC, 2001, which is the modification of the values given by Webster (1958 on the study performed in the United Kingdom in the 50's and 60's. But now-a-days, the situation is far different both for traffic and road user as the characteristics have changed from that time. Hence, in this paper an empirical study was carried out to determine the PCE of different types of vehicle that reflect the actual traffic conditions of Dhaka Metropolitan City. Data were collected from ten signalized intersections and the headway ratio method was used to estimate the PCE of different types of vehicle. The main vehicle compositions observed during the study period consist of passenger cars, auto-rickshaws, mini-buses and buses. The PCE obtained in this study were compared to the values established earlier. It was found that the estimated PCE are smaller than those being used in Bangladesh.

Implications of advanced warning messages on eliminating sun glare disturbances at signalized intersections

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Qing Li

2016-08-01

Full Text Available Due to sun glare disturbances, drivers encounter fatal threats on roadways, particularly at signalized intersections. Many studies have attempted to develop applicable solutions, such as avoiding sun positions, applying road geometric re-directions, and wearing anti-glare glasses. None of these strategies have fully solved the problem. As one of the “Connected Vehicle” practices proposed by the U.S. Department of Transportation, advanced warning messages (AWMs are capable of providing wireless information about traffic controls. AWM acts as a supplement to conventional signs and signals, which can be blocked by obstacles or natural disturbances, such as sun glare. The drivers' smart advisory system (DSAS can provide drivers with AWM. Using a driving simulator this research explores the effects of DSAS messages on driving behaviors under sun glare disturbance. Statistical analyses were applied to assess (1 the negative impacts of sun glare, (2 the compensation of the DSAS AWM to sun glare effects, and (3 the improvement in driving performance due to DSAS AWM. Four performance indexes were measured, including (1 half kinetic energy speed, (2 mean approach speed, (3 brake response time, and (4 braking distance. The effects of the socio-demographic factors, such as gender, age, educational background, and driving experience were also studied. The analytical results illustrate that the DSAS can compensate for reduced visibility due to sun glare and improve driving performance to a normal visual situation, particularly for left turn and through movement.

Differential Apoptosis in Mucosal and Dermal Wound Healing

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Johnson, Ariel; Francis, Marybeth; DiPietro, Luisa Ann

2014-01-01

Objectives: Dermal and mucosal healing are mechanistically similar. However, scarring and closure rates are dramatically improved in mucosal healing, possibly due to differences in apoptosis. Apoptosis, nature's preprogrammed form of cell death, occurs via two major pathways, extrinsic and intrinsic, which intersect at caspase3 (Casp3) cleavage and activation. The purpose of this experiment was to identify the predominant pathways of apoptosis in mucosal and dermal wound healing. Approach: Wounds (1 mm biopsy punch) were made in the dorsal skin (n=3) or tongue (n=3) of female Balb/C mice aged 6 weeks. Wounds were harvested at 6 h, 24 h, day 3 (D3), D5, D7, and D10. RNA was isolated and analyzed using real time reverse transcriptase–polymerase chain reaction. Expression levels for genes in the intrinsic and extrinsic apoptotic pathways were compared in dermal and mucosal wounds. Results: Compared to mucosal healing, dermal wounds exhibited significantly higher expression of Casp3 (at D5; phealing compared to skin. Conclusion: Expression patterns of key regulators of apoptosis in wound healing indicate that apoptosis occurs predominantly through the intrinsic pathway in the healing mucosa, but predominantly through the extrinsic pathway in the healing skin. The identification of differences in the apoptotic pathways in skin and mucosal wounds may allow the development of therapeutics to improve skin healing. PMID:25493209

Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: A new potential therapy for the treatment of melanoma

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Karasic, Thomas B.; Hei, Tom K. [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States); Ivanov, Vladimir N., E-mail: vni3@columbia.edu [Center for Radiological Research, Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 (United States)

2010-07-15

Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9 [1]. All these lines have normal NRAS. WM35, WM793, LU1205 and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for

Anti-apoptotic signaling and failure of apoptosis in the ischemic rat hippocampus

DEFF Research Database (Denmark)

Müller, Georg Johannes; Lassmann, Hans; Johansen, Flemming Fryd

2007-01-01

Several anti-apoptotic proteins are induced in CA1 neurons after transient forebrain ischemia (TFI), but fail to protect the majority of these cells from demise. Correlating cell death morphologies (apoptosis-like and necrosis-like death) with immunohistochemistry (IHC), we investigated whether...... anti-apoptosis contributes to survival, compromises apoptosis effector functions and/or delays death in CA1 neurons 1-7 days after TFI. As surrogate markers for bioenergetic failure, the IHC of respiratory chain complex (RCC) subunits was investigated. Dentate granule cell (DGC) apoptosis following...... colchicine injection severed as a reference for classical apoptosis. Heat shock protein 70 (Hsp70), neuronal apoptosis inhibitory protein (NAIP) and manganese superoxide dismutase (MnSOD) were upregulated in the majority of intact CA1 neurons paralleling the occurrence of CA1 neuronal death (days 3...

Copper excess in liver HepG2 cells interferes with apoptosis and lipid metabolic signaling at the protein level.

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Liu, Yu; Yang, Huarong; Song, Zhi; Gu, Shaojuan

2014-12-01

Copper is an essential trace element that serves as an important catalytic cofactor for cuproenzymes, carrying out major biological functions in growth and development. Although Wilson's disease (WD) is unquestionably caused by mutations in the ATP7B gene and subsequent copper overload, the precise role of copper in inducing pathological changes remains poorly understood. Our study aimed to explore, in HepG2 cells exposed to copper, the cell viability and apoptotic cells was tested by MTT and Hoechst 33342 stainning respectively, and the signaling pathways involved in oxidative stress response, apoptosis and lipid metabolism were determined by real time RT-PCR and Western blot analysis. The results demonstrate dose- and time-dependent cell viability and apoptosis in HepG2 cells following treatment with 10 μM, 200 μM and 500 μM of copper sulfate for 8 and 24 h. Copper overload significantly induced the expression of HSPA1A (heat shock 70 kDa protein 1A), an oxidative stress-responsive signal gene, and BAG3 (BCL2 associated athanogene3), an anti-apoptotic gene, while expression of HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase), a lipid biosynthesis and lipid metabolism gene, was inhibited. These findings provide new insights into possible mechanisms accounting for the development of liver apoptosis and steatosis in the early stages of Wilson's disease.

HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.

LENUS (Irish Health Repository)

Gupta, Sanjeev

2010-01-01

Endoplasmic reticulum (ER) stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR). Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1alpha, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1alpha or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1alpha enhances IRE1alpha\\/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.

Exposure to Cerium Oxide Nanoparticles Is Associated With Activation of Mitogen-activated Protein Kinases Signaling and Apoptosis in Rat Lungs

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Kevin M. Rice

2015-05-01

Full Text Available Objectives: With recent advances in nanoparticle manufacturing and applications, potential exposure to nanoparticles in various settings is becoming increasing likely. No investigation has yet been performed to assess whether respiratory tract exposure to cerium oxide (CeO2 nanoparticles is associated with alterations in protein signaling, inflammation, and apoptosis in rat lungs. Methods: Specific-pathogen-free male Sprague-Dawley rats were instilled with either vehicle (saline or CeO2 nanoparticles at a dosage of 7.0 mg/kg and euthanized 1, 3, 14, 28, 56, or 90 days after exposure. Lung tissues were collected and evaluated for the expression of proteins associated with inflammation and cellular apoptosis. Results: No change in lung weight was detected over the course of the study; however, cerium accumulation in the lungs, gross histological changes, an increased Bax to Bcl-2 ratio, elevated cleaved caspase-3 protein levels, increased phosphorylation of p38 MAPK, and diminished phosphorylation of ERK-1/2-MAPK were detected after CeO2 instillation (p<0.05. Conclusions: Taken together, these data suggest that high-dose respiratory exposure to CeO2 nanoparticles is associated with lung inflammation, the activation of signaling protein kinases, and cellular apoptosis, which may be indicative of a long-term localized inflammatory response.

6-OHDA-induced apoptosis and mitochondrial dysfunction are mediated by early modulation of intracellular signals and interaction of Nrf2 and NF-κB factors

International Nuclear Information System (INIS)

Tobón-Velasco, Julio C.; Limón-Pacheco, Jorge H.; Orozco-Ibarra, Marisol; Macías-Silva, Marina; Vázquez-Victorio, Genaro; Cuevas, Elvis; Ali, Syed F.

2013-01-01

6-Hydroxydopamine (6-OHDA) is a neurotoxin that generates an experimental model of Parkinson's disease in rodents and is commonly employed to induce a lesion in dopaminergic pathways. The characterization of those molecular mechanisms linked to 6-OHDA-induced early toxicity is needed to better understand the cellular events further leading to neurodegeneration. The present work explored how 6-OHDA triggers early downstream signaling pathways that activate neurotoxicity in the rat striatum. Mitochondrial function, caspases-dependent apoptosis, kinases signaling (Akt, ERK 1/2, SAP/JNK and p38) and crosstalk between nuclear factor kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) were evaluated at early times post-lesion. We found that 6-OHDA initiates cell damage via mitochondrial complex I inhibition, cytochrome c and apoptosis-inducing factor (AIF) release, as well as activation of caspases 9 and 3 to induce apoptosis, kinase signaling modulation and NF-κB-mediated inflammatory responses, accompanied by inhibition of antioxidant systems regulated by the Nrf2 pathway. Our results suggest that kinases SAP/JNK and p38 up-regulation may play a role in the early stages of 6-OHDA toxicity to trigger intrinsic pathways for apoptosis and enhanced NF-κB activation. In turn, these cellular events inhibit the activation of cytoprotective mechanisms, thereby leading to a condition of general damage

Lipid Metabolism, Apoptosis and Cancer Therapy

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Chunfa Huang

2015-01-01

Full Text Available Lipid metabolism is regulated by multiple signaling pathways, and generates a variety of bioactive lipid molecules. These bioactive lipid molecules known as signaling molecules, such as fatty acid, eicosanoids, diacylglycerol, phosphatidic acid, lysophophatidic acid, ceramide, sphingosine, sphingosine-1-phosphate, phosphatidylinositol-3 phosphate, and cholesterol, are involved in the activation or regulation of different signaling pathways. Lipid metabolism participates in the regulation of many cellular processes such as cell growth, proliferation, differentiation, survival, apoptosis, inflammation, motility, membrane homeostasis, chemotherapy response, and drug resistance. Bioactive lipid molecules promote apoptosis via the intrinsic pathway by modulating mitochondrial membrane permeability and activating different enzymes including caspases. In this review, we discuss recent data in the fields of lipid metabolism, lipid-mediated apoptosis, and cancer therapy. In conclusion, understanding the underlying molecular mechanism of lipid metabolism and the function of different lipid molecules could provide the basis for cancer cell death rationale, discover novel and potential targets, and develop new anticancer drugs for cancer therapy.

RP105 Protects Against Apoptosis in Ischemia/Reperfusion-Induced Myocardial Damage in Rats by Suppressing TLR4-Mediated Signaling Pathways

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Jun Yang

2015-07-01

Full Text Available Background: Myocardial apoptosis is heavily implicated in the myocardial damage caused by ischemia-reperfusion (I/R. Toll-like receptor 4 (TLR4 is a potent inducer of these apoptotic cascades. In contrast, the radioprotective 105 kDa protein (RP105 is a specific negative regulator of TLR4 signaling pathways. However, the precise mechanisms by which RP105 inhibits myocardium apoptosis via TLR4-associated pathways during I/R is not fully understood. Methods: We utilized a rat model of myocardial ischemic reperfusion injury (MIRI. Animals were pre-treated with Ad-EGFP adenovirus, Ad-EGFP-RP105 adenovirus, saline, or nothing (sham. After three days, rats underwent a 30min left anterior descending coronary artery occlusion and a 4h reperfusion. Mycardial tissue was assessed by immunohistochemistry, TUNEL-staining, Western blot, quantitative RT-PCR, and a morphometric assay. Results: RP105 overexpression resulted in a reduction in infarct size, fewer TUNEL-positive cardiomyocytes, and a reduction in mitochondrial-associated apoptosis cascade activity. Further, RP105 overexpression repressed I/R-induced myocardial injury by attenuating myocardial apoptosis. This was mediated by inhibiting TLR4 activation and the phosphorylation of P38MAPK and the downstream transcription factor AP-1. Conclusion: RP105 overexpression leads to the de-activation of TLR4, P38MAPK, and AP-1 signaling pathways, and subsequently represses apoptotic cascades and ensuing damage of myocardial ischemic reperfusion. These findings may become the basis of a novel therapeutic approach for reducing of cardiac damage caused by MIRI.

Infección por el virus de la Lengua azul: activación de señales celulares que inducen apoptosis Bluetongue virus infection: signaling pathway activated during apoptosis

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E. Mortola

2009-09-01

Full Text Available El virus de la Lengua azul (VLA es un ARN virus de doble cadena que induce apoptosis tanto en cultivos celulares como en tejidos blanco. Con el fin de dilucidar el mecanismo de apoptosis en la infección por el VLA, en el presente trabajo examinamos en detalle, por la técnica de Western blot, las señales celulares de caspasas, Bax, citocromo c, Smac/DIABLO y factor nuclear kappa B (NF-kB que se activan en la infección viral. Hemos comprobado que luego de la infección in vitro con el VLA, se detectó la activación de la caspasa 8 y con ello el mecanismo extrínseco de la apoptosis. También detectamos por primera vez no sólo la activación de miembros de la familia Bcl-2 (Bax, sino también la liberación del citocromo c y la proteína Smac/DIABLO, confirmando que en la infección por el VLA está involucrado el mecanismo secuencial intrínseco de la apoptosis. Asimismo, demostramos que la infección por el VLA activa el NF-kB y que la apoptosis es sustancialmente reducida mediante la inhibición del mismo. La activación de las señales celulares tales como Bax, citocromo c, Smac/DIABLO y NF-kB presentados en este trabajo, esclarecen los mecanismos apoptóticos durante la infección por el VLA para una mayor comprensión del papel primario que juega la apoptosis en la patogénesis del virus.Bluetongue (BTV is a double-stranded RNA virus that induces apoptosis both in mammalian cell cultures and in target tissues. To elucidate the apoptosis pathways in BTV infection, we have examined in detail the apoptosis mechanism by examination of caspases, Bax, cytochrome c, Smac/DIABLO and NF-kB signalling pathways. In this report, after cell infection with BTV, the activation of caspase 8 was detected, proving the extrinsic receptor binding apoptotic pathway. Apoptosis followed a sequential pathway involving the detection of activated Bcl-2 family members. Furthermore, its translocation to the mitochondria, as well as the release of cytochrome c and

Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

International Nuclear Information System (INIS)

Wang, Bing; Wang, Xin-bao; Chen, Li-yu; Huang, Ling; Dong, Rui-zen

2013-01-01

Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells

Belinostat-induced apoptosis and growth inhibition in pancreatic cancer cells involve activation of TAK1-AMPK signaling axis

Energy Technology Data Exchange (ETDEWEB)

Wang, Bing, E-mail: wangbin69@yahoo.com; Wang, Xin-bao; Chen, Li-yu; Huang, Ling; Dong, Rui-zen

2013-07-19

Highlights: •Belinostat activates AMPK in cultured pancreatic cancer cells. •Activation of AMPK is important for belinostat-induced cytotoxic effects. •ROS and TAK1 are involved in belinostat-induced AMPK activation. •AMPK activation mediates mTOR inhibition by belinostat. -- Abstract: Pancreatic cancer accounts for more than 250,000 deaths worldwide each year. Recent studies have shown that belinostat, a novel pan histone deacetylases inhibitor (HDACi) induces apoptosis and growth inhibition in pancreatic cancer cells. However, the underlying mechanisms are not fully understood. In the current study, we found that AMP-activated protein kinase (AMPK) activation was required for belinostat-induced apoptosis and anti-proliferation in PANC-1 pancreatic cancer cells. A significant AMPK activation was induced by belinostat in PANC-1 cells. Inhibition of AMPK by RNAi knockdown or dominant negative (DN) mutation significantly inhibited belinostat-induced apoptosis in PANC-1 cells. Reversely, AMPK activator AICAR and A-769662 exerted strong cytotoxicity in PANC-1 cells. Belinostat promoted reactive oxygen species (ROS) production in PANC-1 cells, increased ROS induced transforming growth factor-β-activating kinase 1 (TAK1)/AMPK association to activate AMPK. Meanwhile, anti-oxidants N-Acetyl-Cysteine (NAC) and MnTBAP as well as TAK1 shRNA knockdown suppressed belinostat-induced AMPK activation and PANC-1 cell apoptosis. In conclusion, we propose that belinostat-induced apoptosis and growth inhibition require the activation of ROS-TAK1-AMPK signaling axis in cultured pancreatic cancer cells.

O-GlcNAcylation regulates ischemia-induced neuronal apoptosis through AKT signaling

OpenAIRE

Shi, Jianhua; Gu, Jin-hua; Dai, Chun-ling; Gu, Jianlan; Jin, Xiaoxia; Sun, Jianming; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

2015-01-01

Apoptosis plays an important role in neural development and neurological disorders. In this study, we found that O-GlcNAcylation, a unique protein posttranslational modification with O-linked β-N-acetylglucosamine (GlcNAc), promoted apoptosis through attenuating phosphorylation/activation of AKT and Bad. By using co-immunoprecipitation and mutagenesis techniques, we identified O-GlcNAc modification at both Thr308 and Ser473 of AKT. O-GlcNAcylation-induced apoptosis was attenuated by over-expr...

Evaluating the Operational Features of an Unconventional Dual-Bay U-Turn Design for Intersections.

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Xiang, Yun; Li, Zhibin; Wang, Wei; Chen, Jingxu; Wang, Hao; Li, Ye

2016-01-01

Median U-turn intersection treatment (MUTIT) has been considered an alternative measure to reduce congestion and traffic conflict at intersection areas. The MUTIT is sometimes difficult to implement in the field because it requires wide median on arterials for U-turn vehicles. The objective of this study is to introduce an unconventional U-turn treatment (UUT) for intersections which requires less median space but is also effective. The UUT has a dual-bay design with different turning radiuses for small and large vehicles. The VISSIM simulation model was developed to evaluate the operational features of the UUT. The model was calibrated using data collected from intersections in China. The capacity, delay and number of stops were evaluated and compared with the direct-left-turn (DLT) for the same intersections. The results showed that the UUT significantly improved the operations at intersection areas, especially when volume/capacity ratio is small, and ratio of left-turn to through traffic is small. With the UUT, the capacity is increased by 9.81% to 10.38%, vehicle delay is decreased by 18.5% to 40.1%, and number of stops is decreased by 23.19% to 36.62%, when volume/capacity ratio is less than 0.50. The study also found that traffic efficiency could be further improved when the UUT is designed in conjunction with signal control. In the case, the UUT plus signalized control increases the capacity by 25% to 26.02%, decreases vehicle delay by 50.5% to 55.8%, and reduces number of stops by 69.5%, compared with the traditional DLT.

DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes

International Nuclear Information System (INIS)

Chen, Rui; Wang, Bin; Chen, Ling; Cai, Dunpeng; Li, Bing; Chen, Chuanxiang; Huang, Enping; Liu, Chao; Lin, Zhoumeng; Xie, Wei-Bing; Wang, Huijun

2016-01-01

Methamphetamine (METH) is an amphetamine-like psychostimulant that is commonly abused. Previous studies have shown that METH can induce damages to the nervous system and recent studies suggest that METH can also cause adverse and potentially lethal effects on the cardiovascular system. Recently, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) regulates METH-induced neurotoxicity. However, the role of DDIT4 in METH-induced cardiotoxicity remains unknown. We hypothesized that DDIT4 may mediate METH-induced autophagy and apoptosis in cardiomyocytes. To test the hypothesis, we examined DDIT4 protein expression in cardiomyocytes and in heart tissues of rats exposed to METH with Western blotting. We also determined the effects on METH-induced autophagy and apoptosis after silencing DDIT4 expression with synthetic siRNA with or without pretreatment of a mTOR inhibitor rapamycin in cardiomyocytes using Western blot analysis, fluorescence microscopy and TUNEL staining. Our results showed that METH exposure increased DDIT4 expression and decreased phosphorylation of mTOR that was accompanied with increased autophagy and apoptosis both in vitro and in vivo. These effects were normalized after silencing DDIT4. On the other hand, rapamycin promoted METH-induced autophagy and apoptosis in DDIT4 knockdown cardiomyocytes. These results suggest that DDIT4 mediates METH-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes. - Highlights: • METH exposure increases DDIT4 expression in cardiomyocytes. • DDIT4 mediates METH-induced autophagy and apoptosis in cardiomyocytes. • DDIT4 silencing protects cardiomyocytes against METH-caused autophagy and apoptosis.

DNA damage-inducible transcript 4 (DDIT4) mediates methamphetamine-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes

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Chen, Rui [Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Department of Forensic Medicine, Guangdong Medical University, Dongguan 523808 (China); Wang, Bin; Chen, Ling; Cai, Dunpeng; Li, Bing; Chen, Chuanxiang; Huang, Enping [Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Liu, Chao [Guangzhou Forensic Science Institute, Guangzhou 510030 (China); Lin, Zhoumeng [Institute of Computational Comparative Medicine and Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506 (United States); Xie, Wei-Bing, E-mail: xieweib@126.com [Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China); Wang, Huijun, E-mail: hjwang711@yahoo.cn [Department of Forensic Medicine, School of Basic Medical Science, Southern Medical University, Guangzhou 510515 (China)

2016-03-15

Methamphetamine (METH) is an amphetamine-like psychostimulant that is commonly abused. Previous studies have shown that METH can induce damages to the nervous system and recent studies suggest that METH can also cause adverse and potentially lethal effects on the cardiovascular system. Recently, we demonstrated that DNA damage-inducible transcript 4 (DDIT4) regulates METH-induced neurotoxicity. However, the role of DDIT4 in METH-induced cardiotoxicity remains unknown. We hypothesized that DDIT4 may mediate METH-induced autophagy and apoptosis in cardiomyocytes. To test the hypothesis, we examined DDIT4 protein expression in cardiomyocytes and in heart tissues of rats exposed to METH with Western blotting. We also determined the effects on METH-induced autophagy and apoptosis after silencing DDIT4 expression with synthetic siRNA with or without pretreatment of a mTOR inhibitor rapamycin in cardiomyocytes using Western blot analysis, fluorescence microscopy and TUNEL staining. Our results showed that METH exposure increased DDIT4 expression and decreased phosphorylation of mTOR that was accompanied with increased autophagy and apoptosis both in vitro and in vivo. These effects were normalized after silencing DDIT4. On the other hand, rapamycin promoted METH-induced autophagy and apoptosis in DDIT4 knockdown cardiomyocytes. These results suggest that DDIT4 mediates METH-induced autophagy and apoptosis through mTOR signaling pathway in cardiomyocytes. - Highlights: • METH exposure increases DDIT4 expression in cardiomyocytes. • DDIT4 mediates METH-induced autophagy and apoptosis in cardiomyocytes. • DDIT4 silencing protects cardiomyocytes against METH-caused autophagy and apoptosis.

Puerarin protects differentiated PC12 cells from H₂O₂-induced apoptosis through the PI3K/Akt signalling pathway.

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Zhang, Qin; Huang, Wei-Dong; Lv, Xue-Ying; Yang, Yun-Mei

2012-05-01

Oxidative stress has been implicated as a major mechanism underlying the pathogenesis of neurodegenerative disorders. ROS (reactive oxygen species) can cause cell death via apoptosis. NGF (nerve growth factor) differentiated rat PC12 cells have been extensively used to study the differentiation and apoptosis of neurons. This study has investigated the protective effects of puerarin in H2O2-induced apoptosis of differentiated PC12 cells, and the possible molecular mechanisms involved. Differentiated PC12 cells were incubated with 700 μM H2O2 in the absence or presence of different doses of puerarin (4, 8 and 16 μM). Apoptosis was assessed by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay, TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) analysis and Annexin V-PI (propidium iodide) double staining flow cytometry. Protein levels of phospho-Akt and phospho-BAD (Bcl-2/Bcl-XL-antagonist, causing cell death) were assayed by Western blotting. After stimulation with H2O2 for 18 h, the viability of differentiated PC12 cells decreased significantly and a large number of cells underwent apoptosis. Differentiated PC12 cells were rescued from H2O2-induced apoptosis at different concentrations of puerarin in a dose-dependent manner. This was through increased production of phospho-Akt and phospho-BAD, an effect that could be reversed by wortmannin, an inhibitor of PI3K (phosphoinositide 3-kinase). The results suggest that puerarin may have neuroprotective effect through activation of the PI3K/Akt signalling pathway.

Analysis on influencing factors and decision-making of pedestrian crossing at intersections

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Liu, Likun; Wang, Ziyang

2017-10-01

The city signal intersection always has complex traffic flow and many traffic accidents. As vulnerable participants, the proportion of traffic accidents involving pedestrians remain high. And a lot of insecure crossing behavior seriously reduce the safety of the intersection. Therefore, it is necessary to carry out in-depth study on the traversing characteristics of pedestrians, reveal the inherent laws of pedestrian crossing, and then put forward targeted measures to improve pedestrian traffic environment, protect pedestrian crossing safety and improve traffic efficiency.

CONTROLLING TRAFFIC FLOW IN MULTILANE-ISOLATED INTERSECTION USING ANFIS APPROACH TECHNIQUES

OpenAIRE

G. R. LAI; A. CHE SOH; H. MD. SARKAN; R. Z. ABDUL RAHMAN; M. K. HASSAN

2015-01-01

Many controllers have applied the Adaptive Neural-Fuzzy Inference System (ANFIS) concept for optimizing the controller performance. However, there are less traffic signal controllers developed using the ANFIS concept. ANFIS traffic signal controller with its fuzzy rule base and its ability to learn from a set of sample data could improve the performance of Existing traffic signal controlling system to reduce traffic congestions at most of the busy traffic intersections in city such as Kuala L...

HSP72 protects cells from ER stress-induced apoptosis via enhancement of IRE1alpha-XBP1 signaling through a physical interaction.

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Sanjeev Gupta

2010-07-01

Full Text Available Endoplasmic reticulum (ER stress is a feature of secretory cells and of many diseases including cancer, neurodegeneration, and diabetes. Adaptation to ER stress depends on the activation of a signal transduction pathway known as the unfolded protein response (UPR. Enhanced expression of Hsp72 has been shown to reduce tissue injury in response to stress stimuli and improve cell survival in experimental models of stroke, sepsis, renal failure, and myocardial ischemia. Hsp72 inhibits several features of the intrinsic apoptotic pathway. However, the molecular mechanisms by which Hsp72 expression inhibits ER stress-induced apoptosis are not clearly understood. Here we show that Hsp72 enhances cell survival under ER stress conditions. The UPR signals through the sensor IRE1alpha, which controls the splicing of the mRNA encoding the transcription factor XBP1. We show that Hsp72 enhances XBP1 mRNA splicing and expression of its target genes, associated with attenuated apoptosis under ER stress conditions. Inhibition of XBP1 mRNA splicing either by dominant negative IRE1alpha or by knocking down XBP1 specifically abrogated the inhibition of ER stress-induced apoptosis by Hsp72. Regulation of the UPR was associated with the formation of a stable protein complex between Hsp72 and the cytosolic domain of IRE1alpha. Finally, Hsp72 enhanced the RNase activity of recombinant IRE1alpha in vitro, suggesting a direct regulation. Our data show that binding of Hsp72 to IRE1alpha enhances IRE1alpha/XBP1 signaling at the ER and inhibits ER stress-induced apoptosis. These results provide a physical connection between cytosolic chaperones and the ER stress response.

EMPIRICAL STUDY ON USABILITY OF CROSSING SUPPORT SYSTEM FOR VISUALLY DISABLED AT SIGNALIZED INTERSECTION

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Suzuki, Koji; Fujita, Motohiro; Matsuura, Kazuma; Fukuzono, Kazuyuki

This paper evaluates the adjustment process for crossing support system for visually disabled at signalized intersections with the use of pedestrian traffic signals in concert with visible light communication (VLC) technology through outdoor experiments. As for the experiments, we put a blindfold on sighted people by eye mask in order to analyze the behavior of acquired visually disabled. And we used a full-scale crosswalk which is taking into consideration the crossing slope, the bumps at the edge of a crosswalk between the roadway and the sidewalkand crosswalk line. From the results of the survey, it is found that repetitive use of the VLC system decreased the number of lost their bearings completely and ended up standing immobile and reduced the crossing time for each person. On the other hand, it is shown that the performance of our VLC system is nearly equal to the existing support system from the view point of crossing time and the number of standing immobile and we clarified the effect factor for guidance accuracy by the regression analyses. Then we broke test subjects down into patterns by cluster analysis, and explained the walking characteristics for each group as they used the VLC system. In addition, we conducted the additional surveys for the quasi-blind subjects who had difficulty walking by using VLC system and visually impaired users. As a result, it is revealed that guidance accuracy was improved by providing the information about their receiving movement at several points on crosswalk and the habit of their walks for each user.

Apoptosis Induction of Human Prostate Carcinoma DU145 Cells by Diallyl Disulfide via Modulation of JNK and PI3K/AKT Signaling Pathways

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Young Hyun Yoo

2012-11-01

Full Text Available Diallyl disulfide (DADS, a sulfur compound derived from garlic, has various biological properties, such as anticancer, antiangiogenic and anti-inflammatory effects. However, the mechanisms of action underlying the compound's anticancer activity have not been fully elucidated. In this study, the apoptotic effects of DADS were investigated in DU145 human prostate carcinoma cells. Our results showed that DADS markedly inhibited the growth of the DU145 cells by induction of apoptosis. Apoptosis was accompanied by modulation of Bcl-2 and inhibitor of apoptosis protein (IAP family proteins, depolarization of the mitochondrial membrane potential (MMP, ΔΨm and proteolytic activation of caspases. We also found that the expression of death-receptor 4 (DR4 and Fas ligand (FasL proteins was increased and that the level of intact Bid proteins was down-regulated by DADS. Moreover, treatment with DADS induced phosphorylation of mitogen-activated protein kinases (MAPKs, including extracellular-signal regulating kinase (ERK, p38 MAPK and c-Jun N-terminal kinase (JNK. A specific JNK inhibitor, SP600125, significantly blocked DADS-induced-apoptosis, whereas inhibitors of the ERK (PD98059 and p38 MAPK (SB203580 had no effect. The induction of apoptosis was also accompanied by inactivation of phosphatidylinositol 3-kinase (PI3K/Akt and the PI3K inhibitor LY29004 significantly increased DADS-induced cell death. These findings provide evidence demonstrating that the proapoptotic effect of DADS is mediated through the activation of JNK and the inhibition of the PI3K/Akt signaling pathway in DU145 cells.

Luteolin Prevents H2O2-Induced Apoptosis in H9C2 Cells through Modulating Akt-P53/Mdm2 Signaling Pathway

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Hong Chang

2016-01-01

Full Text Available Introduction. Luteolin, a falconoid compound in many Chinese herbs and formula, plays important roles in cardiovascular diseases. The underlying mechanism of luteolin remains to be further elaborated. Methods. A model of hydrogen peroxide- (H2O2- induced H9C2 cells apoptosis was established. Cell viabilities were examined with an MTT assay. 2′,7′-Dichlorofluorescin diacetate (DCFH-DA and flow cytometry were used to detect ROS level and apoptosis rate, respectively. The expressions of signaling proteins related to apoptosis were analyzed by western blot and mRNA levels were detected by real-time polymerase chain reaction (PCR. Quercetin was applied as positive drug. Results. Incubation with various concentrations of H2O2 (0, 50, 100, and 200 μM for 1 h caused dose-dependent loss of cell viability and 100 μM H2O2 reduced the cell viability to approximately 50%. Treatments with luteolin and quercetin protected cells from H2O2-induced cytotoxicity and reduced cellular ROS level and apoptosis rate. Moreover, luteolin could downregulate the expressions of Bax, caspase-8, cleaved-caspase-3, and p53 in apoptotic signaling pathway. Further study showed that the expressions of Akt, Bcl-2, and Mdm2 were upregulated by luteolin. Conclusion. Luteolin protects H9C2 cells from H2O2-induced apoptosis. The protective and antiapoptotic effects of luteolin could be mediated by regulating the Akt-P53/Mdm2 apoptotic pathway.

Endogenous sulfur dioxide regulates hippocampal neuron apoptosis in developing epileptic rats and is associated with the PERK signaling pathway.

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Niu, Manman; Han, Ying; Li, Qinrui; Zhang, Jing

2018-02-05

Epilepsy is among the most common neurological diseases in children. Recurrent seizures can result in hippocampal damage and seriously impair learning and memory functions in children. However, the mechanisms underlying epilepsy-related brain injury are unclear. Neuronal apoptosis is among the most common neuropathological manifestations of brain injury. Endogenous sulfur dioxide (SO 2 ) has been shown to be involved in seizures and related neuron apoptosis. However, the role of endogenous SO 2 in epilepsy remains unclear. This study assessed whether endogenous SO 2 is involved in epilepsy and its underlying mechanisms. Using a rat epilepsy model induced by an intraperitoneal injection of kainic acid (KA), we found that hippocampal neuron apoptosis was induced in epileptic rats, and the SO 2 content and aspartate aminotransferase (AAT) activity in the plasma were increased compared to those in the control group. However, the inhibition of SO 2 production by l-aspartate-β-hydroxamate (HDX) can subvert this response 72h after an epileptic seizure. No difference in apoptosis was observed 7 d after the epileptic seizure in the KA and KA+HDX groups. The protein expression levels of AAT2, glucose-regulated protein 78 (GRP78), pancreatic eIF2 kinase-like ER kinase (PERK) and phospho-PERK (p-PERK) were remarkably elevated in the hippocampi of the epileptic rats, while the HDX treatment was capable of reversing this process 7 d after the epileptic seizure. These results indicate that the inhibition of endogenous SO 2 production can alleviate neuronal apoptosis and is associated with the PERK signaling pathway during the initial stages after epileptic seizure, but inhibiting SO 2 production only delayed the occurrence of apoptosis and did not prevent neuronal apoptosis in the epileptic rats. Copyright © 2017 Elsevier B.V. All rights reserved.

Cell wall mannoprotein of Candida albicans induces cell cycle alternation and inhibits apoptosis of HaCaT cells via NF-κB signal pathway.

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Han, Yang; Jiang, Hang-Hang; Zhang, Yu-Jing; Hao, Xing-Jia; Sun, Yu-Zhe; Qi, Rui-Qun; Chen, Hong-Duo; Gao, Xing-Hua

2017-10-01

Candida albicans (C. albicans) is a commensal organism in human and a well-known dimorphic opportunistic pathogenic fungus. Though plenty of researches on the pathogenesis of C. albicans have been performed, the mechanism is not fully understood. The cell wall components of C. albicans have been documented to play important roles in its pathogenic processes. To further study the infectious mechanism of C. albicans, we investigated the potential functional role of its cell wall mannoprotein in cell cycle and apoptosis of HaCaT cells. We found that mannoprotein could promote the transition of cell cycle from G1/G0 to S phase, in which Cyclin D1, CDK4 and p-Rb, the major regulators of the cell cycle progression, showed significant upregulation, and CDKN1A (cyclin dependent kinase inhibitor 1A (p21)) showed significant downregulation. Mannoprotein also could inhibit apoptosis of HaCaT cells, which was well associated with increased expression of BCL2 (Bcl-2). Moreover, mannoprotein could increase the phosphorylation levels of RELA (p65) and NFKBIA (IκBα), as the key factors of NF-κB signal pathway in HaCaT cells, suggesting the activation of NF-κB signal pathway. Additionally, a NF-κB specific inhibitor, PDTC, could rescue the effect of mannoprotein on cell cycle and apoptosis of HaCaT cells, which suggested that mannoprotein could activate NF-κB signal pathway to mediate cell cycle alternation and inhibit apoptosis. Copyright © 2017. Published by Elsevier Ltd.

d,l-Sulforaphane Induces ROS-Dependent Apoptosis in Human Gliomablastoma Cells by Inactivating STAT3 Signaling Pathway

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Ziwei Miao

2017-01-01

Full Text Available d,l-Sulforaphane (SFN, a synthetic analogue of broccoli-derived isomer l-SFN, exerts cytotoxic effects on multiple tumor cell types through different mechanisms and is more potent than the l-isomer at inhibiting cancer growth. However, the means by which SFN impairs glioblastoma (GBM cells remains poorly understood. In this study, we investigated the anti-cancer effect of SFN in GBM cells and determined the underlying molecular mechanisms. Cell viability assays, flow cytometry, immunofluorescence, and Western blot results revealed that SFN could induced apoptosis of GBM cells in a dose- and time-dependent manner, via up-regulation of caspase-3 and Bax, and down-regulation of Bcl-2. Mechanistically, SFN treatment led to increase the intracellular reactive oxygen species (ROS level in GBM cells. Meanwhile, SFN also suppressed both constitutive and IL-6-induced phosphorylation of STAT3, and the activation of upstream JAK2 and Src tyrosine kinases, dose- and time-dependently. Moreover, blockage of ROS production by using the ROS inhibitor N-acetyl-l-cysteine totally reversed SFN-mediated down-regulation of JAK2/Src-STAT3 signaling activation and the subsequent effects on apoptosis by blocking the induction of apoptosis-related genes in GBM cells. Taken together, our data suggests that SFN induces apoptosis in GBM cells via ROS-dependent inactivation of STAT3 phosphorylation. These findings motivate further evaluation of SFN as a cancer chemopreventive agent in GBM treatment.

Fisetin induces apoptosis and endoplasmic reticulum stress in human non-small cell lung cancer through inhibition of the MAPK signaling pathway.

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Kang, Kyoung Ah; Piao, Mei Jing; Madduma Hewage, Susara Ruwan Kumara; Ryu, Yea Seong; Oh, Min Chang; Kwon, Taeg Kyu; Chae, Sungwook; Hyun, Jin Won

2016-07-01

Fisetin (3,3',4',7-tetrahydroxyflavone), a dietary flavonoid compound, is currently being investigated for its anticancer effect in various cancer models, including lung cancer. Recent studies show that fisetin induces cell growth inhibition and apoptosis in the human non-small cell lung cancer line NCI-H460. In this study, we investigated whether fisetin can induce endoplasmic reticulum (ER) stress-mediated apoptosis in NCI-H460 cells. Fisetin induced mitochondrial reactive oxygen species (ROS) and characteristic signs of ER stress: ER staining; mitochondrial Ca(2+) overload; expression of ER stress-related proteins; glucose-regulated protein (GRP)-78, phosphorylation of protein kinase RNA (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylation of eukaryotic initiation factor-2 α subunit; cleavage of activating transcription factor-6; phosphorylation of inositol-requiring kinase-1 and splicing of X-box transcription factor-1; induction of C/EBP homologous protein and cleaved caspase-12. siRNA-mediated knockdown of CHOP and ATF-6 attenuated fisetin-induced apoptotic cell death. In addition, fisetin induced phosphorylation of ERK, JNK, and p38 MAPK. Moreover, silencing of the MAPK signaling pathway prevented apoptotic cell death. In summary, our results indicate that, in NCI-H460 cells, fisetin induces apoptosis and ER stress that is mediated by induction of the MAPK signaling pathway.

Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma.

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Peponi, Evangelia; Drakos, Elias; Reyes, Guadalupe; Leventaki, Vasiliki; Rassidakis, George Z; Medeiros, L Jeffrey

2006-12-01

Mantle cell lymphoma (MCL) is characterized by the t(11;14) and cyclin D1 overexpression. However, additional molecular events are most likely required for oncogenesis, possibly through cell cycle and apoptosis deregulation. We hypothesized that mammalian target of rapamycin (mTOR) is activated in MCL and contributes to tumor proliferation and survival. In MCL cell lines, pharmacological inhibition of the phosphoinositide 3-kinase/AKT pathway was associated with decreased phosphorylation (activation) of mTOR and its downstream targets phosphorylated (p)-4E-BP1, p-p70S6 kinase, and p-ribosomal protein S6, resulting in apoptosis and cell cycle arrest. These changes were associated with down-regulation of cyclin D1 and the anti-apoptotic proteins cFLIP, BCL-XL, and MCL-1. Furthermore, silencing of mTOR expression using mTOR-specific short interfering RNA decreased phosphorylation of mTOR signaling proteins and induced cell cycle arrest and apoptosis. Silencing of eukaryotic initiation factor (eIF4E), a downstream effector of mTOR, recapitulated these results. We also assessed mTOR signaling in MCL tumors using immunohistochemical methods and a tissue microarray: 10 of 30 (33%) expressed Ser473p-AKT, 13 of 21 (62%) Ser2448p-mTOR, 22 of 22 (100%) p-p70S6K, and 5 of 20 (25%) p-ribosomal protein S6. Total eIF4E binding protein 1 and eukaryotic initiation factor 4E were expressed in 13 of 14 (93%) and 16 of 29 (55%) MCL tumors, respectively. These findings suggest that the mTOR signaling pathway is activated and may contribute to cell cycle progression and tumor cell survival in MCL.

Multiple, disparate roles for calcium signaling in apoptosis of human prostate and cervical cancer cells exposed to diindolylmethane.

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Savino, John A; Evans, Jodi F; Rabinowitz, Dorianne; Auborn, Karen J; Carter, Timothy H

2006-03-01

Diindolylmethane (DIM), derived from indole-3-carbinol in cruciferous vegetables, causes growth arrest and apoptosis of cancer cells in vitro. DIM also induces endoplasmic reticulum (ER) stress, and thapsigargin, a specific inhibitor of the sarcoplasmic reticulum/ER calcium-dependent ATPase, enhances this effect. We asked whether elevated cytosolic free calcium [Ca2+]i is required for cytotoxicity of DIM and thapsigargin in two cancer cells lines (C33A, from cervix, and DU145, from prostate). [Ca2+]i was measured in real-time by FURA-2 fluorescence. We tested whether DIM, thapsigargin, and DIM + thapsigargin cause apoptosis, measured by nucleosome release, under conditions that prevented elevation of [Ca2+]i, using both cell-permeable and cell-impermeable forms of the specific calcium chelator BAPTA. DIM, like thapsigargin, rapidly mobilized ER calcium. C33A and DU145 responded differently to perturbations in Ca2+ homeostasis, suggesting that DIM induces apoptosis by different mechanisms in these two cell lines and/or that calcium mobilization also activates different survival pathways in C33A and DU145. Apoptosis in C33A was independent of increased [Ca2+]i, suggesting that depletion of ER Ca2+ stores may be sufficient for cell killing, whereas apoptosis in DU145 required elevated [Ca2+]i for full response. Inhibitor studies using cyclosporin A and KN93 showed that Ca2+ signaling is important for cell survival but the characteristics of this response also differed in the two cell lines. Our results underscore the complex and variable nature of cellular responses to disrupted Ca2+ homeostasis and suggest that alteration Ca2+ homeostasis in the ER can induce cellular apoptosis by both calcium-dependent and calcium-independent mechanisms.

JNK signaling pathway regulates sorbitol-induced Tau proteolysis and apoptosis in SH-SY5Y cells by targeting caspase-3.

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Olivera Santa-Catalina, Marta; Caballero Bermejo, Montaña; Argent, Ricardo; Alonso, Juan C; Centeno, Francisco; Lorenzo, María J

2017-12-15

Growing evidence suggests that Diabetes Mellitus increases the risk of developing Alzheimer's disease. It is well known that hyperglycemia, a key feature of Diabetes Mellitus, may induce plasma osmolarity disturbances. Both hyperglycemia and hyperosmolarity promote the altered post-translational regulation of microtubule-associated protein Tau. Interestingly, abnormal hyperphosphorylation and cleavage of Tau have been proven to lead to the genesis of filamentous structures referred to as neurofibrillary tangles, the main pathological hallmark of Alzheimer's disease. We have previously described that hyperosmotic stress induced by sorbitol promotes Tau proteolysis and apoptosis in SH-SY5Y cells via caspase-3 activation. In order to gain insights into the regulatory mechanisms of such processes, in this work we explored the intracellular signaling pathways that regulate these events. We found that sorbitol treatment significantly enhanced the activation of conventional families of MAPK in SH-SY5Y cells. Tau proteolysis was completely prevented by JNK inhibition but not affected by either ERK1/2 or p38 MAPK blockade. Moreover, inhibition of JNK, but not ERK1/2 or p38 MAPK, efficiently prevented sorbitol-induced apoptosis and caspase-3 activation. In summary, we provide evidence that JNK signaling pathway is an upstream regulator of hyperosmotic stress-induced Tau cleavage and apoptosis in SH-SY5Y through the control of caspase-3 activation. Copyright © 2017 Elsevier Inc. All rights reserved.

BMP-2 functions independently of SHH signaling and triggers cell condensation and apoptosis in regenerating axolotl limbs

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Finnson Kenneth

2010-02-01

Full Text Available Abstract Background Axolotls have the unique ability, among vertebrates, to perfectly regenerate complex body parts, such as limbs, after amputation. In addition, axolotls pattern developing and regenerating autopods from the anterior to posterior axis instead of posterior to anterior like all tetrapods studied to date. Sonic hedgehog is important in establishing this anterior-posterior axis of limbs in all tetrapods including axolotls. Interestingly, its expression is conserved (to the posterior side of limb buds and blastemas in axolotl limbs as in other tetrapods. It has been suggested that BMP-2 may be the secondary mediator of sonic hedgehog, although there is mounting evidence to the contrary in mice. Since BMP-2 expression is on the anterior portion of developing and regenerating limbs prior to digit patterning, opposite to the expression of sonic hedgehog, we examined whether BMP-2 expression was dependent on sonic hedgehog signaling and whether it affects patterning of the autopod during regeneration. Results The expression of BMP-2 and SOX-9 in developing and regenerating axolotl limbs corresponded to the first digits forming in the anterior portion of the autopods. The inhibition of sonic hedgehog signaling with cyclopamine caused hypomorphic limbs (during development and regeneration but did not affect the expression of BMP-2 and SOX-9. Overexpression of BMP-2 in regenerating limbs caused a loss of digits. Overexpression of Noggin (BMP inhibitor in regenerating limbs also resulted in a loss of digits. Histological analysis indicated that the loss due to BMP-2 overexpression was the result of increased cell condensation and apoptosis while the loss caused by Noggin was due to a decrease in cell division. Conclusion The expression of BMP-2 and its target SOX-9 was independent of sonic hedgehog signaling in developing and regenerating limbs. Their expression correlated with chondrogenesis and the appearance of skeletal elements has

Traffic signal design and simulation for vulnerable road users safety and bus preemption

International Nuclear Information System (INIS)

Lo, Shih-Ching; Huang, Hsieh-Chu

2015-01-01

Mostly, pedestrian car accidents occurred at a signalized interaction is because pedestrians cannot across the intersection safely within the green light. From the viewpoint of pedestrian, there might have two reasons. The first one is pedestrians cannot speed up to across the intersection, such as the elders. The other reason is pedestrians do not sense that the signal phase is going to change and their right-of-way is going to be lost. Developing signal logic to protect pedestrian, who is crossing an intersection is the first purpose of this study. In addition, to improve the reliability and reduce delay of public transportation service is the second purpose. Therefore, bus preemption is also considered in the designed signal logic. In this study, the traffic data of the intersection of Chong-Qing North Road and Min-Zu West Road, Taipei, Taiwan, is employed to calibrate and validate the signal logic by simulation. VISSIM 5.20, which is a microscopic traffic simulation software, is employed to simulate the signal logic. From the simulated results, the signal logic presented in this study can protect pedestrians crossing the intersection successfully. The design of bus preemption can reduce the average delay. However, the pedestrian safety and bus preemption signal will influence the average delay of cars largely. Thus, whether applying the pedestrian safety and bus preemption signal logic to an intersection or not should be evaluated carefully

Traffic signal design and simulation for vulnerable road users safety and bus preemption

Energy Technology Data Exchange (ETDEWEB)

Lo, Shih-Ching; Huang, Hsieh-Chu [Department of Transportation Technology and Logistics Management, Chung Hua University, No. 707, Sec. 2, WuFu Rd., Hsinchu, 300, Taiwan (China)

2015-01-22

Mostly, pedestrian car accidents occurred at a signalized interaction is because pedestrians cannot across the intersection safely within the green light. From the viewpoint of pedestrian, there might have two reasons. The first one is pedestrians cannot speed up to across the intersection, such as the elders. The other reason is pedestrians do not sense that the signal phase is going to change and their right-of-way is going to be lost. Developing signal logic to protect pedestrian, who is crossing an intersection is the first purpose of this study. In addition, to improve the reliability and reduce delay of public transportation service is the second purpose. Therefore, bus preemption is also considered in the designed signal logic. In this study, the traffic data of the intersection of Chong-Qing North Road and Min-Zu West Road, Taipei, Taiwan, is employed to calibrate and validate the signal logic by simulation. VISSIM 5.20, which is a microscopic traffic simulation software, is employed to simulate the signal logic. From the simulated results, the signal logic presented in this study can protect pedestrians crossing the intersection successfully. The design of bus preemption can reduce the average delay. However, the pedestrian safety and bus preemption signal will influence the average delay of cars largely. Thus, whether applying the pedestrian safety and bus preemption signal logic to an intersection or not should be evaluated carefully.

Death Receptor-Induced Apoptosis Signalling Regulation by Ezrin Is Cell Type Dependent and Occurs in a DISC-Independent Manner in Colon Cancer Cells

Science.gov (United States)

Iessi, Elisabetta; Zischler, Luciana; Etringer, Aurélie; Bergeret, Marion; Morlé, Aymeric; Jacquemin, Guillaume; Morizot, Alexandre; Shirley, Sarah; Lalaoui, Najoua; Elifio-Esposito, Selene L.; Fais, Stefano; Garrido, Carmen; Solary, Eric; Micheau, Olivier

2015-01-01

Ezrin belongs to the ERM (ezrin-radixin-moesin) protein family and has been demonstrated to regulate early steps of Fas receptor signalling in lymphoid cells, but its contribution to TRAIL-induced cell death regulation in adherent cancer cells remains unknown. In this study we report that regulation of FasL and TRAIL-induced cell death by ezrin is cell type dependant. Ezrin is a positive regulator of apoptosis in T-lymphoma cell line Jurkat, but a negative regulator in colon cancer cells. Using ezrin phosphorylation or actin-binding mutants, we provide evidence that negative regulation of death receptor-induced apoptosis by ezrin occurs in a cytoskeleton- and DISC-independent manner, in colon cancer cells. Remarkably, inhibition of apoptosis induced by these ligands was found to be tightly associated with regulation of ezrin phosphorylation on serine 66, the tumor suppressor gene WWOX and activation of PKA. Deficiency in WWOX expression in the liver cancer SK-HEP1 or the pancreatic Mia PaCa-2 cell lines as well as WWOX silencing or modulation of PKA activation by pharmacological regulators, in the colon cancer cell line SW480, abrogated regulation of TRAIL signalling by ezrin. Altogether our results show that death receptor pro-apoptotic signalling regulation by ezrin can occur downstream of the DISC in colon cancer cells. PMID:26010871

Death Receptor-Induced Apoptosis Signalling Regulation by Ezrin Is Cell Type Dependent and Occurs in a DISC-Independent Manner in Colon Cancer Cells.

Directory of Open Access Journals (Sweden)

Elisabetta Iessi

Full Text Available Ezrin belongs to the ERM (ezrin-radixin-moesin protein family and has been demonstrated to regulate early steps of Fas receptor signalling in lymphoid cells, but its contribution to TRAIL-induced cell death regulation in adherent cancer cells remains unknown. In this study we report that regulation of FasL and TRAIL-induced cell death by ezrin is cell type dependant. Ezrin is a positive regulator of apoptosis in T-lymphoma cell line Jurkat, but a negative regulator in colon cancer cells. Using ezrin phosphorylation or actin-binding mutants, we provide evidence that negative regulation of death receptor-induced apoptosis by ezrin occurs in a cytoskeleton- and DISC-independent manner, in colon cancer cells. Remarkably, inhibition of apoptosis induced by these ligands was found to be tightly associated with regulation of ezrin phosphorylation on serine 66, the tumor suppressor gene WWOX and activation of PKA. Deficiency in WWOX expression in the liver cancer SK-HEP1 or the pancreatic Mia PaCa-2 cell lines as well as WWOX silencing or modulation of PKA activation by pharmacological regulators, in the colon cancer cell line SW480, abrogated regulation of TRAIL signalling by ezrin. Altogether our results show that death receptor pro-apoptotic signalling regulation by ezrin can occur downstream of the DISC in colon cancer cells.

In Vivo and In Vitro Effects of ATM/ATR Signaling Pathway on Proliferation, Apoptosis, and Radiosensitivity of Nasopharyngeal Carcinoma Cells.

Science.gov (United States)

Wang, Ming; Liu, Gang; Shan, Guo-Ping; Wang, Bing-Bing

2017-08-01

The study investigated the ability of ataxia-telangiectasia mutated (ATM)/Rad3-related (ATR) signaling pathway to influence the proliferation, apoptosis, and radiosensitivity of nasopharyngeal carcinoma (NPC) cells. NPC tissues and corresponding adjacent normal tissues were collected from 143 NPC patients. The NPC CNE2 cells were assigned into a control group, X-ray group, CGK-733 group, and X-ray+CGK-733 group. The mRNA levels of ATM and ATR were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) and the protein levels of ATM and ATR using western blotting. The positive expression of ATM and ATR in tissues and nude mouse tumor tissues was determined by immunohistochemistry. Cell proliferation, migration, invasion, and apoptosis rates were analyzed by the 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, scratch test, transwell assay, and flow cytometry, respectively. A nude mouse model of NPC was established to observe tumor volume and growth. The mRNA levels of ATR and ATM and the expression of ATR and ATM protein in NPC tissues were significantly higher than those in adjacent normal tissues. The colony formation assay showed that the colony-forming rate decreased, showing radiation dose-dependent and CGK-733 concentration-dependent manners. Expression of ATM, ATR, Chk1, and Chk2 was evidently increased in the X-ray, CGK-733, and X-ray+CGK-733groups compared with the control group, and the aforementioned expression was highest in the X-ray+CGK-733 group among the four groups. The cell proliferation, invasion, and migration were decreased, tumor volume decreased and cell apoptosis increased in the X-ray, CGK-733, and X-ray+CGK-733 groups compared with the control group; the X-ray+CGK-733 group exhibited lowest cell proliferation, invasion and migration, smallest tumor volume, and highest cell apoptosis among the four groups. Inhibition of ATM/ATR signaling pathway reduces proliferation and enhances apoptosis and

FoxP3 inhibits proliferation and induces apoptosis of gastric cancer cells by activating the apoptotic signaling pathway

International Nuclear Information System (INIS)

Ma, Gui-Fen; Chen, Shi-Yao; Sun, Zhi-Rong; Miao, Qing; Liu, Yi-Mei; Zeng, Xiao-Qing; Luo, Tian-Cheng; Ma, Li-Li; Lian, Jing-Jing; Song, Dong-Li

2013-01-01

Highlights: ► The article revealed FoxP3 gene function in gastric cancer firstly. ► Present the novel roles of FoxP3 in inhibiting proliferation and promoting apoptosis in gastric cancer cells. ► Overexpression of FoxP3 increased proapoptotic molecules and repressed antiapoptotic molecules. ► Silencing of FoxP3 reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. ► FoxP3 is sufficient for activating the apoptotic signaling pathway. -- Abstract: Forkhead Box Protein 3 (FoxP3) was identified as a key transcription factor to the occurring and function of the regulatory T cells (Tregs). However, limited evidence indicated its function in tumor cells. To elucidate the precise roles and underlying molecular mechanism of FoxP3 in gastric cancer (GC), we examined the expression of FoxP3 and the consequences of interfering with FoxP3 gene in human GC cell lines, AGS and MKN45, by multiple cellular and molecular approaches, such as immunofluorescence, gene transfection, CCK-8 assay, clone formation assay, TUNEL assay, Flow cytometry, immunoassay and quantities polymerase chain reaction (PCR). As a result, FoxP3 was expressed both in nucleus and cytoplasm of GC cells. Up-regulation of FoxP3 inhibited cell proliferation and promoted cell apoptosis. Overexpression of FoxP3 increased the protein and mRNA levels of proapoptotic molecules, such as poly ADP-ribose polymerase1 (PARP), caspase-3 and caspase-9, and repressed the expression of antiapoptotic molecules, such as cellular inhibitor of apoptosis-1 (c-IAP1) and the long isoform of B cell leukemia/lymphoma-2 (Bcl-2). Furthermore, silencing of FoxP3 by siRNA in GC cells reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Collectively, our findings identify the novel roles of FoxP3 in inhibiting proliferation and inducing apoptosis in GC cells by regulating apoptotic signaling, which could be a promising therapeutic approach for gastric cancer.

Fas-induced apoptosis in malnourished infants

African Journals Online (AJOL)

EL-HAKIM

deprivation in animals, including man11. Factor of apoptosis signal (Fas) induces apoptosis in activated T cells when they are repeatedly stimulated by antigen and functions to maintain T cell tolerance by deleting auto reactive cells12. The functional role of Fas (CD95) in the immune system has been examined in a variety ...

Vehicular crash data used to rank intersections by injury crash frequency and severity

OpenAIRE

Liu, Yi; Li, Zongzhi; Liu, Jingxian; Patel, Harshingar

2016-01-01

This article contains data on research conducted in “A double standard model for allocating limited emergency medical service vehicle resources ensuring service reliability” (Liu et al., 2016) [1]. The crash counts were sorted out from comprehensive crash records of over one thousand major signalized intersections in the city of Chicago from 2004 to 2010. For each intersection, vehicular crashes were counted by crash severity levels, including fatal, injury Types A, B, and C for major, modera...

Curcumin Inhibits Apoptosis of Chondrocytes through Activation ERK1/2 Signaling Pathways Induced Autophagy

Directory of Open Access Journals (Sweden)

Xiaodong Li

2017-04-01

Full Text Available Osteoarthritis (OA is an inflammatory disease of load-bearing synovial joints that is currently treated with drugs that exhibit numerous side effects and are only temporarily effective in treating pain, the main symptom of the disease. Consequently, there is an acute need for novel, safe, and more effective chemotherapeutic agents for the treatment of osteoarthritis and related arthritic diseases. Curcumin, the principal curcuminoid and the most active component in turmeric, is a biologically active phytochemical. Evidence from several recent in vitro studies suggests that curcumin may exert a chondroprotective effect through actions such as anti-inflammatory, anti-oxidative stress, and anti-catabolic activity that are critical for mitigating OA disease pathogenesis and symptoms. In the present study, we investigated the protective mechanisms of curcumin on interleukin 1β (IL-1β-stimulated primary chondrocytes in vitro. The treatment of interleukin (IL-1β significantly reduces the cell viability of chondrocytes in dose and time dependent manners. Co-treatment of curcumin with IL-1β significantly decreased the growth inhibition. We observed that curcumin inhibited IL-1β-induced apoptosis and caspase-3 activation in chondrocytes. Curcumin can increase the expression of phosphorylated extracellular signal-regulated kinases 1/2 (ERK1/2, autophagy marker light chain 3 (LC3-II, and Beclin-1 in chondrocytes. The expression of autophagy markers could be decreased when the chondrocytes were incubated with ERK1/2 inhibitor U0126. Our results suggest that curcumin suppresses apoptosis and inflammatory signaling through its actions on the ERK1/2-induced autophagy in chondrocytes. We propose that curcumin should be explored further for the prophylactic treatment of osteoarthritis in humans and companion animals.

Evaluating the Operational Features of an Unconventional Dual-Bay U-Turn Design for Intersections.

Directory of Open Access Journals (Sweden)

Yun Xiang

Full Text Available Median U-turn intersection treatment (MUTIT has been considered an alternative measure to reduce congestion and traffic conflict at intersection areas. The MUTIT is sometimes difficult to implement in the field because it requires wide median on arterials for U-turn vehicles. The objective of this study is to introduce an unconventional U-turn treatment (UUT for intersections which requires less median space but is also effective. The UUT has a dual-bay design with different turning radiuses for small and large vehicles. The VISSIM simulation model was developed to evaluate the operational features of the UUT. The model was calibrated using data collected from intersections in China. The capacity, delay and number of stops were evaluated and compared with the direct-left-turn (DLT for the same intersections. The results showed that the UUT significantly improved the operations at intersection areas, especially when volume/capacity ratio is small, and ratio of left-turn to through traffic is small. With the UUT, the capacity is increased by 9.81% to 10.38%, vehicle delay is decreased by 18.5% to 40.1%, and number of stops is decreased by 23.19% to 36.62%, when volume/capacity ratio is less than 0.50. The study also found that traffic efficiency could be further improved when the UUT is designed in conjunction with signal control. In the case, the UUT plus signalized control increases the capacity by 25% to 26.02%, decreases vehicle delay by 50.5% to 55.8%, and reduces number of stops by 69.5%, compared with the traditional DLT.

Effects of turning and through lane sharing on traffic performance at intersections

Science.gov (United States)

Li, Xiang; Sun, Jian-Qiao

2016-02-01

Turning vehicles strongly influence traffic flows at intersections. Effective regulation of turning vehicles is important to achieve better traffic performance. This paper studies the impact of lane sharing and turning signals on traffic performance at intersections by using cellular automata. Both right-turn and left-turn lane sharing are studied. Interactions between vehicles and pedestrians are considered. The transportation efficiency, road safety and energy economy are the traffic performance metrics. Extensive simulations are carried out to study the traffic performance indices. It is observed that shared turning lanes and permissive left-turn signal improve the transportation efficiency and reduce the fuel consumption in most cases, but the safety is usually sacrificed. It is not always beneficial for the through vehicles when they are allowed to be in the turning lanes.

Broad targeting of resistance to apoptosis in cancer

Science.gov (United States)

Mohammad, Ramzi M.; Muqbil, Irfana; Lowe, Leroy; Yedjou, Clement; Hsu, Hsue-Yin; Lin, Liang-Tzung; Siegelin, Markus David; Fimognari, Carmela; Kumar, Nagi B.; Dou, Q. Ping; Yang, Huanjie; Samadi, Abbas K.; Russo, Gian Luigi; Spagnuolo, Carmela; Ray, Swapan K.; Chakrabarti, Mrinmay; Morre, James D.; Coley, Helen M.; Honoki, Kanya; Fujii, Hiromasa; Georgakilas, Alexandros G.; Amedei, Amedeo; Niccolai, Elena; Amin, Amr; Ashraf, S. Salman; Helferich, William G.; Yang, Xujuan; Boosani, Chandra S.; Guha, Gunjan; Bhakta, Dipita; Ciriolo, Maria Rosa; Aquilano, Katia; Chen, Sophie; Mohammed, Sulma I.; Keith, W. Nicol; Bilsland, Alan; Halicka, Dorota; Nowsheen, Somaira; Azmi, Asfar S.

2015-01-01

Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer. PMID:25936818

L'intersectionnalité contre l'intersection

NARCIS (Netherlands)

Chauvin, S.; Jaunait, A.

2015-01-01

Intersectionality against intersection. Is the notion of intersectionality doomed to being part of the problem it designates? Intersectionality theory was not developed to merely point at intersections but to capture subject positions made invisible by dominant systems of normative representation.

Vehicular crash data used to rank intersections by injury crash frequency and severity

Directory of Open Access Journals (Sweden)

Yi Liu

2016-09-01

Full Text Available This article contains data on research conducted in “A double standard model for allocating limited emergency medical service vehicle resources ensuring service reliability” (Liu et al., 2016 [1]. The crash counts were sorted out from comprehensive crash records of over one thousand major signalized intersections in the city of Chicago from 2004 to 2010. For each intersection, vehicular crashes were counted by crash severity levels, including fatal, injury Types A, B, and C for major, moderate, and minor injury levels, property damage only (PDO, and unknown. The crash data was further used to rank intersections by equivalent injury crash frequency. The top 200 intersections with the highest number of crash occurrences identified based on crash frequency- and severity-based scenarios are shared in this brief. The provided data would be a valuable source for research in urban traffic safety analysis and could also be utilized to examine the effectiveness of traffic safety improvement planning and programming, intersection design enhancement, incident and emergency management, and law enforcement strategies.

Bortezomib induces apoptosis and suppresses cell growth and metastasis by inactivation of Stat3 signaling in chondrosarcoma.

Science.gov (United States)

Bao, Xing; Ren, Tingting; Huang, Yi; Ren, Chongmin; Yang, Kang; Zhang, Hongliang; Guo, Wei

2017-02-01

Bortezomib, formerly known as PS341, is a novel proteasome inhibitor with in vitro and in vivo antineoplastic effects in many malignancies. However, diverse antitumor mechanisms of bortezomib have been identified in many investigations and preclinical studies. Understanding the molecular and cellular mechanisms through which bortezomib acts will improve the therapeutic utility of this drug in different cancer types. In the present study, we investigated the in vitro and in vivo effects of bortezomib on chondrosarcoma. Bortezomib selectively inhibited cell growth in chondrosarcoma cells but not in normal articular cartilage cells. In addition to growth inhibition, apoptosis and cell cycle arrest, bortezomib triggered alleviation of migratory and invasive properties of chondrosarcoma cells. Mechanistically, signal transducer and activator of transcription 3 (Stat3) and its downstream targets Bcl-2, cyclin D1 and c-Myc was inactivated by bortezomib treatment. Accordingly, small interfering RNA (siRNA)-mediated Stat3 knockdown enhanced bortezomib-induced apoptosis, and concomitantly enhanced the inhibitory effect of bortezomib on cell viability, migration and invasion. Moreover, while Slug, MMP9, MMP2, CD44, N-cadherin and vimentin, the mesenchymal cell markers, were repressed by bortezomib concomitant increased expression of E-cadherin was observed. In vivo, bortezomib downregulated Stat3 activity and mesenchymal cell marker expression, induced apoptosis and inhibition of metastasis and tumor growth. Together, inactivation of Stat3 signaling contributes to bortezomib-induced inhibition of tumor growth, migration and invation on chondrosarcoma. Bortezomib demonstrates an antineoplastic role on chondrosarcoma both in vitro and in vivo. These beneficial effects can be explained by bortezomib-mediated Stat3 supression. The present study suggests a promising therapeutics target in chondrosarcoma and probably in other kinds of metastatic malignant tumors.

Hsp27 regulates Akt activation and polymorphonuclear leukocyte apoptosis by scaffolding MK2 to Akt signal complex.

Science.gov (United States)

Wu, Rui; Kausar, Hina; Johnson, Paul; Montoya-Durango, Diego E; Merchant, Michael; Rane, Madhavi J

2007-07-27

We have shown previously that Akt exists in a signal complex with p38 MAPK, MAPK-activated protein kinase-2 (MK2), and heat shock protein 27 (Hsp27) and MK2 phosphorylates Akt on Ser-473. Additionally, dissociation of Hsp27 from Akt, prior to Akt activation, induced polymorphonuclear leukocyte (PMN) apoptosis. However, the role of Hsp27 in regulating Akt activation was not examined. This study tested the hypothesis that Hsp27 regulates Akt activation and promotes cell survival by scaffolding MK2 to the Akt signal complex. Here we show that loss of Akt/Hsp27 interaction by anti-Hsp27 antibody treatment resulted in loss of Akt/MK2 interaction, loss of Akt-Ser-473 phosphorylation, and induced PMN apoptosis. Transfection of myristoylated Akt (AktCA) in HK-11 cells induced Akt-Ser-473 phosphorylation, activation, and Hsp27-Ser-82 phosphorylation. Cotransfection of AktCA with Hsp27 short interfering RNA, but not scrambled short interfering RNA, silenced Hsp27 expression, without altering Akt expression in HK-11 cells. Silencing Hsp27 expression inhibited Akt/MK2 interaction, inhibited Akt phosphorylation and Akt activation, and induced HK-11 cell death. Deletion mutagenesis studies identified acidic linker region (amino acids 117-128) on Akt as an Hsp27 binding region. Deletion of amino acids 117-128 on Akt resulted in loss of its interaction with Hsp27 and MK2 but not with Hsp90 as demonstrated by immunoprecipitation and glutathione S-transferase pulldown studies. Co-transfection studies demonstrated that constitutively active MK2 (MK2EE) phosphorylated Aktwt (wild type) on Ser-473 but failed to phosphorylate Akt(Delta117-128) mutant in transfixed cells. These studies collectively define a novel role of Hsp27 in regulating Akt activation and cellular apoptosis by mediating interaction between Akt and its upstream activator MK2.

Vehicular traffic flow at an intersection with the possibility of turning

International Nuclear Information System (INIS)

Foulaadvand, M Ebrahim; Belbasi, Somayyeh

2011-01-01

We have developed a Nagel-Schreckenberg cellular automata model for describing a vehicular traffic flow at a single intersection. A set of traffic lights operating in a fixed-time scheme controls the traffic flow. An open boundary condition is applied to the streets each of which conducts a unidirectional flow. Streets are single lane and cars can turn upon reaching to the intersection with prescribed probabilities. Extensive Monte Carlo simulations are carried out to find the model flow characteristics. In particular, we investigate the flow dependence on signalization parameters, turning probabilities and input rates. It is shown that for each set of parameters, there exists a plateau region inside which the total outflow from the intersection remains almost constant. We also compute total waiting time of vehicles per cycle behind red lights for various control parameters.

Methylcobalamin promotes proliferation and migration and inhibits apoptosis of C2C12 cells via the Erk1/2 signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Okamoto, Michio [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Tanaka, Hiroyuki, E-mail: tanahiro-osk@umin.ac.jp [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Okada, Kiyoshi [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Kuroda, Yusuke [Department of Orthopaedic Surgery, Kansai Rosai Hospital, 3-1-69 Inabaso, Amagasaki, Hyogo 660-8511 (Japan); Nishimoto, Shunsuke; Murase, Tsuyoshi; Yoshikawa, Hideki [Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)

2014-01-17

Highlights: •Methylcobalamin activated the Erk1/2 signaling pathway in C2C12 cells. •Methylcobalamin promoted the proliferation and migration in C2C12 cells. •C2C12 cell apoptosis during differentiation was inhibited by methylcobalamin. -- Abstract: Methylcobalamin (MeCbl) is a vitamin B12 analog that has some positive effects on peripheral nervous disorders. Although some previous studies revealed the effects of MeCbl on neurons, its effect on the muscle, which is the final target of motoneuron axons, remains to be elucidated. This study aimed to determine the effect of MeCbl on the muscle. We found that MeCbl promoted the proliferation and migration of C2C12 myoblasts in vitro and that these effects are mediated by the Erk1/2 signaling pathway without affecting the activity of the Akt signaling pathway. We also demonstrated that MeCbl inhibits C2C12 cell apoptosis during differentiation. Our results suggest that MeCbl has beneficial effects on the muscle in vitro. MeCbl administration may provide a novel therapeutic approach for muscle injury or degenerating muscle after denervation.

ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.

Science.gov (United States)

Darling, Nicola J; Balmanno, Kathryn; Cook, Simon J

2017-01-01

Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.

ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death.

Directory of Open Access Journals (Sweden)

Nicola J Darling

Full Text Available Disruption of protein folding in the endoplasmic reticulum (ER causes ER stress. Activation of the unfolded protein response (UPR acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2 signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway.

Role of DNA mismatch repair and p53 in signaling induction of apoptosis by alkylating agents

OpenAIRE

Hickman, Mark J.; Samson, Leona D.

1999-01-01

All cells are unavoidably exposed to chemicals that can alkylate DNA to form genotoxic damage. Among the various DNA lesions formed, O6-alkylguanine lesions can be highly cytotoxic, and we recently demonstrated that O6-methylguanine (O6MeG) and O6-chloroethylguanine (O6CEG) specifically initiate apoptosis in hamster cells. Here we show, in both hamster and human cells, that the MutSα branch of the DNA mismatch repair pathway (but not the MutSβ branch) is absolutely required for signaling the ...

Honokiol inhibits sphere formation and xenograft growth of oral cancer side population cells accompanied with JAK/STAT signaling pathway suppression and apoptosis induction

International Nuclear Information System (INIS)

Huang, Jhy-Shrian; Yao, Chih-Jung; Chuang, Shuang-En; Yeh, Chi-Tai; Lee, Liang-Ming; Chen, Ruei-Ming; Chao, Wan-Ju; Whang-Peng, Jacqueline; Lai, Gi-Ming

2016-01-01

Eliminating cancer stem cells (CSCs) has been suggested for prevention of tumor recurrence and metastasis. Honokiol, an active compound of Magnolia officinalis, had been proposed to be a potential candidate drug for cancer treatment. We explored its effects on the elimination of oral CSCs both in vitro and in vivo. By using the Hoechst side population (SP) technique, CSCs-like SP cells were isolated from human oral squamous cell carcinoma (OSCC) cell lines, SAS and OECM-1. Effects of honokiol on the apoptosis and signaling pathways of SP-derived spheres were examined by Annexin V/Propidium iodide staining and Western blotting, respectively. The in vivo effectiveness was examined by xenograft mouse model and immunohistochemical tissue staining. The SP cells possessed higher stemness marker expression (ABCG2, Ep-CAM, Oct-4 and Nestin), clonogenicity, sphere formation capacity as well as tumorigenicity when compared to the parental cells. Treatment of these SP-derived spheres with honokiol resulted in apoptosis induction via Bax/Bcl-2 and caspase-3-dependent pathway. This apoptosis induction was associated with marked suppression of JAK2/STAT3, Akt and Erk signaling pathways in honokiol-treated SAS spheres. Consistent with its effect on JAK2/STAT3 suppression, honokiol also markedly inhibited IL-6-mediated migration of SAS cells. Accordingly, honokiol dose-dependently inhibited the growth of SAS SP xenograft and markedly reduced the immunohistochemical staining of PCNA and endothelial marker CD31 in the xenograft tumor. Honokiol suppressed the sphere formation and xenograft growth of oral CSC-like cells in association with apoptosis induction and inhibition of survival/proliferation signaling pathways as well as angiogenesis. These results suggest its potential as an integrative medicine for combating oral cancer through targeting on CSCs. The online version of this article (doi:10.1186/s12885-016-2265-6) contains supplementary material, which is available to

Melatonin Inhibits Neural Cell Apoptosis and Promotes Locomotor Recovery via Activation of the Wnt/β-Catenin Signaling Pathway After Spinal Cord Injury.

Science.gov (United States)

Shen, Zhaoliang; Zhou, Zipeng; Gao, Shuang; Guo, Yue; Gao, Kai; Wang, Haoyu; Dang, Xiaoqian

2017-08-01

The spinal cord is highly sensitive to spinal cord injury (SCI) by external mechanical damage, resulting in irreversible neurological damage. Activation of the Wnt/β-catenin signaling pathway can effectively reduce apoptosis and protect against SCI. Melatonin, an indoleamine originally isolated from bovine pineal tissue, exerts neuroprotective effects after SCI through activation of the Wnt/β-catenin signaling pathway. In this study, we demonstrated that melatonin exhibited neuroprotective effects on neuronal apoptosis and supported functional recovery in a rat SCI model by activating the Wnt/β-catenin signaling pathway. We found that melatonin administration after SCI significantly upregulated the expression of low-density lipoprotein receptor related protein 6 phosphorylation (p-LRP-6), lymphoid enhancer factor-1 (LEF-1) and β-catenin protein in the spinal cord. Melatonin enhanced motor neuronal survival in the spinal cord ventral horn and improved the locomotor functions of rats after SCI. Melatonin administration after SCI also reduced the expression levels of Bax and cleaved caspase-3 in the spinal cord and the proportion of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) positive cells, but increased the expression level of Bcl-2. These results suggest that melatonin attenuated SCI by activating the Wnt/β-catenin signaling pathway.

Propolis augments apoptosis induced by butyrate via targeting cell survival pathways.

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Eric Drago

Full Text Available Diet is one of the major lifestyle factors affecting incidence of colorectal cancer (CC, and despite accumulating evidence that numerous diet-derived compounds modulate CC incidence, definitive dietary recommendations are not available. We propose a strategy that could facilitate the design of dietary supplements with CC-preventive properties. Thus, nutrient combinations that are a source of apoptosis-inducers and inhibitors of compensatory cell proliferation pathways (e.g., AKT signaling may produce high levels of programmed death in CC cells. Here we report the combined effect of butyrate, an apoptosis inducer that is produced through fermentation of fiber in the colon, and propolis, a honeybee product, on CC cells. We established that propolis increases the apoptosis of CC cells exposed to butyrate through suppression of cell survival pathways such as the AKT signaling. The programmed death of CC cells by combined exposure to butyrate and propolis is further augmented by inhibition of the JNK signaling pathway. Analyses on the contribution of the downstream targets of JNK signaling, c-JUN and JAK/STAT, to the apoptosis of butyrate/propolis-treated CC cells ascertained that JAK/STAT signaling has an anti-apoptotic role; whereas, the role of cJUN might be dependent upon regulatory cell factors. Thus, our studies ascertained that propolis augments apoptosis of butyrate-sensitive CC cells and re-sensitizes butyrate-resistant CC cells to apoptosis by suppressing AKT signaling and downregulating the JAK/STAT pathway. Future in vivo studies should evaluate the CC-preventive potential of a dietary supplement that produces high levels of colonic butyrate, propolis, and diet-derived JAK/STAT inhibitors.

X-linked inhibitor of apoptosis regulates T cell effector function

DEFF Research Database (Denmark)

Zehntner, Simone P; Bourbonnière, Lyne; Moore, Craig S

2007-01-01

To understand how the balance between pro- and anti-apoptotic signals influences effector function in the immune system, we studied the X-linked inhibitor of apoptosis (XIAP), an endogenous regulator of cellular apoptosis. Real-time PCR showed increased XIAP expression in blood of mice with exper......To understand how the balance between pro- and anti-apoptotic signals influences effector function in the immune system, we studied the X-linked inhibitor of apoptosis (XIAP), an endogenous regulator of cellular apoptosis. Real-time PCR showed increased XIAP expression in blood of mice...... dramatically reduced within the CNS. Flow cytometry showed an 88-93% reduction in T cells. The proportion of TUNEL(+) apoptotic CD4(+) T cells in the CNS was increased from Neurons...... and oligodendrocytes were not affected; neither did apoptosis increase in liver, where XIAP knockdown also occurred. ASO-XIAP increased susceptibility of T cells to activation-induced apoptosis in vitro. Our results identify XIAP as a critical controller of apoptotic susceptibility of effector T cell function...

Pomegranate Bioactive Constituents Suppress Cell Proliferation and Induce Apoptosis in an Experimental Model of Hepatocellular Carcinoma: Role of Wnt/β-Catenin Signaling Pathway

Directory of Open Access Journals (Sweden)

Deepak Bhatia

2013-01-01

Full Text Available Hepatocellular carcinoma (HCC is the third leading cause of cancer-related death worldwide, and chemoprevention represents a viable approach in lowering the mortality of this disease. Pomegranate fruit, an abundant source of anti-inflammatory phytochemicals, is gaining tremendous attention for its wide-spectrum health benefits. We previously reported that a characterized pomegranate emulsion (PE prevents diethylnitrosamine (DENA-induced rat hepatocarcinogenesis though inhibition of nuclear factor-kappaB (NF-κB. Since NF-κB concurrently induces Wnt/β-catenin signaling implicated in cell proliferation, cell survival, and apoptosis evasion, we examined antiproliferative, apoptosis-inducing and Wnt/β-catenin signaling-modulatory mechanisms of PE during DENA rat hepatocarcinogenesis. PE (1 or 10 g/kg was administered 4 weeks before and 18 weeks following DENA exposure. There was a significant increase in hepatic proliferation (proliferating cell nuclear antigen and alteration in cell cycle progression (cyclin D1 due to DENA treatment, and PE dose dependently reversed these effects. PE substantially induced apoptosis by upregulating proapoptotic protein Bax and downregulating antiapoptotic protein Bcl-2. PE dose dependently reduced hepatic β-catenin and augmented glycogen synthase kinase-3β expression. Our study provides evidence that pomegranate phytochemicals exert chemoprevention of hepatic cancer through antiproliferative and proapoptotic mechanisms by modulating Wnt/β-catenin signaling. PE, thus, targets two interconnected molecular circuits (canonical NF-κB and Wnt/β-catenin pathways to exert chemoprevention of HCC.

Intersectionality research in counseling psychology.

Science.gov (United States)

Grzanka, Patrick R; Santos, Carlos E; Moradi, Bonnie

2017-10-01

This article introduces the special section on intersectionality research in counseling psychology. Across the 4 manuscripts that constitute this special section, a clear theme emerges: a need to return to the roots and politics of intersectionality. Importantly, the 2 empirical articles in this special section (Jerald, Cole, Ward, & Avery, 2017; Lewis, Williams, Peppers, & Gadson, 2017) are studies of Black women's experiences: a return, so to speak, to the subject positions and social locations from which intersectionality emanates. Shin et al. (2017) explore why this focus on Black feminist thought and social justice is so important by highlighting the persistent weaknesses in how much research published in leading counseling psychology journals has tended to use intersectionality as a way to talk about multiple identities, rather than as a framework for critiquing systemic, intersecting forms of oppression and privilege. Shin and colleagues also point to the possibilities intersectionality affords us when scholars realize the transformative potential of this critical framework. Answers to this call for transformative practices are foregrounded in Moradi and Grzanka's (2017) contribution, which surveys the interdisciplinary literature on intersectionality and presents a series of guidelines for using intersectionality responsibly. We close with a discussion of issues concerning the applications of intersectionality to counseling psychology research that spans beyond the contributions of each manuscript in this special section. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/β-catenin signaling in an Alzheimer's disease model

Energy Technology Data Exchange (ETDEWEB)

Yao, Yingjia [School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600 (China); Gao, Zhong [Department of Interventional Therapy, Dalian Municipal Central Hospital, Dalian 116033 (China); Liang, Wenbo [Medical College of Dalian University, Dalian 116600, Liaoning (China); Kong, Liang; Jiao, Yanan; Li, Shaoheng; Tao, Zhenyu; Yan, Yuhui [School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600 (China); Yang, Jingxian, E-mail: jingxianyang@yahoo.com [School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600 (China)

2015-12-15

Neurogenesis is the process by which neural stem cells (NSCs) proliferate and differentiate into neurons. This is diminished in several neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by the deposition of amyloid (A)β peptides and neuronal loss. Stimulating NSCs to replace lost neurons is therefore a promising approach for AD treatment. Our previous study demonstrated that osthole modulates NSC proliferation and differentiation, and may reduce Aβ protein expression in nerve cells. Here we investigated the mechanism underlying the effects of osthole on NSCs. We found that osthole enhances NSC proliferation and neuronal differentiation while suppressing apoptosis, effects that were exerted via activation of Wnt/β-catenin signaling. These results provide evidence that osthole can potentially be used as a therapeutic agent in the treatment of AD and other neurodegenerative disorders. - Highlights: • An Alzheimer's disease model was successfully established by transfecting APP gene into neural stem cells in vitro. • Roles of osthole in experimental AD cells were studied. • Osthole promotes proliferation and differentiation into neurons and inhibits accumulation of Aβ{sub 1–42} peptide and apoptosis. • Osthole exerts protection via Wnt/β-catenin signaling pathway.

Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/β-catenin signaling in an Alzheimer's disease model

International Nuclear Information System (INIS)

Yao, Yingjia; Gao, Zhong; Liang, Wenbo; Kong, Liang; Jiao, Yanan; Li, Shaoheng; Tao, Zhenyu; Yan, Yuhui; Yang, Jingxian

2015-01-01

Neurogenesis is the process by which neural stem cells (NSCs) proliferate and differentiate into neurons. This is diminished in several neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by the deposition of amyloid (A)β peptides and neuronal loss. Stimulating NSCs to replace lost neurons is therefore a promising approach for AD treatment. Our previous study demonstrated that osthole modulates NSC proliferation and differentiation, and may reduce Aβ protein expression in nerve cells. Here we investigated the mechanism underlying the effects of osthole on NSCs. We found that osthole enhances NSC proliferation and neuronal differentiation while suppressing apoptosis, effects that were exerted via activation of Wnt/β-catenin signaling. These results provide evidence that osthole can potentially be used as a therapeutic agent in the treatment of AD and other neurodegenerative disorders. - Highlights: • An Alzheimer's disease model was successfully established by transfecting APP gene into neural stem cells in vitro. • Roles of osthole in experimental AD cells were studied. • Osthole promotes proliferation and differentiation into neurons and inhibits accumulation of Aβ 1–42 peptide and apoptosis. • Osthole exerts protection via Wnt/β-catenin signaling pathway.

INTERSECTIONAL DISCRIMINATION AGAINST CHILDREN

DEFF Research Database (Denmark)

Ravnbøl, Camilla Ida

This paper adds a perspective to existing research on child protection by engaging in a debate on intersectional discrimination and its relationship to child protection. The paper has a twofold objective, (1) to further establish intersectionality as a concept to address discrimination against...... children, and (2) to illustrate the importance of addressing intersectionality within rights-based programmes of child protection....

Electromagnetic radiation at 900 MHz induces sperm apoptosis through bcl-2, bax and caspase-3 signaling pathways in rats.

Science.gov (United States)

Liu, Qi; Si, Tianlei; Xu, Xiaoyun; Liang, Fuqiang; Wang, Lufeng; Pan, Siyi

2015-08-04

The decreased reproductive capacity of men is an important factor contributing to infertility. Accumulating evidence has shown that Electromagnetic radiation potentially has negative effects on human health. However, whether radio frequency electromagnetic radiation (RF-EMR) affects the human reproductive system still requires further investigation. Therefore, The present study investigates whether RF-EMR at a frequency of 900 MHz can trigger sperm cell apoptosis and affect semen morphology, concentration, and microstructure. Twenty four rats were exposed to 900 MHz electromagnetic radiation with a special absorption rate of 0.66 ± 0.01 W/kg for 2 h/d. After 50d, the sperm count, morphology, apoptosis, reactive oxygen species (ROS), and total antioxidant capacity (TAC), representing the sum of enzymatic and nonenzymatic antioxidants, were investigated. Western blotting and reverse transcriptase PCR were used to determine the expression levels of apoptosis-related proteins and genes, including bcl-2, bax, cytochrome c, and capase-3. In the present study, the percentage of apoptotic sperm cells in the exposure group was significantly increased by 91.42% compared with the control group. Moreover, the ROS concentration in exposure group was increased by 46.21%, while the TAC was decreased by 28.01%. Radiation also dramatically decreased the protein and mRNA expression of bcl-2 and increased that of bax, cytochrome c, and capase-3. RF-EMR increases the ROS level and decreases TAC in rat sperm. Excessive oxidative stress alters the expression levels of apoptosis-related genes and triggers sperm apoptosis through bcl-2, bax, cytochrome c and caspase-3 signaling pathways.

Licochalcone A induces apoptosis in KB human oral cancer cells via a caspase-dependent FasL signaling pathway.

Science.gov (United States)

Kim, Jae-Sung; Park, Mi-Ra; Lee, Sook-Young; Kim, Do Kyoung; Moon, Sung-Min; Kim, Chun Sung; Cho, Seung Sik; Yoon, Goo; Im, Hee-Jeong; You, Jae-Seek; Oh, Ji-Su; Kim, Su-Gwan

2014-02-01

Licochalcone A (Lico-A) is a natural phenol licorice compound with multiple bioactivities, including anti-inflammatory, anti-microbial, anti-fungal and osteogenesis-inducing properties. In the present study, we investigated the Lico-A-induced apoptotic effects and examined the associated apoptosis pathway in KB human oral cancer cells. Lico-A decreased the number of viable KB oral cancer cells. However, Lico-A did not have an effect on primary normal human oral keratinocytes. In addition, the IC50 value of Lico-A was determined to be ~50 µM following dose-dependent stimulation. KB oral cancer cells stimulated with Lico-A for 24 h showed chromatin condensation by DAPI staining, genomic DNA fragmentation by agarose gel electrophoresis and a gradually increased apoptotic cell population by FACS analysis. These data suggest that Lico-A induces apoptosis in KB oral cancer cells. Additionally, Lico‑A‑induced apoptosis in KB oral cancer cells was mediated by the expression of factor associated suicide ligand (FasL) and activated caspase-8 and -3 and poly(ADP-ribose) polymerase (PARP). Furthermore, in the KB oral cancer cells co-stimulation with a caspase inhibitor (Z-VAD-fmk) and Lico-A significantly abolished the apoptotic phenomena. Our findings demonstrated that Lico‑A-induced apoptosis in KB oral cancer cells involves the extrinsic apoptotic signaling pathway, which involves a caspase-dependent FasL-mediated death receptor pathway. Our data suggest that Lico-A be developed as a chemotherapeutic agent for the management of oral cancer.

Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Zhang, Jian, E-mail: zhangjian197011@yahoo.com [Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China); Zhang, Tao [Department of Thoracic Surgery, Tangdu Hospital, The Fourth Military Medical University, Xi' an 710038 (China); Ti, Xinyu; Shi, Jieran; Wu, Changgui; Ren, Xinling [Department of Respiratory Medicine, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China); Yin, Hong, E-mail: yinnhong@yahoo.com [The Medical Image Center, Xijing Hospital, The Fourth Military Medical University, Xi' an 710032 (China)

2010-08-13

Research highlights: {yields} Curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells {yields} Curcumin promotes apoptosis in A549/DDP cells through a miRNA signaling pathway {yields} Curcumin induces A549/DDP cell apoptosis by downregulating miR-186* {yields} miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin -- Abstract: Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186* in A549/DDP. In addition, transfection of cells with a miR-186* inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186* significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway

International Nuclear Information System (INIS)

Zhang, Jian; Zhang, Tao; Ti, Xinyu; Shi, Jieran; Wu, Changgui; Ren, Xinling; Yin, Hong

2010-01-01

Research highlights: → Curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells → Curcumin promotes apoptosis in A549/DDP cells through a miRNA signaling pathway → Curcumin induces A549/DDP cell apoptosis by downregulating miR-186* → miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin -- Abstract: Curcumin extracted from the rhizomes of Curcuma longa L. has been shown to have inhibitory effects on cancers through its anti-proliferative and pro-apoptotic activities. Emerging evidence demonstrates that curcumin can overcome drug resistance to classical chemotherapies. Thus, the mechanisms underlying the anti-tumor activities of curcumin require further study. In our study, we first demonstrated that curcumin had anti-cancer effects on A549/DDP multidrug-resistant human lung adenocarcinoma cells. Further studies showed that curcumin altered miRNA expression; in particular, significantly downregulated the expression of miR-186* in A549/DDP. In addition, transfection of cells with a miR-186* inhibitor promoted A549/DDP apoptosis, and overexpression of miR-186* significantly inhibited curcumin-induced apoptosis in A549/DDP cells. These observations suggest that miR-186* may serve as a potential gene therapy target for refractory lung cancer that is sensitive to curcumin.

Ghrelin inhibits the apoptosis of MC3T3-E1 cells through ERK and AKT signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Liang, Qiu-Hua; Liu, Yuan; Wu, Shan-Shan; Cui, Rong-Rong; Yuan, Ling-Qing, E-mail: allenylq@hotmail.com; Liao, Er-Yuan, E-mail: eyliao@21cn.com

2013-11-01

Ghrelin is a 28-amino-acid peptide that acts as a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR) and strongly stimulates the release of growth hormone from the hypothalamus–pituitary axis. Previous studies have identified the important physiological effects of ghrelin on bone metabolism, such as regulating proliferation and differentiation of osteoblasts, independent of GH/IGF-1 axis. However, research on effects and mechanisms of ghrelin on osteoblast apoptosis is still rare. In this study, we identified expression of GHSR in MC3T3-E1 cells and determined the effects of ghrelin on the apoptosis of osteoblastic MC3T3-E1 cells and the mechanism involved. Our data demonstrated that ghrelin inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as determined by terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate nick end-labeling (TUNEL) and ELISA assays. Moreover, ghrelin upregulated Bcl-2 expression and downregulated Bax expression in a dose-dependent manner. Our study also showed decreased activated caspase-3 activity under the treatment of ghrelin. Further study suggested that ghrelin stimulated the phosphorylation of ERK and AKT. Pretreatment of cells with the ERK inhibitor PD98059, PI3K inhibitor LY294002, and GHSR-siRNA blocked the ghrelin-induced activation of ERK and AKT, respectively; however, ghrelin did not stimulate the phosphorylation of p38 or JNK. PD90859, LY294002 and GHSR-siRNA attenuated the anti-apoptosis effect of ghrelin in MC3T3-E1 cells. In conclusion, ghrelin inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, which may be mediated by activating the GHSR/ERK and GHSR/PI3K/AKT signaling pathways. - Highlights: • We explored the effects of ghrelin on serum deprivation-induced MC3T3-E1 cells apoptosis. • Both ELISA and TUNEL were used to detect the apoptosis. • The receptor of ghrelin, GHSR, was expressed in MC3T3-E1

Ghrelin inhibits the apoptosis of MC3T3-E1 cells through ERK and AKT signaling pathway

International Nuclear Information System (INIS)

Liang, Qiu-Hua; Liu, Yuan; Wu, Shan-Shan; Cui, Rong-Rong; Yuan, Ling-Qing; Liao, Er-Yuan

2013-01-01

Ghrelin is a 28-amino-acid peptide that acts as a natural endogenous ligand of the growth hormone secretagogue receptor (GHSR) and strongly stimulates the release of growth hormone from the hypothalamus–pituitary axis. Previous studies have identified the important physiological effects of ghrelin on bone metabolism, such as regulating proliferation and differentiation of osteoblasts, independent of GH/IGF-1 axis. However, research on effects and mechanisms of ghrelin on osteoblast apoptosis is still rare. In this study, we identified expression of GHSR in MC3T3-E1 cells and determined the effects of ghrelin on the apoptosis of osteoblastic MC3T3-E1 cells and the mechanism involved. Our data demonstrated that ghrelin inhibited the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, as determined by terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate nick end-labeling (TUNEL) and ELISA assays. Moreover, ghrelin upregulated Bcl-2 expression and downregulated Bax expression in a dose-dependent manner. Our study also showed decreased activated caspase-3 activity under the treatment of ghrelin. Further study suggested that ghrelin stimulated the phosphorylation of ERK and AKT. Pretreatment of cells with the ERK inhibitor PD98059, PI3K inhibitor LY294002, and GHSR-siRNA blocked the ghrelin-induced activation of ERK and AKT, respectively; however, ghrelin did not stimulate the phosphorylation of p38 or JNK. PD90859, LY294002 and GHSR-siRNA attenuated the anti-apoptosis effect of ghrelin in MC3T3-E1 cells. In conclusion, ghrelin inhibits the apoptosis of osteoblastic MC3T3-E1 cells induced by serum deprivation, which may be mediated by activating the GHSR/ERK and GHSR/PI3K/AKT signaling pathways. - Highlights: • We explored the effects of ghrelin on serum deprivation-induced MC3T3-E1 cells apoptosis. • Both ELISA and TUNEL were used to detect the apoptosis. • The receptor of ghrelin, GHSR, was expressed in MC3T3-E1

Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

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Radhakrishnan Sridhar

2010-05-01

Full Text Available Abstract Background Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene, a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. Methods We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Results Resveratrol (100-150 μM exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G0/G1-S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. Conclusions For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and

Resveratrol suppresses IGF-1 induced human colon cancer cell proliferation and elevates apoptosis via suppression of IGF-1R/Wnt and activation of p53 signaling pathways

International Nuclear Information System (INIS)

Vanamala, Jairam; Reddivari, Lavanya; Radhakrishnan, Sridhar; Tarver, Chris

2010-01-01

Obesity is a global phenomenon and is associated with various types of cancer, including colon cancer. There is a growing interest for safe and effective bioactive compounds that suppress the risk for obesity-promoted colon cancer. Resveratrol (trans-3, 4', 5,-trihydroxystilbene), a stilbenoid found in the skin of red grapes and peanuts suppresses many types of cancers by regulating cell proliferation and apoptosis through a variety of mechanisms, however, resveratrol effects on obesity-promoted colon cancer are not clearly established. We investigated the anti-proliferative effects of resveratrol on HT-29 and SW480 human colon cancer cells in the presence and absence of insulin like growth factor-1 (IGF-1; elevated during obesity) and elucidated the mechanisms of action using IGF-1R siRNA in HT-29 cells which represents advanced colon carcinogenesis. Resveratrol (100-150 μM) exhibited anti-proliferative properties in HT-29 cells even after IGF-1 exposure by arresting G 0 /G 1 -S phase cell cycle progression through p27 stimulation and cyclin D1 suppression. Treatment with resveratrol suppressed IGF-1R protein levels and concurrently attenuated the downstream Akt/Wnt signaling pathways that play a critical role in cell proliferation. Targeted suppression of IGF-1R using IGF-1R siRNA also affected these signaling pathways in a similar manner. Resveratrol treatment induced apoptosis by activating tumor suppressor p53 protein, whereas IGF-1R siRNA treatment did not affect apoptosis. Our data suggests that resveratrol not only suppresses cell proliferation by inhibiting IGF-1R and its downstream signaling pathways similar to that of IGF-1R siRNA but also enhances apoptosis via activation of the p53 pathway. For the first time, we report that resveratrol suppresses colon cancer cell proliferation and elevates apoptosis even in the presence of IGF-1 via suppression of IGF-1R/Akt/Wnt signaling pathways and activation of p53, suggesting its potential role as a

Proposition of delay model for signalized intersections with queueing theory analytical models usage

Directory of Open Access Journals (Sweden)

Grzegorz SIERPIŃSKI

2007-01-01

Full Text Available Time delay on intersections is a very important transport problem. Thearticle includes a proposition of time delay model. Variance of service times is considered by used average waiting time in queue for queuing system with compressed queuing processes usage as a part of proposed time delays model.

Signal transducers and activators of transcription as regulators of growth, apoptosis and breast development

International Nuclear Information System (INIS)

Bromberg, Jacqueline

2000-01-01

STAT transcription factors were discovered 10 years ago as mediators of interferon-induced gene expression. They now form an important group, comprising seven members, that are activated by virtually every cytokine and growth factor. Their critical role in development and normal cell signaling has been largely determined through the analysis of transgenic mice lacking individual STAT genes. In addition, cell culture work has further delineated their importance in cellular transformation, apoptosis, differentiation and growth control. This review discusses the specific phenotypes of STAT-deficient animals with a focus on STAT5 and STAT3, as these two STAT molecules are required for normal breast development and involution, respectively, and may play an important role in breast carcinogenesis

Inhibition of phospholipaseD2 increases hypoxia-induced human colon cancer cell apoptosis through inactivating of the PI3K/AKT signaling pathway.

Science.gov (United States)

Liu, Maoxi; Fu, Zhongxue; Wu, Xingye; Du, Kunli; Zhang, Shouru; Zeng, Li

2016-05-01

Hypoxia is a common feature of solid tumor, and is a direct stress that triggers apoptosis in many human cell types. As one of solid cancer, hypoxia exists in the whole course of colon cancer occurrence and progression. Our previous studies shown that hypoxia induce high expression of phospholipase D2 (PLD2) and survivin in colon cancer cells. However, the correlation between PLD2 and survivin in hypoxic colon cancer cells remains unknown. In this study, we observed significantly elevated PLD2 and survivin expression levels in colon cancer tissues and cells. This is a positive correlation between of them, and co-expression of PLD2 and survivin has a positive correlation with the clinicpatholic features including tumor size, TNM stage, and lymph node metastasis. We also found that hypoxia induced the activity of PLD increased significant mainly caused by PLD2 in colon cancer cells. However, inhibition the activity of PLD2 induced by hypoxia promotes the apoptosis of human colon cancer cells, as well as decreased the expression of apoptosis markers including survivin and bcl2. Moreover, the pharmacological inhibition of PI3K/AKT supported the hypothesis that promotes the apoptosis of hypoxic colon cancer cells by PLD2 activity inhibition may through inactivation of the PI3K/AKT signaling pathway. Furthermore, interference the PLD2 gene expression leaded to the apoptosis of hypoxic colon cancer cells increased and also decreased the expression level of survivin and bcl2 may through inactivation of PI3K/AKT signaling pathway. These results indicated that PLD2 play antiapoptotic role in colon cancer under hypoxic conditions, inhibition of the activity, or interference of PLD2 gene expression will benefit for the treatment of colon cancer patients.

Methylselenium and Prostate Cancer Apoptosis

National Research Council Canada - National Science Library

Lu, Junxuan

2008-01-01

The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of prostate cancer (PCa...

Methylselenium and Prostate Cancer Apoptosis

National Research Council Canada - National Science Library

Lu, Junxuan

2005-01-01

The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of prostate cancer (PCa...

Methylselenium and Prostate Cancer Apoptosis

National Research Council Canada - National Science Library

Lu, Junxuan

2007-01-01

The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of prostate cancer (PCa...

Methylselenium and Prostate Cancer Apoptosis

National Research Council Canada - National Science Library

Lu, Junxuan

2006-01-01

The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of prostate cancer (PCa...

CTGF enhances resistance to 5-FU-mediating cell apoptosis through FAK/MEK/ERK signal pathway in colorectal cancer

Directory of Open Access Journals (Sweden)

Yang K

2016-11-01

Full Text Available Kai Yang, Kai Gao, Gui Hu, Yanguang Wen, Changwei Lin, Xiaorong Li Department of General Surgery, The Third Affiliated Hospital of Central South University, Central South University, Changsha, Hunan, People’s Republic of China Abstract: Colorectal cancer (CRC is one of the most commonly diagnosed cancers among both males and females; the chemotherapy drug 5-fluorouracil (5-FU is one of a doctors’ first lines of defense against CRC. However, therapeutic failures are common because of the emergence of drug resistance. Connective tissue growth factor (CTGF is a secreted protein that binds to integrins, and regulates the invasiveness and metastasis of certain carcinoma cells. Here, we found that CTGF was upregulated in drug-resistant phenotype of human CRC cells. Overexpression of CTGF enhanced the resistance to 5-FU-induced cell apoptosis. Moreover, downregulating the expression of CTGF promoted the curative effect of chemotherapy and blocked the cell cycle in the G1 phase. We also found that CTGF facilitated resistance to 5-FU-induced apoptosis by increasing the expression of B-cell lymphoma-extra large (Bcl-xL and survivin. Then we pharmacologically blocked MEK/ERK signal pathway and assessed 5-FU response by MTT assays. Our current results indicate that the expression of phosphorylated forms of MEK/ERK increased in high CTGF expression cells and MEK inhibited increases in 5-FU-mediated apoptosis of resistant CRC cells. Therefore, our data suggest that MEK/ERK signaling contributes to 5-FU resistance through upstream of CTGF, and supports CRC cell growth. Comprehending the molecular mechanism underlying 5-FU resistance may ultimately aid the fight against CRC. Keywords: connective tissue growth factor, 5-fluorouracil, mitogen-activated protein kinase/extracellular regulated protein kinases, phosphatidyl inositol 3-kinase/serine/threonine kinase Akt, colorectal cancer

Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling.

Science.gov (United States)

Adan, Aysun; Baran, Yusuf

2016-05-01

Fisetin and hesperetin, naturally occurring flavonoids, have been reported as novel antioxidants with chemopreventive/chemotherapeutic potential against various types of cancer. However, their mechanism of action in CML is still unknown. This particular study aims to evaluate the therapeutic potentials of fisetin and hesperetin and their effects on cell proliferation, apoptosis, and cell cycle progression in human K562 CML cells. The results indicated that fisetin and hesperetin inhibited cell proliferation and triggered programmed cell death in these cells. The latter was confırmed by mitochondrial membrane depolarization and an increase in caspase-3 activation. In addition to that, we have detected S and G2/M cell cycle arrests and G0/G1 arrest upon fisetin and hesperetin treatment, respectively. To identify the altered genes and genetic networks in response to fisetin and hesperetin, whole-genome microarray analysis was performed. The microarray gene profiling analysis revealed some important signaling pathways including JAK/STAT pathway, KIT receptor signaling, and growth hormone receptor signaling that were altered upon fisetin and hesperetin treatment. Moreover, microarray data suggested potential candidate genes for targeted CML therapy. Fisetin and hesperetin significantly modulated the expression of genes involved in cell proliferation and division, apoptosis, cell cycle regulation, and other significant cellular processes such as replication, transcription, and translation. In conclusion, our results suggest that fisetin and hesperetin as potential natural agents for CML therapy.

Comparing the effects of infrastructure on bicycling injury at intersections and non-intersections using a case–crossover design

Science.gov (United States)

Harris, M Anne; Reynolds, Conor C O; Winters, Meghan; Cripton, Peter A; Shen, Hui; Chipman, Mary L; Cusimano, Michael D; Babul, Shelina; Brubacher, Jeffrey R; Friedman, Steven M; Hunte, Garth; Monro, Melody; Vernich, Lee; Teschke, Kay

2013-01-01

Background This study examined the impact of transportation infrastructure at intersection and non-intersection locations on bicycling injury risk. Methods In Vancouver and Toronto, we studied adult cyclists who were injured and treated at a hospital emergency department. A case–crossover design compared the infrastructure of injury and control sites within each injured bicyclist's route. Intersection injury sites (N=210) were compared to randomly selected intersection control sites (N=272). Non-intersection injury sites (N=478) were compared to randomly selected non-intersection control sites (N=801). Results At intersections, the types of routes meeting and the intersection design influenced safety. Intersections of two local streets (no demarcated traffic lanes) had approximately one-fifth the risk (adjusted OR 0.19, 95% CI 0.05 to 0.66) of intersections of two major streets (more than two traffic lanes). Motor vehicle speeds less than 30 km/h also reduced risk (adjusted OR 0.52, 95% CI 0.29 to 0.92). Traffic circles (small roundabouts) on local streets increased the risk of these otherwise safe intersections (adjusted OR 7.98, 95% CI 1.79 to 35.6). At non-intersection locations, very low risks were found for cycle tracks (bike lanes physically separated from motor vehicle traffic; adjusted OR 0.05, 95% CI 0.01 to 0.59) and local streets with diverters that reduce motor vehicle traffic (adjusted OR 0.04, 95% CI 0.003 to 0.60). Downhill grades increased risks at both intersections and non-intersections. Conclusions These results provide guidance for transportation planners and engineers: at local street intersections, traditional stops are safer than traffic circles, and at non-intersections, cycle tracks alongside major streets and traffic diversion from local streets are safer than no bicycle infrastructure. PMID:23411678

FoxP3 inhibits proliferation and induces apoptosis of gastric cancer cells by activating the apoptotic signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Ma, Gui-Fen [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Chen, Shi-Yao, E-mail: shiyao_chen@163.com [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai (China); Sun, Zhi-Rong [Department of Anesthesiology, Cancer Center, Fudan University, Shanghai (China); Miao, Qing; Liu, Yi-Mei; Zeng, Xiao-Qing; Luo, Tian-Cheng [Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai (China); Ma, Li-Li; Lian, Jing-Jing [Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai (China); Song, Dong-Li [Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai (China)

2013-01-11

Highlights: Black-Right-Pointing-Pointer The article revealed FoxP3 gene function in gastric cancer firstly. Black-Right-Pointing-Pointer Present the novel roles of FoxP3 in inhibiting proliferation and promoting apoptosis in gastric cancer cells. Black-Right-Pointing-Pointer Overexpression of FoxP3 increased proapoptotic molecules and repressed antiapoptotic molecules. Black-Right-Pointing-Pointer Silencing of FoxP3 reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Black-Right-Pointing-Pointer FoxP3 is sufficient for activating the apoptotic signaling pathway. -- Abstract: Forkhead Box Protein 3 (FoxP3) was identified as a key transcription factor to the occurring and function of the regulatory T cells (Tregs). However, limited evidence indicated its function in tumor cells. To elucidate the precise roles and underlying molecular mechanism of FoxP3 in gastric cancer (GC), we examined the expression of FoxP3 and the consequences of interfering with FoxP3 gene in human GC cell lines, AGS and MKN45, by multiple cellular and molecular approaches, such as immunofluorescence, gene transfection, CCK-8 assay, clone formation assay, TUNEL assay, Flow cytometry, immunoassay and quantities polymerase chain reaction (PCR). As a result, FoxP3 was expressed both in nucleus and cytoplasm of GC cells. Up-regulation of FoxP3 inhibited cell proliferation and promoted cell apoptosis. Overexpression of FoxP3 increased the protein and mRNA levels of proapoptotic molecules, such as poly ADP-ribose polymerase1 (PARP), caspase-3 and caspase-9, and repressed the expression of antiapoptotic molecules, such as cellular inhibitor of apoptosis-1 (c-IAP1) and the long isoform of B cell leukemia/lymphoma-2 (Bcl-2). Furthermore, silencing of FoxP3 by siRNA in GC cells reduced the expression of proapoptotic genes, such as PARP, caspase-3 and caspase-9. Collectively, our findings identify the novel roles of FoxP3 in inhibiting proliferation and inducing apoptosis

A Two-Stage Fuzzy Logic Control Method of Traffic Signal Based on Traffic Urgency Degree

OpenAIRE

Yan Ge

2014-01-01

City intersection traffic signal control is an important method to improve the efficiency of road network and alleviate traffic congestion. This paper researches traffic signal fuzzy control method on a single intersection. A two-stage traffic signal control method based on traffic urgency degree is proposed according to two-stage fuzzy inference on single intersection. At the first stage, calculate traffic urgency degree for all red phases using traffic urgency evaluation module and select t...

The intersection between DNA damage response and cell death pathways.

Science.gov (United States)

Nowsheen, S; Yang, E S

2012-10-01

Apoptosis is a finely regulated process that serves to determine the fate of cells in response to various stresses. One such stress is DNA damage, which not only can signal repair processes but is also intimately involved in regulating cell fate. In this review we examine the relationship between the DNA damage/repair response in cell survival and apoptosis following insults to the DNA. Elucidating these pathways and the crosstalk between them is of great importance, as they eventually contribute to the etiology of human disease such as cancer and may play key roles in determining therapeutic response. This article is part of a Special Issue entitled "Apoptosis: Four Decades Later".

Protective properties of sesamin against fluoride-induced oxidative stress and apoptosis in kidney of carp (Cyprinus carpio) via JNK signaling pathway.

Science.gov (United States)

Cao, Jinling; Chen, Jianjie; Xie, Lingtian; Wang, Jundong; Feng, Cuiping; Song, Jing

2015-10-01

Sesamin, a major lignan derived from sesame seeds, has been reported to have many benefits and medicinal properties. However, its protective effects against fluoride-induced injury in kidney of fish have not been clarified. Previously we found that fluoride exposure caused damage and apoptosis in the kidneys of the common carp, Cyprinus carpio. In this study, the effects of sesamin on renal oxidative stress and apoptosis in fluoride-exposed fish were determined. The results showed that sesamin alleviated significantly fluoride-induced renal damage and apoptosis of carp in a dose-dependent manner, indicated by the histopathological examination and ultrastructural observation. Moreover, treatment with sesamin also inhibited significantly fluoride-induced remarkable enhancement of reactive oxygen species (ROS) production and oxidative stress, such as the increase of lipid peroxidation level and the depletion of intracellular reduced glutathione (GSH) level in kidney. To explore the underlying mechanisms of sesamin action, we found that activities of caspase-3 were notably inhibited by treatment with sesamin in the kidney of fluoride-exposed fish. Sesamin decreased the levels of p-JNK protein in kidney, which in turn inactivated pro-apoptotic signaling events by restoring the balance between mitochondrial pro- and anti-apoptotic Bcl-2 and Bax proteins and by decreasing the release of mitochondrial cytochrome c in kidney of fluoride-exposed fish. JNK was also involved in the mitochondrial extrinsic apoptotic pathways of sesamin effects against fluoride-induced renal injury by regulating the levels of p-c-Jun, necrosis factor-alpha (TNF-α) and Bak proteins. These findings indicated that sesamin could protect kidney against fluoride-induced apoptosis by the oxidative stress downstream-mediated change in the inactivation of JNK signaling pathway. Taken together, sesamin plays an important role in maintaining renal health and preventing kidney from toxic damage induced by

Apoptosis: Targets in Pancreatic Cancer

Directory of Open Access Journals (Sweden)

Kalthoff Holger

2003-01-01

Full Text Available Abstract Pancreatic adenocarcinoma is characterized by poor prognosis, because of late diagnosis and lack of response to chemo- and/or radiation therapies. Resistance to apoptosis mainly causes this insensitivity to conventional therapies. Apoptosis or programmed cell death is a central regulator of tissue homeostasis. Certain genetic disturbances of apoptotic signaling pathways have been found in carcinomas leading to tumor development and progression. In the past few years, the knowledge about the complex pathways of apoptosis has strongly increased and new therapeutic approaches based on this knowledge are being developed. This review will focus on the role of apoptotic proteins contributing to pancreatic cancer development and progression and will demonstrate possible targets to influence this deadly disease.

Opposing effects of PI3K/Akt and Smad-dependent signaling pathways in NAG-1-induced glioblastoma cell apoptosis.

Directory of Open Access Journals (Sweden)

Zhiguo Zhang

Full Text Available Nonsteroidal anti-inflammatory drug (NSAID activated gene-1 (NAG-1 is a divergent member of the transforming growth factor-beta (TGF-β superfamily. NAG-1 plays remarkable multifunctional roles in controlling diverse physiological and pathological processes including cancer. Like other TGF-β family members, NAG-1 can play dual roles during cancer development and progression by negatively or positively modulating cancer cell behaviors. In glioblastoma brain tumors, NAG-1 appears to act as a tumor suppressor gene; however, the precise underlying mechanisms have not been well elucidated. In the present study, we discovered that overexpression of NAG-1 induced apoptosis in U87 MG, U118 MG, U251 MG, and T98G cell lines via the intrinsic mitochondrial pathway, but not in A172 and LN-229 cell lines. NAG-1 could induce the phosphorylation of PI3K/Akt and Smad2/3 in all six tested glioblastoma cell lines, except Smad3 phosphorylation in A172 and LN-229 cell lines. In fact, Smad3 expression and its phosphorylation were almost undetectable in A172 and LN-229 cells. The PI3K inhibitors promoted NAG-1-induced glioblastoma cell apoptosis, while siRNAs to Smad2 and Smad3 decreased the apoptosis rate. NAG-1 also stimulated the direct interaction between Akt and Smad3 in glioblastoma cells. Elevating the level of Smad3 restored the sensitivity to NAG-1-induced apoptosis in A172 and LN-229 cells. In conclusion, our results suggest that PI3K/Akt and Smad-dependent signaling pathways display opposing effects in NAG-1-induced glioblastoma cell apoptosis.

BMP signaling in the human fetal ovary is developmentally regulated and promotes primordial germ cell apoptosis.

Science.gov (United States)

Childs, Andrew J; Kinnell, Hazel L; Collins, Craig S; Hogg, Kirsten; Bayne, Rosemary A L; Green, Samira J; McNeilly, Alan S; Anderson, Richard A

2010-08-01

Primordial germ cells (PGCs) are the embryonic precursors of gametes in the adult organism, and their development, differentiation, and survival are regulated by a combination of growth factors collectively known as the germ cell niche. Although many candidate niche components have been identified through studies on mouse PGCs, the growth factor composition of the human PGC niche has not been studied extensively. Here we report a detailed analysis of the expression of components of the bone morphogenetic protein (BMP) signaling apparatus in the human fetal ovary, from postmigratory PGC proliferation to the onset of primordial follicle formation. We find developmentally regulated and reciprocal patterns of expression of BMP2 and BMP4 and identify germ cells to be the exclusive targets of ovarian BMP signaling. By establishing long-term cultures of human fetal ovaries in which PGCs are retained within their physiological niche, we find that BMP4 negatively regulates postmigratory PGC numbers in the human fetal ovary by promoting PGC apoptosis. Finally, we report expression of both muscle segment homeobox (MSX)1 and MSX2 in the human fetal ovary and reveal a selective upregulation of MSX2 expression in human fetal ovary in response to BMP4, suggesting this gene may act as a downstream effector of BMP-induced apoptosis in the ovary, as in other systems. These data reveal for the first time growth factor regulation of human PGC development in a physiologically relevant context and have significant implications for the development of cultures systems for the in vitro maturation of germ cells, and their derivation from pluripotent stem cells.

Licochalcone A induces apoptosis in KB human oral cancer cells via a caspase-dependent FasL signaling pathway

Science.gov (United States)

KIM, JAE-SUNG; PARK, MI-RA; LEE, SOOK-YOUNG; KIM, DO KYOUNG; MOON, SUNG-MIN; KIM, CHUN SUNG; CHO, SEUNG SIK; YOON, GOO; IM, HEE-JEONG; YOU, JAE-SEEK; OH, JI-SU; KIM, SU-GWAN

2014-01-01

Licochalcone A (Lico-A) is a natural phenol licorice compound with multiple bioactivities, including anti-inflammatory, anti-microbial, anti-fungal and osteogenesis-inducing properties. In the present study, we investigated the Lico-A-induced apoptotic effects and examined the associated apoptosis pathway in KB human oral cancer cells. Lico-A decreased the number of viable KB oral cancer cells. However, Lico-A did not have an effect on primary normal human oral keratinocytes. In addition, the IC50 value of Lico-A was determined to be ~50 μM following dose-dependent stimulation. KB oral cancer cells stimulated with Lico-A for 24 h showed chromatin condensation by DAPI staining, genomic DNA fragmentation by agarose gel electrophoresis and a gradually increased apoptotic cell population by FACS analysis. These data suggest that Lico-A induces apoptosis in KB oral cancer cells. Additionally, Lico-A-induced apoptosis in KB oral cancer cells was mediated by the expression of factor associated suicide ligand (FasL) and activated caspase-8 and −3 and poly(ADP-ribose) polymerase (PARP). Furthermore, in the KB oral cancer cells co-stimulation with a caspase inhibitor (Z-VAD-fmk) and Lico-A significantly abolished the apoptotic phenomena. Our findings demonstrated that Lico-A-induced apoptosis in KB oral cancer cells involves the extrinsic apoptotic signaling pathway, which involves a caspase-dependent FasL-mediated death receptor pathway. Our data suggest that Lico-A be developed as a chemotherapeutic agent for the management of oral cancer. PMID:24337492

Methylselenium and Prostate Cancer Apoptosis

National Research Council Canada - National Science Library

Lu, Junxuan

2003-01-01

The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of PCa cells by methyl selenium (Se...

Intersectional perspective in elderly care.

Science.gov (United States)

Cuesta, Marta; Rämgård, Margareta

2016-01-01

Earlier research has shown that power relationships at workplaces are constructed by power structures. Processes related to power always influence the working conditions for (in this study in elderly care) the working groups involved. Power structures are central for intersectional analysis, in the sense that the intersectional perspective highlights aspects such as gender and ethnicity (subjective dimensions) and interrelates them to processes of power (objective dimension). This qualitative study aims to explore in what way an intersectional perspective could contribute to increased knowledge of power structures in a nursing home where the employees were mostly immigrants from different countries. By using reflexive dialogues related to an intersectional perspective, new knowledge which contributes to the employees' well-being could develop. Narrative analysis was the method used to conduct this study. Through a multi-stage focus group on six occasions over 6 months, the staff were engaged in intersectional and critical reflections about power relationship with the researchers, by identifying patterns in their professional activities that could be connected to their subjectivities (gender, ethnicity, etc.). The result of this study presents three themes that express the staff's experiences and connect these experiences to structural discrimination. 1) Intersectionality, knowledge, and experiences of professionalism; 2) Intersectionality, knowledge, and experiences of collaboration; and 3) Intersectionality, knowledge, and experiences of discrimination. The result demonstrates that an intersectional perspective reinforces the involved abilities, during the conversations, into being clear about, for example, their experiences of discrimination, and consequently developing a better understanding of their professionalism and collaboration. Such deeper reflections became possible through a process of consciousness raising, strengthening the employee's self

Intersectional perspective in elderly care

Directory of Open Access Journals (Sweden)

Marta Cuesta

2016-05-01

Full Text Available Earlier research has shown that power relationships at workplaces are constructed by power structures. Processes related to power always influence the working conditions for (in this study in elderly care the working groups involved. Power structures are central for intersectional analysis, in the sense that the intersectional perspective highlights aspects such as gender and ethnicity (subjective dimensions and interrelates them to processes of power (objective dimension. This qualitative study aims to explore in what way an intersectional perspective could contribute to increased knowledge of power structures in a nursing home where the employees were mostly immigrants from different countries. By using reflexive dialogues related to an intersectional perspective, new knowledge which contributes to the employees’ well-being could develop. Narrative analysis was the method used to conduct this study. Through a multi-stage focus group on six occasions over 6 months, the staff were engaged in intersectional and critical reflections about power relationship with the researchers, by identifying patterns in their professional activities that could be connected to their subjectivities (gender, ethnicity, etc.. The result of this study presents three themes that express the staff's experiences and connect these experiences to structural discrimination. 1 Intersectionality, knowledge, and experiences of professionalism; 2 Intersectionality, knowledge, and experiences of collaboration; and 3 Intersectionality, knowledge, and experiences of discrimination. The result demonstrates that an intersectional perspective reinforces the involved abilities, during the conversations, into being clear about, for example, their experiences of discrimination, and consequently developing a better understanding of their professionalism and collaboration. Such deeper reflections became possible through a process of consciousness raising, strengthening the employee

Intersectional perspective in elderly care

Science.gov (United States)

Cuesta, Marta; Rämgård, Margareta

2016-01-01

Earlier research has shown that power relationships at workplaces are constructed by power structures. Processes related to power always influence the working conditions for (in this study in elderly care) the working groups involved. Power structures are central for intersectional analysis, in the sense that the intersectional perspective highlights aspects such as gender and ethnicity (subjective dimensions) and interrelates them to processes of power (objective dimension). This qualitative study aims to explore in what way an intersectional perspective could contribute to increased knowledge of power structures in a nursing home where the employees were mostly immigrants from different countries. By using reflexive dialogues related to an intersectional perspective, new knowledge which contributes to the employees’ well-being could develop. Narrative analysis was the method used to conduct this study. Through a multi-stage focus group on six occasions over 6 months, the staff were engaged in intersectional and critical reflections about power relationship with the researchers, by identifying patterns in their professional activities that could be connected to their subjectivities (gender, ethnicity, etc.). The result of this study presents three themes that express the staff's experiences and connect these experiences to structural discrimination. 1) Intersectionality, knowledge, and experiences of professionalism; 2) Intersectionality, knowledge, and experiences of collaboration; and 3) Intersectionality, knowledge, and experiences of discrimination. The result demonstrates that an intersectional perspective reinforces the involved abilities, during the conversations, into being clear about, for example, their experiences of discrimination, and consequently developing a better understanding of their professionalism and collaboration. Such deeper reflections became possible through a process of consciousness raising, strengthening the employee's self

Effect of pH on radiation-induced apoptosis

International Nuclear Information System (INIS)

Chang, W. Song; Park, Heon J.; Lyons, John C.; Auger, Elizabeth A.; Lee, Hyung-Sik

1996-01-01

Purpose/Objective: The effect of environmental pH on the radiation-induced apoptosis in tumor cells in vitro was investigated. Materials and Methods: SCK mammary adenocarcinoma cells of A/J mice were irradiated with γ-rays using a 137 Cs irradiator and incubated in media of different pHs. After incubation at 37 degree sign C for 24-120 hrs., the extent of apoptosis was determined using agarose gel electrophoresis of DNA, in situ TUNEL staining, flow cytometry, and release of 3 H from 3 H-thymidine labeled cells. The membrane integrity, using the trypan blue exclusion method, and the clonogenicity of the cells were also determined. Results: Irradiation with 2-12 Gy of γ-rays induced apoptosis in pH 7.5 medium within 48 hrs. The radiation-induced apoptosis progressively declined as the medium pH was lowered so that little apoptosis occurred in 48 hrs. after irradiation with 12 Gy in pH 6.6 medium. However, when the cells were irradiated and incubated for 48 hrs. in pH 6.6 medium and then medium was replaced with pH 7.5 medium, apoptosis promptly occurred. Apoptosis also occurred even in pH 6.6 medium when the cells were irradiated and maintained in pH 7.5 medium for 8 hrs. or longer post-irradiation before incubation in pH 6.6 medium. Conclusion: An acidic environment markedly suppresses radiation-induced apoptosis probably by suppressing the expression of initial signals responsible for irradiation-induced apoptosis. Indications are that the signals persist in an acidic environment and trigger apoptosis when the environmental acidity is eased. Our results suggest that the acidic environment in human tumors may inhibit the apoptosis after irradiation. However, apoptosis may be triggered when reoxygenation occurs after irradiation, and thus, the intratumor environment becomes less acidic after irradiation. Not only the change in pO 2 but the change in pH during the course of fractionated radiotherapy may greatly influence the outcome of the treatment

Spatial database for intersections.

Science.gov (United States)

2015-08-01

Deciding which intersections in the state of Kentucky warrant safety improvements requires a comprehensive inventory : with information on every intersection in the public roadway network. The Kentucky Transportation Cabinet (KYTC) : had previously c...

Methylselenium and Prostate Cancer Apoptosis

National Research Council Canada - National Science Library

Lu, Junxuan

2004-01-01

The purpose of this research is to gain a better understanding of the biochemical pathways and molecular targets for the selective induction of apoptosis signaling and execution of PCa cells by methyl selenium (Se)/selenol...

Modulation of apoptosis sensitivity through the interplay with autophagic and proteasomal degradation pathways

Science.gov (United States)

Delgado, M E; Dyck, L; Laussmann, M A; Rehm, M

2014-01-01

Autophagic and proteasomal degradation constitute the major cellular proteolysis pathways. Their physiological and pathophysiological adaptation and perturbation modulates the relative abundance of apoptosis-transducing proteins and thereby can positively or negatively adjust cell death susceptibility. In addition to balancing protein expression amounts, components of the autophagic and proteasomal degradation machineries directly interact with and co-regulate apoptosis signal transduction. The influence of autophagic and proteasomal activity on apoptosis susceptibility is now rapidly gaining more attention as a significant modulator of cell death signalling in the context of human health and disease. Here we present a concise and critical overview of the latest knowledge on the molecular interplay between apoptosis signalling, autophagy and proteasomal protein degradation. We highlight that these three pathways constitute an intricate signalling triangle that can govern and modulate cell fate decisions between death and survival. Owing to rapid research progress in recent years, it is now possible to provide detailed insight into the mechanisms of pathway crosstalk, common signalling nodes and the role of multi-functional proteins in co-regulating both protein degradation and cell death. PMID:24457955

Structural Insight into the 14-3-3 Protein-dependent Inhibition of Protein Kinase ASK1 (Apoptosis Signal-regulating kinase 1)

Czech Academy of Sciences Publication Activity Database

Petrvalská, Olivia; Košek, Dalibor; Kukačka, Zdeněk; Tošner, Z.; Man, Petr; Večeř, J.; Herman, P.; Obšilová, Veronika; Obšil, Tomáš

2016-01-01

Roč. 291, č. 39 (2016), s. 20753-20765 ISSN 0021-9258 R&D Projects: GA ČR(CZ) GA14-10061S Institutional support: RVO:67985823 ; RVO:61388971 Keywords : 14-3-3 protein * apoptosis signal-regulating kinase 1 (ASK1) * fluorescence * nuclear magnetic resonance (NMR) * protein cross-linking * small-angle x-ray scattering (SAXS) Subject RIV: CE - Biochemistry Impact factor: 4.125, year: 2016

Development of Evaluation Technology for Detection of Axial Crack at Eggcrate Intersection of Steam Generator Tube

International Nuclear Information System (INIS)

Choi, Myung Sik; Hur, Do Haeng; Kim, Kyung Mo; Han, Jung Ho; Lee, Deok Hyun; Song, Myung Ho

2011-01-01

The occurrence of outer diameter (OD) axial stress corrosion crack at egg crate intersection of steam generator tube in operating power plant is inspected primarily by the eddy current test using bobbin coil probe. Therefore, the characteristics of the bobbin coil signal from the axial crack at egg crate intersection of steam generator tube should be understood for the accurate and earlier detection of the crack. In this study, the mockup assembly simulating the steam generator tube with OD axial stress corrosion crack and tube support egg crate was manufactured, and the characteristics of bobbin coil eddy current signal was examined in order to extract the improved evaluation technique for the detection of the crack

Continuous and Discrete-Time Optimal Controls for an Isolated Signalized Intersection

Directory of Open Access Journals (Sweden)

Jiyuan Tan

2017-01-01

Full Text Available A classical control problem for an isolated oversaturated intersection is revisited with a focus on the optimal control policy to minimize total delay. The difference and connection between existing continuous-time planning models and recently proposed discrete-time planning models are studied. A gradient descent algorithm is proposed to convert the optimal control plan of the continuous-time model to the plan of the discrete-time model in many cases. Analytic proof and numerical tests for the algorithm are also presented. The findings shed light on the links between two kinds of models.

Andrographolide, a Novel NF-κB Inhibitor, Induces Vascular Smooth Muscle Cell Apoptosis via a Ceramide-p47phox-ROS Signaling Cascade

Directory of Open Access Journals (Sweden)

Yu-Ying Chen

2013-01-01

Full Text Available Atherosclerosis is linked with the development of many cardiovascular complications. Abnormal proliferation of vascular smooth muscle cells (VSMCs plays a crucial role in the development of atherosclerosis. Accordingly, the apoptosis of VSMCs, which occurs in the progression of vascular proliferation, may provide a beneficial strategy for managing cardiovascular diseases. Andrographolide, a novel nuclear factor-κB inhibitor, is the most active and critical constituent isolated from the leaves of Andrographis paniculata. Recent studies have indicated that andrographolide is a potential therapeutic agent for treating cancer through the induction of apoptosis. In this study, the apoptosis-inducing activity and mechanisms in andrographolide-treated rat VSMCs were characterized. Andrographolide significantly induced reactive oxygen species (ROS formation, p53 activation, Bax, and active caspase-3 expression, and these phenomena were suppressed by pretreating the cells with N-acetyl-L-cysteine, a ROS scavenger, or diphenylene iodonium, a nicotinamide adenine dinucleotide phosphate (NADPH oxidase (Nox inhibitor. Furthermore, p47phox, a Nox subunit protein, was phosphorylated in andrographolide-treated rat VSMCs. However, pretreatment with 3-O-methyl-sphingomyelin, a neutral sphingomyelinase inhibitor, significantly inhibited andrographolide-induced p47phox phosphorylation as well as Bax and active caspase-3 expression. Our results collectively demonstrate that andrographolide-reduced cell viability can be attributed to apoptosis in VSMCs, and this apoptosis-inducing activity was associated with the ceramide-p47phox-ROS signaling cascade.

Autonomous rexinoid death signaling is suppressed by converging signaling pathways in immature leukemia cells.

Science.gov (United States)

Benoit, G R; Flexor, M; Besançon, F; Altucci, L; Rossin, A; Hillion, J; Balajthy, Z; Legres, L; Ségal-Bendirdjian, E; Gronemeyer, H; Lanotte, M

2001-07-01

On their own, retinoid X receptor (RXR)-selective ligands (rexinoids) are silent in retinoic acid receptor (RAR)-RXR heterodimers, and no selective rexinoid program has been described as yet in cellular systems. We report here on the rexinoid signaling capacity that triggers apoptosis of immature promyelocytic NB4 cells as a default pathway in the absence of survival factors. Rexinoid-induced apoptosis displays all features of bona fide programmed cell death and is inhibited by RXR, but not RAR antagonists. Several types of survival signals block rexinoid-induced apoptosis. RARalpha agonists switch the cellular response toward differentiation and induce the expression of antiapoptosis factors. Activation of the protein kinase A pathway in the presence of rexinoid agonists induces maturation and blocks immature cell apoptosis. Addition of nonretinoid serum factors also blocks cell death but does not induce cell differentiation. Rexinoid-induced apoptosis is linked to neither the presence nor stability of the promyelocytic leukemia-RARalpha fusion protein and operates also in non-acute promyelocytic leukemia cells. Together our results support a model according to which rexinoids activate in certain leukemia cells a default death pathway onto which several other signaling paradigms converge. This pathway is entirely distinct from that triggered by RAR agonists, which control cell maturation and postmaturation apoptosis.

Neuronal apoptosis and synaptic density in the dentate gyrus of ischemic rats' response to chronic mild stress and the effects of Notch signaling.

Directory of Open Access Journals (Sweden)

Shaohua Wang

Full Text Available Our previous research highlighted an inconsistency with Notch1 signaling-related compensatory neurogenesis after chronic mild stress (CMS in rodents suffering from cerebral ischemia, which continue to display post-stroke depressive symptoms. Here, we hypothesize that CMS aggrandized ischemia-related apoptosis injury and worsened synaptic integrity via gamma secretase-meditated Notch1 signaling. Adult rats were exposed to a CMS paradigm after left middle cerebral artery occlusion (MCAO. Open-field and sucrose consumption testing were employed to assess depression-like behavior. Gene expression of pro-apoptotic Bax, anti-apoptotic Bcl-2, and synaptic density-related synaptophysin were measured by western blotting and real-time PCR on Day 28 after MCAO surgery. CMS induced depressive behaviors in ischemic rats, which was accompanied by an elevation in Bax/bcl-2 ratio, TUNEL staining in neurons and reduced synaptophysin expression in the dentate gyrus. These collective effects were reversed by the gamma-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl]-S-phenyl-glycine t-butyl ester. We found that post-stroke stressors made neurons in the dentate gyrus vulnerable to apoptosis, which supports a putative role for Notch signaling in neural integrity, potentially in newborn cells' synaptic deficit with regard to preexisting cells. These findings suggest that post-stroke depression therapeutically benefits from blocking gamma secretase mediated Notch signaling, and whether this signaling pathway could be a therapeutic target needs to be further investigated.

α-Lactose Improves the Survival of Septic Mice by Blockade of TIM-3 Signaling to Prevent NKT Cell Apoptosis and Attenuate Cytokine Storm.

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Yao, Yao; Deng, Hai; Li, Pingfei; Zhang, Jian; Zhang, Junbo; Wang, Deping; Li, Songbo; Luo, Yixing; Wei, Zhengping; Bi, Guoyu; Yang, Xiang-Ping; Tang, Zhao-Hui

2017-03-01

Sepsis is the leading cause of death among critically ill patients and natural killer T (NKT) cell activation is essential to induce inflammatory cytokine cascade in sepsis. However, little is known about what regulates the NKT cell function during sepsis. Herein, we showed that T-cell immunoglobulin and mucin domain 3 (Tim-3) expression in NKT cells is elevated in experimental mice during sepsis. Tim-3 expression was positively correlated with NKT cell activation and apoptosis. In sepsis, interleukin (IL)-12 secreted by dendritic cell exposure to lipopolysaccharide increased the expression of Tim-3 in NKT cells. Administration of α-lactose to block Tim-3 signaling pathway significantly improved the survival of septic mice, concomitant with reduced IL-12 production by dendritic cells, reduced Tim-3 expression, prevented NKT cell apoptosis, and attenuated production of inflammatory cytokines. Collectively, Tim-3 signaling in NKT cells plays a critical role in the immunopathogenesis of sepsis. Thus, α-lactose could be a promising immunomodulatory agent in the treatment of sepsis.

Ceramide-Induced Apoptosis in Renal Tubular Cells: A Role of Mitochondria and Sphingosine-1-Phoshate

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Ueda, Norishi

2015-01-01

Ceramide is synthesized upon stimuli, and induces apoptosis in renal tubular cells (RTCs). Sphingosine-1 phosphate (S1P) functions as a survival factor. Thus, the balance of ceramide/S1P determines ceramide-induced apoptosis. Mitochondria play a key role for ceramide-induced apoptosis by altered mitochondrial outer membrane permeability (MOMP). Ceramide enhances oligomerization of pro-apoptotic Bcl-2 family proteins, ceramide channel, and reduces anti-apoptotic Bcl-2 proteins in the MOM. This process alters MOMP, resulting in generation of reactive oxygen species (ROS), cytochrome C release into the cytosol, caspase activation, and apoptosis. Ceramide regulates apoptosis through mitogen-activated protein kinases (MAPKs)-dependent and -independent pathways. Conversely, MAPKs alter ceramide generation by regulating the enzymes involving ceramide metabolism, affecting ceramide-induced apoptosis. Crosstalk between Bcl-2 family proteins, ROS, and many signaling pathways regulates ceramide-induced apoptosis. Growth factors rescue ceramide-induced apoptosis by regulating the enzymes involving ceramide metabolism, S1P, and signaling pathways including MAPKs. This article reviews evidence supporting a role of ceramide for apoptosis and discusses a role of mitochondria, including MOMP, Bcl-2 family proteins, ROS, and signaling pathways, and crosstalk between these factors in the regulation of ceramide-induced apoptosis of RTCs. A balancing role between ceramide and S1P and the strategy for preventing ceramide-induced apoptosis by growth factors are also discussed. PMID:25751724

Low-dose strontium stimulates osteogenesis but high-dose doses cause apoptosis in human adipose-derived stem cells via regulation of the ERK1/2 signaling pathway.

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Aimaiti, Abudousaimi; Maimaitiyiming, Asihaerjiang; Boyong, Xu; Aji, Kaisaier; Li, Cao; Cui, Lei

2017-12-19

Strontium is a widely used anti-osteoporotic agent due to its dual effects on inhibiting bone resorption and stimulating bone formation. Thus, we studied the dose response of strontium on osteo-inductive efficiency in human adipose-derived stem cells (hASCs). Qualitative alkaline phosphatase (ALP) staining, quantitative ALP activity, Alizarin Red staining, real-time polymerase chain reaction and Western blot were used to investigate the in vitro effects of a range of strontium concentrations on hASC osteogenesis and associated signaling pathways. In vitro work revealed that strontium (25-500 μM) promoted osteogenic differentiation of hASCs according to ALP activity, extracellular calcium deposition, and expression of osteogenic genes such as runt-related transcription factor 2, ALP, collagen-1, and osteocalcin. However, osteogenic differentiation of hASCs was significantly inhibited with higher doses of strontium (1000-3000 μM). These latter doses of strontium promoted apoptosis, and phosphorylation of ERK1/2 signaling was increased and accompanied by the downregulation of Bcl-2 and increased phosphorylation of BAX. The inhibition of ERK1/2 decreased apoptosis in hASCs. Lower concentrations of strontium facilitate osteogenic differentiation of hASCs up to a point; higher doses cause apoptosis of hASCs, with activation of the ERK1/2 signaling pathway contributing to this process.

The Effects of Agaricus blazei Murill Polysaccharides on Cadmium-Induced Apoptosis and the TLR4 Signaling Pathway of Peripheral Blood Lymphocytes in Chicken.

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Liu, Wenjing; Ge, Ming; Hu, Xuequan; Lv, Ai; Ma, Dexing; Huang, Xiaodan; Zhang, Ruili

2017-11-01

In this study, we investigated the effects of Agaricus blazei Murill polysaccharides (ABP) on cadmium (Cd)-induced apoptosis and the TLR4 signaling pathway of chicken peripheral blood lymphocytes (PBLs). Seven-day-old healthy chickens were randomly divided into four groups, and each group contained 20 males. The cadmium-supplemented diet group (Cd group) was fed daily with full feed that contained 140 mg cadmium chloride (CdCl 2 )/kg and 0.2 mL saline. The A. blazei Murill polysaccharide diet group (ABP group) was fed daily with full feed with 0.2 mL ABP solution (30 mg/mL) by oral gavage. The cadmium-supplemented plus A. blazei Murill polysaccharide diet group (Cd + ABP group) was fed daily with full feed containing 140 mg CdCl 2 /kg and 0.2 mL ABP solution (30 mg/mL) by gavage. The control group was fed daily with full feed with 0.2 mL saline per day. We measured the apoptosis rate and messenger RNA (mRNA) levels of apoptosis genes (caspase-3, Bax, and Bcl-2), the mRNA levels of TLR4 and TLR4 signaling pathway-related factors (MyD88, TRIF, NF-κB, and IRF3), the TLR4 protein expression, and the concentrations of inflammatory cytokines (IL-1β, IL-6, and TNF-α) in chicken PBLs. The results showed that the PBL apoptosis rate was significantly increased, the mRNA levels of caspase-3 and Bax were significantly increased, while that of Bcl-2 was significantly reduced. The Bax/Bcl-2 ratio was significantly increased in the Cd group at 20, 40, and 60 days after treatment compared with that in the control group. After treatment with ABP, the above changes were clearly suppressed. At the same time, ABP reduced the concentrations of IL-1β, IL-6, and TNF-α induced by Cd. We also found that ABP inhibited the TLR4 mRNA level and protein expression and inhibited the mRNA levels of MyD88, TRIF, NF-κB, and IRF3. The results demonstrated that Cd could induce apoptosis, activate the TLR4 signaling pathway, and induce the expression of inflammatory cytokines in

Saponin 1 induces apoptosis and suppresses NF-κB-mediated survival signaling in glioblastoma multiforme (GBM.

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Juan Li

Full Text Available Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells and human hepatocellular carcinoma (Hep-G2 cells. Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP family members,(e.g., survivin and XIAP by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM.

Saponin 1 Induces Apoptosis and Suppresses NF-κB-Mediated Survival Signaling in Glioblastoma Multiforme (GBM)

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Tang, Chi; Li, Bo; Wang, Yuangang; Gao, Zhenhui; Luo, Peng; Yin, Anan; Wang, Xiaoyang; Cheng, Guang; Fei, Zhou

2013-01-01

Saponin 1 is a triterpeniod saponin extracted from Anemone taipaiensis, a traditional Chinese medicine against rheumatism and phlebitis. It has also been shown to exhibit significant anti-tumor activity against human leukemia (HL-60 cells) and human hepatocellular carcinoma (Hep-G2 cells). Herein we investigated the effect of saponin 1 in human glioblastoma multiforme (GBM) U251MG and U87MG cells. Saponin 1 induced significant growth inhibition in both glioblastoma cell lines, with a 50% inhibitory concentration at 24 h of 7.4 µg/ml in U251MG cells and 8.6 µg/ml in U87MG cells, respectively. Nuclear fluorescent staining and electron microscopy showed that saponin 1 caused characteristic apoptotic morphological changes in the GBM cell lines. Saponin 1-induced apoptosis was also verified by DNA ladder electrophoresis and flow cytometry. Additionally, immunocytochemistry and western blotting analyses revealed a time-dependent decrease in the expression and nuclear location of NF-κB following saponin 1 treatment. Western blotting data indicated a significant decreased expression of inhibitors of apoptosis (IAP) family members,(e.g., survivin and XIAP) by saponin 1. Moreover, saponin 1 caused a decrease in the Bcl-2/Bax ratio and initiated apoptosis by activating caspase-9 and caspase-3 in the GBM cell lines. These findings indicate that saponin 1 inhibits cell growth of GBM cells at least partially by inducing apoptosis and inhibiting survival signaling mediated by NF-κB. In addition, in vivo study also demonstrated an obvious inhibition of saponin 1 treatment on the tumor growth of U251MG and U87MG cells-produced xenograft tumors in nude mice. Given the minimal toxicities of saponin 1 in non-neoplastic astrocytes, our results suggest that saponin 1 exhibits significant in vitro and in vivo anti-tumor efficacy and merits further investigation as a potential therapeutic agent for GBM. PMID:24278406

Emerging role of Hippo signalling in pancreatic biology: YAP re-expression and plausible link to islet cell apoptosis and replication.

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Sharma, Anjana; Yerra, Veera Ganesh; Kumar, Ashutosh

2017-02-01

Diabetes mellitus is an ailment that develops when the functional capacity of the pancreas does not meet the metabolic requirements of the whole body, either due to insulin insufficiency or resistance to insulin action. Current therapies that control glycaemia are limited by their unwanted effects or their inability to prevent the development of long-term complications. Regeneration and replacement of beta cell therapies are shaping the goals of future management of diabetes. The Hippo pathway, first discovered in Drosophila melanogaster, plays a vital role in controlling the organ size. Nuclear recruitment of YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif), a mammalian analogue of Yorkie protein found in Drosophila, activates cell proliferation and inhibits apoptosis. YAP was found to regulate early pancreatic development followed by downregulation during Ngn3-specific endocrine lineage maturation corresponding to their mitotic quiescence. Recent evidences have shown that optimum modulation of upstream kinases in the Hippo signalling pathway may lead to apoptosis inhibition and renewal of progenitor as well as stem cells in case of tissue or cell injury. This article reviews the evidences linking the role of various components of the Hippo pathway to pancreatic regeneration. In particular, the focus is on the beneficial role of induced YAP expression and its nuclear distribution on apoptosis and replication of adult pancreatic β islets. This approach may be of immense significance towards our fight against diabetes; thus, more insightful research is warranted in the area of Hippo signalling pathway and its involvement in pancreatic regeneration. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

To signal or not to signal: that should not be the question.

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Faw, Harold W

2013-10-01

The purpose of the present research was to examine rates of turn signal use, a positive and potentially valuable means by which drivers can communicate. A second purpose was to explore factors that might impact these rates, including the modeling influence of other drivers. A series of observations involving more than 5600 vehicles making turns were recorded at a variety of intersections in British Columbia, Canada. Though the occurrence of signal use varied widely, ranging from a low of 54% to a high of 95%, the overall rate was 76%. Drivers used turn signals significantly less often when making right as compared with left turns, when traffic volume was higher, and when a designated turning lane was provided. In addition, compared with drivers following another vehicle not using signals, those following a vehicle with turn signals on were significantly more likely to activate their turn signals, suggesting a possible modeling effect. Both internal and external influences on turn signal use by drivers were considered. External factors explored in this research included direction of turn, traffic volume, intersection configuration, and the example of other drivers. It was concluded that the practice of signaling turns merits more research attention, since consistent use of signals is a potential contributor to enhanced safety for all road users. Copyright © 2013 Elsevier Ltd. All rights reserved.

Notch signaling regulates expression of Mcl-1 and apoptosis in PPD-treated macrophages.

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Palaga, Tanapat; Ratanabunyong, Siriluk; Pattarakankul, Thitiporn; Sangphech, Naunpun; Wongchana, Wipawee; Hadae, Yukihiro; Kueanjinda, Patipark

2013-09-01

Macrophages are cellular targets for infection by bacteria and viruses. The fate of infected macrophages plays a key role in determining the outcome of the host immune response. Apoptotic cell death of macrophages is considered to be a protective host defense that eliminates pathogens and infected cells. In this study, we investigated the involvement of Notch signaling in regulating apoptosis in macrophages treated with tuberculin purified protein derivative (PPD). Murine bone marrow-derived macrophages (BMMs) treated with PPD or infected with Mycobacterium bovis Bacillus Calmette-Guérin (BCG) induced upregulation of Notch1. This upregulation correlated well with the upregulation of the anti-apoptotic gene mcl-1 both at the transcriptional and translational levels. Decreased levels of Notch1 and Mcl-1 were observed in BMM treated with PPD when a gamma secretase inhibitor (GSI), which inhibits the processing of Notch receptors, was used. Moreover, silencing Notch1 in the macrophage-like cell line RAW264.7 decreased Mcl-1 protein expression, suggesting that Notch1 is critical for Mcl-1 expression in macrophages. A significant increase in apoptotic cells was observed upon treatment of BMM with PPD in the presence of GSI compared to the vehicle-control treated cells. Finally, analysis of the mcl-1 promoter in humans and mice revealed a conserved potential CSL/RBP-Jκ binding site. The association of Notch1 with the mcl-1 promoter was confirmed by chromatin immunoprecipitation. Taken together, these results indicate that Notch1 inhibits apoptosis of macrophages stimulated with PPD by directly controlling the mcl-1 promoter.

Mitochondrial disfunction and apoptosis in leukemia cells

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Annamaria PALLAG

2008-05-01

Full Text Available Apoptosis or programmed cell death is a process which involves the intentional degradation of the cell from the inside, the participation of the mitochondria to propagate the apoptotic signal, the alteration of the phospholipid cell membrane composition, the perturbation and alteration of the cell metabolism.The antineoplastic drugs is inducing the apoptotic process in the sensitive cells.It have been studied acute lymphoblastic leukemia cells. Using Annexin V-PE Apoptosis Detection Kit and flow cytometer, the amount of cells undergoing apoptosis, in various stages of the antineoplasic treatment, was detected. At the same time, were monitored, the serum level of malondialdehyde. The results obtained confirm the alteration of the mitochondrial metabolism. We can observed the mitochondrial dysfunction role in cell apoptosis.

Fluid shear stress suppresses TNF-α-induced apoptosis in MC3T3-E1 cells: Involvement of ERK5-AKT-FoxO3a-Bim/FasL signaling pathways

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Bin, Geng; Bo, Zhang; Jing, Wang; Jin, Jiang; Xiaoyi, Tan; Cong, Chen; Liping, An; Jinglin, Ma; Cuifang, Wang; Yonggang, Chen [The Second Hospital of Lanzhou University, #82 Cuiyingmen, Lanzhou, 730000 Gansu (China); Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu (China); Yayi, Xia, E-mail: xiayayildey@163.com [The Second Hospital of Lanzhou University, #82 Cuiyingmen, Lanzhou, 730000 Gansu (China); Orthopaedics Key Laboratory of Gansu Province, Lanzhou, 730000 Gansu (China)

2016-05-01

TNF-α is known to induce osteoblasts apoptosis, whereas mechanical stimulation has been shown to enhance osteoblast survival. In the present study, we found that mechanical stimulation in the form of fluid shear stress (FSS) suppresses TNF-α induced apoptosis in MC3T3-E1 cells. Extracellular signal-regulated kinase 5 (ERK5) is a member of the mitogen-activated protein kinase (MAPK) family that has been implicated in cell survival. We also demonstrated that FSS imposed by flow chamber in vitro leads to a markedly activation of ERK5, which was shown to be protective against TNF-α-induced apoptosis, whereas the transfection of siRNA against ERK5 (ERK5-siRNA) reversed the FSS-medicated anti-apoptotic effects. An initial FSS-mediated activation of ERK5 that phosphorylates AKT to increase its activity, and a following forkhead box O 3a (FoxO3a) was phosphorylated by activated AKT. Phosphorylated FoxO3a is sequestered in the cytoplasm, and prevents it from translocating to nucleus where it can increase the expression of FasL and Bim. The inhibition of AKT-FoxO3a signalings by a PI3K (PI3-kinase)/AKT inhibitor (LY294002) or the transfection of ERK5-siRNA led to the nuclear translocation of non-phosphorylated FoxO3a, and increased the protein expression of FasL and Bim. In addition, the activation of caspase-3 by TNF-α was significantly inhibited by aforementioned FSS-medicated mechanisms. In brief, the activation of ERK5-AKT-FoxO3a signaling pathways by FSS resulted in a decreased expression of FasL and Bim and an inhibition of caspase-3 activation, which exerts a protective effect that prevents osteoblasts from apoptosis. - Highlights: • Fluid shear stress inhibits osteoblast apoptosis induced by TNF-α. • Inhibition of ERK5 activity by transfection of ERK5 siRNA blocks FSS-mediated anti-apoptotic effect in osteoblast. • Activated ERK5-AKT-FoxO3a-Bim/FasL signaling pathways by FSS is required to protect osteoblast from apoptosis.

Ubiquitin specific peptidase 5 mediates Histidine-rich protein Hpn induced cell apoptosis in hepatocellular carcinoma through P14-P53 signaling.

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Liu, Yi; Wang, Wei-Mao; Zou, Li-Yi; Li, Li; Feng, Lu; Pan, Ming-Zhu; Lv, Min-Yi; Cao, Ying; Wang, Hua; Kung, Hsiang-Fu; Pang, Jian-Xin; Fu, Wei-Ming; Zhang, Jin-Fang

2017-06-01

Hpn is a small histidine-rich cytoplasmic protein from Helicobacter pylori and has been recognized as a high-risk factor for several cancers including gastric cancer, colorectal cancer, and MALT lymphoma. However, the relationship between Hpn and cancers remains elusive. In this study, we discovered that Hpn protein effectively suppressed cell growth and induced apoptosis in hepatocellular carcinoma (HCC). A two-dimensional gel electrophoresis and mass spectrometry-based comparative proteomics was performed to find the molecular targets of Hpn in HCC cells. It was identified that twelve proteins were differentially expressed, with USP5 being one of the most significantly downregulated protein. The P14 ARF -P53 signaling was activated by USP5 knockdown in HCC cells. Furthermore, USP5 overexpression significantly rescued the suppressive effect of Hpn on the viability of HCC cells. In conclusion, our study suggests that Hpn plays apoptosis-inducing roles through suppressing USP5 expression and activating the P14 ARF -P53 signaling. Therefore, Hpn may be a potential candidate for developing novel anti-HCC drugs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Optimal Signal Design for Mixed Equilibrium Networks with Autonomous and Regular Vehicles

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Nan Jiang

2017-01-01

Full Text Available A signal design problem is studied for efficiently managing autonomous vehicles (AVs and regular vehicles (RVs simultaneously in transportation networks. AVs and RVs move on separate lanes and two types of vehicles share the green times at the same intersections. The signal design problem is formulated as a bilevel program. The lower-level model describes a mixed equilibrium where autonomous vehicles follow the Cournot-Nash (CN principle and RVs follow the user equilibrium (UE principle. In the upper-level model, signal timings are optimized at signalized intersections to allocate appropriate green times to both autonomous and RVs to minimize system travel cost. The sensitivity analysis based method is used to solve the bilevel optimization model. Various signal control strategies are evaluated through numerical examples and some insightful findings are obtained. It was found that the number of phases at intersections should be reduced for the optimal control of the AVs and RVs in the mixed networks. More importantly, incorporating AVs into the transportation network would improve the system performance due to the value of AV technologies in reducing random delays at intersections. Meanwhile, travelers prefer to choose AVs when the networks turn to be congested.

A Monoclonal Antibody against Wnt-1 Induces Apoptosis in Human Cancer Cells

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Biao He

2004-01-01

Full Text Available Aberrant activation of the Wingless-type (Wnt/β-catenin signaling pathway is associated with a variety of human cancers. Little is known regarding the role that Wnt ligands play in human carcinogenesis. To test whether a Wnt-1 signal is a survival factor in human cancer cells and thus may serve as a potential cancer therapeutic target, we investigated the effect of inhibition of Wnt-1 signaling in a variety of human cancer cell lines, including non small cell lung cancer, breast cancer, mesothelioma, and sarcoma. Both monoclonal antibody and RNA interference (RNAi were used to inhibit Wnt-1 signaling. We found that incubation of a monoclonal anti-Wnt-1 antibody induced apoptosis and caused downstream protein changes in cancer cells overexpressing Wnt-1. In contrast, apoptosis was not detected in cells lacking or having minimal Wnt-1 expression after the antibody incubation. RNAi targeting of Wnt-1 in cancer cells overexpressing Wnt-1 demonstrated similar downstream protein changes and induction of apoptosis. The antibody also suppressed tumor growth in vivo. Our results indicate that both monoclonal anti-Wnt-1 antibody and Wnt-1 siRNA inhibit Wnt-1 signaling and can induce apoptosis in human cancer cells. These findings hold promise as a novel therapeutic strategy for cancer.

EJWS retrospective on intersectionality

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Davis, K.E.; Zarkov, Dubravka

2017-01-01

The EJWS has been at the forefront of debates about intersectionality in Europe. In the past two decades, the journal has published countless articles on intersectionality as theory, methodology, and political framework for doing critical feminist research. We have selected some of these articles

Epothilones Suppress Neointimal Thickening in the Rat Carotid Balloon-Injury Model by Inducing Vascular Smooth Muscle Cell Apoptosis through p53-Dependent Signaling Pathway.

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Son, Dong Ju; Jung, Jae Chul; Hong, Jin Tae

2016-01-01

Microtubule stabilizing agents (MTSA) are known to inhibit vascular smooth muscle cell (VSMC) proliferation and migration, and effectively reduce neointimal hyperplasia and restenosis. Epothilones (EPOs), non-taxane MTSA, have been found to be effective in the inhibition of VSMC proliferation and neointimal formation by cell cycle arrest. However, effect of EPOs on apoptosis in hyper-proliferated VSMCs as a possible way to reduce neointimal formation and its action mechanism related to VSMC viability has not been suited yet. Thus, the purposes of the present study was to investigate whether EPOs are able to inhibit neointimal formation by inducing apoptosis within the region of neointimal hyperplasia in balloon-injured rat carotid artery, as well as underlying action mechanism. Treatment of EPO-B and EPO-D significantly induced apoptotic cell death and mitotic catastrophe in hyper-proliferated VSMCs, resulting in cell growth inhibition. Further, EPOs significantly suppressed VSMC proliferation and induced apoptosis by activation of p53-dependent apoptotic signaling pathway, Bax/cytochrome c/caspase-3. We further demonstrated that the local treatment of carotid arteries with EPOs potently inhibited neointimal lesion formation by induction of apoptosis in rat carotid injury model. Our findings demonstrate a potent anti-neointimal hyperplasia property of EPOs by inducing p53-depedent apoptosis in hyper-proliferated VSMCs.

Similar to spironolactone, oxymatrine is protective in aldosterone-induced cardiomyocyte injury via inhibition of calpain and apoptosis-inducing factor signaling.

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Ting-Ting Xiao

Full Text Available Accumulating evidence indicates that oxymatrine (OMT possesses variously pharmacological properties, especially on the cardiovascular system. We previously demonstrated that activated calpain/apoptosis-inducing factor (AIF-mediated pathway was the key molecular mechanism in aldosterone (ALD induces cardiomyocytes apoptosis. In the present study, we extended the experimentation by investigating the effect of OMT on cardiomyocytes exposed to ALD, as compared to spironolactone (Spiro, a classical ALD receptor antagonist. Cardiomyocytes were pre-incubated with OMT, Spiro or vehicle for 1 h, and then, cardiomyocytes were exposed to ALD 24 h. The cell injury was evaluated by 3-(4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT assay and lactate dehydrogenase (LDH leakage ratio. Apoptosis was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL assay, annexin V/PI staining, and relative caspase-3 activity assay. Furthermore, expression of pro-apoptotic proteins including truncated Bid (tBid, calpain and AIF were evaluated by western blot analysis. ALD stimulation increased cardiomyocytes apoptosis, caspase-3 activity and protein expression of calpain, tBid and AIF in the cytosol (p<0.05. Pre-incubated with cardiomyocytes injury and increased caspase-3 activity were significantly attenuated (p<0.05. Furthermore, OMT suppressed ALD-induced high expression of calpain and AIF. And these effects of OMT could be comparable to Spiro. These findings indicated that OMT might be a potential cardioprotective-agent against excessive ALD-induced cardiotoxicity, at least in part, mediated through inhibition of calpain/AIF signaling.

Functional role of apoptosis in oral diseases: An update.

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Misra, Akansha; Rai, Shalu; Misra, Deepankar

2016-01-01

Cell death appears to be a basic biological phenomenon which is maintained by the human body. The term apoptosis, also known as programmed cell death, is characterized by several unique morphological and biochemical features. Apoptosis and its different forms are essential for tissue homeostasis. Alteration in molecular mechanisms involved in apoptotic signaling contributes to a vast range of oral diseases. An understanding of the regulation of apoptosis has led to the development of many therapeutic approaches and better management of oral diseases. The review updates us the correlation between apoptosis in normal oral tissues and oral diseases.

Autophagy capacity and sub-mitochondrial heterogeneity shape Bnip3-induced mitophagy regulation of apoptosis.

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Choe, Sehyo Charley; Hamacher-Brady, Anne; Brady, Nathan Ryan

2015-08-08

Mitochondria are key regulators of apoptosis. In response to stress, BH3-only proteins activate pro-apoptotic Bcl2 family proteins Bax and Bak, which induce mitochondrial outer membrane permeabilization (MOMP). While the large-scale mitochondrial release of pro-apoptotic proteins activates caspase-dependent cell death, a limited release results in sub-lethal caspase activation which promotes tumorigenesis. Mitochondrial autophagy (mitophagy) targets dysfunctional mitochondria for degradation by lysosomes, and undergoes extensive crosstalk with apoptosis signaling, but its influence on apoptosis remains undetermined. The BH3-only protein Bnip3 integrates apoptosis and mitophagy signaling at different signaling domains. Bnip3 inhibits pro-survival Bcl2 members via its BH3 domain and activates mitophagy through its LC3 Interacting Region (LIR), which is responsible for binding to autophagosomes. Previously, we have shown that Bnip3-activated mitophagy prior to apoptosis induction can reduce mitochondrial activation of caspases, suggesting that a reduction to mitochondrial levels may be pro-survival. An outstanding question is whether organelle dynamics and/or recently discovered subcellular variations of protein levels responsible for both MOMP sensitivity and crosstalk between apoptosis and mitophagy can influence the cellular apoptosis decision event. To that end, here we undertook a systems biology analysis of mitophagy-apoptosis crosstalk at the level of cellular mitochondrial populations. Based on experimental findings, we developed a multi-scale, hybrid model with an individually adaptive mitochondrial population, whose actions are determined by protein levels, embedded in an agent-based model (ABM) for simulating subcellular dynamics and local feedback via reactive oxygen species signaling. Our model, supported by experimental evidence, identified an emergent regulatory structure within canonical apoptosis signaling. We show that the extent of mitophagy is

Modulation of iridovirus-induced apoptosis by endocytosis, early expression, JNK, and apical caspase

International Nuclear Information System (INIS)

Chitnis, Nilesh S.; D'Costa, Susan M.; Paul, Eric R.; Bilimoria, Shaen L.

2008-01-01

Chilo iridescent virus (CIV) is the type species for the family Iridoviridae, which are large, isometric, cytoplasmic dsDNA viruses. We examined the mechanism of apoptosis induction by CIV. High CIV doses (CIV XS ; 400 μg/ml), UV-irradiated virus (CIV UV ; 10 μg/ml) and CVPE (CIV protein extract; 10 μg/ml) induced apoptosis in 60% of treated Choristoneura fumiferana (IPRI-CF-124T) cells. Normal doses of infectious CIV (10 μg/ml) induced apoptosis in only 10% of C. fumiferana (CF) cells. Apoptosis was inhibited by Z-IETD-FMK, an apical caspase inhibitor, indicating that CIV-induced apoptosis requires caspase activity. The putative caspase in CF cells was designated Cf-caspase-i. CIV UV or CVPE enhanced Cf-caspase-i activity by 80% at 24 h relative to mock-treated cells. Since the MAP kinase pathway induces or inhibits apoptosis depending on the context, we used JNK inhibitor SP600125 and demonstrated drastic suppression of CVPE-induced apoptosis. Thus, the JNK signaling pathway is significant for apoptosis in this system. Virus interaction with the cell surface was not sufficient for apoptosis since CIV UV particles bound to polysterene beads failed to induce apoptosis. Endocytosis inhibitors (bafilomycin or ammonium chloride) negated apoptosis induction by CIV UV , CIV XS or CVPE indicating that entry through this mode is required. Given the weak apoptotic response to infectious CIV, we postulated that viral gene expression inhibited apoptosis. CIV infection of cells pretreated with cycloheximide induced apoptosis in 69% of the cells compared to 10% in normal infections. Furthermore, blocking viral DNA replication with aphidicolin or phosphonoacetic acid suppressed apoptosis and Cf-caspase-i activity, indicating that early viral expression is necessary for inhibition of apoptosis, and de novo synthesis of viral proteins is not required for induction. We show for the first time that, in a member of the family Iridoviridae, apoptosis: (i) requires entry and

Down-Regulation of AKT Signalling by Ursolic Acid Induces Intrinsic Apoptosis and Sensitization to Doxorubicin in Soft Tissue Sarcoma.

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Victor Hugo Villar

Full Text Available Several important biological activities have been attributed to the pentacyclic triterpene ursolic acid (UA, being its antitumoral effect extensively studied in human adenocarcinomas. In this work, we focused on the efficacy and molecular mechanisms involved in the antitumoral effects of UA, as single agent or combined with doxorubicin (DXR, in human soft tissue sarcoma cells. UA (5-50 μM strongly inhibited (up to 80% the viability of STS cells at 24 h and its proliferation in soft agar, with higher concentrations increasing apoptotic death up to 30%. UA treatment (6-9 h strongly blocked the survival AKT/GSK3β/β-catenin signalling pathway, which led to a concomitant reduction of the anti-apoptotic proteins c-Myc and p21, altogether resulting in the activation of intrinsic apoptosis. Interestingly, UA at low concentrations (10-15 μM enhanced the antitumoral effects of DXR by up to 2-fold, while in parallel inhibiting DXR-induced AKT activation and p21 expression, two proteins implicated in antitumoral drug resistance and cell survival. In conclusion, UA is able to induce intrinsic apoptosis in human STS cells and also to sensitize these cells to DXR by blocking the AKT signalling pathway. Therefore, UA may have beneficial effects, if used as nutraceutical adjuvant during standard chemotherapy treatment of STS.

Intersectionality, Race-Gender Subordination, and Education

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Harris, Angela; Leonardo, Zeus

2018-01-01

In this chapter, we unpack "intersectionality as an analytical framework." First, we cite Black Lives Matter as an impetus for discussing intersectionality's current traction. Second, we review the genealogy of "intersectionality" beginning with Kimberlé Crenshaw's formulation, which brought a Black Studies provocation into…

Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

Energy Technology Data Exchange (ETDEWEB)

Beildeck, Marcy E. [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States); Gelmann, Edward P. [Columbia University, Department of Medicine, New York, NY (United States); Byers, Stephen W., E-mail: byerss@georgetown.edu [Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20057 (United States)

2010-07-01

Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

Cross-regulation of signaling pathways: An example of nuclear hormone receptors and the canonical Wnt pathway

International Nuclear Information System (INIS)

Beildeck, Marcy E.; Gelmann, Edward P.; Byers, Stephen W.

2010-01-01

Predicting the potential physiological outcome(s) of any given molecular pathway is complex because of cross-talk with other pathways. This is particularly evident in the case of the nuclear hormone receptor and canonical Wnt pathways, which regulate cell growth and proliferation, differentiation, apoptosis, and metastatic potential in numerous tissues. These pathways are known to intersect at many levels: in the intracellular space, at the membrane, in the cytoplasm, and within the nucleus. The outcomes of these interactions are important in the control of stem cell differentiation and maintenance, feedback loops, and regulating oncogenic potential. The aim of this review is to demonstrate the importance of considering pathway cross-talk when predicting functional outcomes of signaling, using nuclear hormone receptor/canonical Wnt pathway cross-talk as an example.

Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells

Energy Technology Data Exchange (ETDEWEB)

Perumal, NaveenKumar [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu (India); Perumal, MadanKumar [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu (India); Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390 (United States); Kannan, Anbarasu [Department of Cellular and Molecular Biology, The University of Texas Health Science Center, Tyler, Texas (United States); Subramani, Kumar [Centre for Biotechnology, Anna University, Chennai 600025, Tamil Nadu (India); Halagowder, Devaraj [Department of Zoology, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu (India); Sivasithamparam, NiranjaliDevaraj, E-mail: profniranjali@gmail.com [Department of Biochemistry, University of Madras, Guindy Campus, Chennai 600025, Tamil Nadu (India)

2017-06-15

Recent clinical and experimental evidences strongly acclaim Yes-associated protein (Yap), a key oncogenic driver in liver carcinogenesis, as a therapeutic target. Of the known multiple schemes to inhibit Yap activity, activation of Mammalian Sterile 20-like Kinase 1 (Mst1), an upstream regulator of Yap, appears to be a promising one. In this study, we hypothesize that morin, a bioflavonoid, mediates its anti-cancer effect through the activation of Mst1/hippo signaling in liver cancer cells. To test this hypothesis, both full length Mst1 (F-Mst1) and kinase active N-terminal Mst1 (N-Mst1)-overexpressed HepG2 cells were used. Exposure of F-Mst1 overexpressed HepG2 cells to morin activated Mst1 by caspase-3 cleavage and thereby inhibited Yap nuclear translocation and fostered apoptosis. Morin suppressed NF-κB p65 and Wnt/β-catenin signaling through Mst1 activation via cleavage and phosphorylation, leading to cell death. Annexin-V/PI staining further confirmed the induction of apoptosis in morin treated F-Mst1 overexpressed cells. The present study shows that morin targets cell survival molecules such as NF-κB p65 and β-catenin through activation of hippo signaling. Therefore, morin could be considered as a potential anti-cancer agent against liver cancer. - Highlights: • Morin induced cytotoxicity in cultured HepG2 cells. • Morin activated hippo pathway via Mst1 activation in transfected HepG2 cells. • Morin suppressed Wnt/β-catenin signaling and induced G0/G1 cell cycle arrest. • Morin inhibited NF-κB signaling through Mst1 activation in transfected HepG2 cells. • Morin potentiates apoptosis through Mst1-JNK-caspase mediated mechanism in HepG2 cells.

Morin impedes Yap nuclear translocation and fosters apoptosis through suppression of Wnt/β-catenin and NF-κB signaling in Mst1 overexpressed HepG2 cells

International Nuclear Information System (INIS)

Perumal, NaveenKumar; Perumal, MadanKumar; Kannan, Anbarasu; Subramani, Kumar; Halagowder, Devaraj; Sivasithamparam, NiranjaliDevaraj

2017-01-01

Recent clinical and experimental evidences strongly acclaim Yes-associated protein (Yap), a key oncogenic driver in liver carcinogenesis, as a therapeutic target. Of the known multiple schemes to inhibit Yap activity, activation of Mammalian Sterile 20-like Kinase 1 (Mst1), an upstream regulator of Yap, appears to be a promising one. In this study, we hypothesize that morin, a bioflavonoid, mediates its anti-cancer effect through the activation of Mst1/hippo signaling in liver cancer cells. To test this hypothesis, both full length Mst1 (F-Mst1) and kinase active N-terminal Mst1 (N-Mst1)-overexpressed HepG2 cells were used. Exposure of F-Mst1 overexpressed HepG2 cells to morin activated Mst1 by caspase-3 cleavage and thereby inhibited Yap nuclear translocation and fostered apoptosis. Morin suppressed NF-κB p65 and Wnt/β-catenin signaling through Mst1 activation via cleavage and phosphorylation, leading to cell death. Annexin-V/PI staining further confirmed the induction of apoptosis in morin treated F-Mst1 overexpressed cells. The present study shows that morin targets cell survival molecules such as NF-κB p65 and β-catenin through activation of hippo signaling. Therefore, morin could be considered as a potential anti-cancer agent against liver cancer. - Highlights: • Morin induced cytotoxicity in cultured HepG2 cells. • Morin activated hippo pathway via Mst1 activation in transfected HepG2 cells. • Morin suppressed Wnt/β-catenin signaling and induced G0/G1 cell cycle arrest. • Morin inhibited NF-κB signaling through Mst1 activation in transfected HepG2 cells. • Morin potentiates apoptosis through Mst1-JNK-caspase mediated mechanism in HepG2 cells.

A Fully-Distributed Heuristic Algorithm for Control of Autonomous Vehicle Movements at Isolated Intersections

Directory of Open Access Journals (Sweden)

Abdallah A. Hassan

2014-12-01

Full Text Available Optimizing autonomous vehicle movements through roadway intersections is a challenging problem. It has been demonstrated in the literature that traditional traffic control, such as traffic signal and stop sign control are not optimal especially for heavy traffic demand levels. Alternatively, centralized autonomous vehicle control strategies are costly and not scalable given that the ability of a central controller to track and schedule the movement of hundreds of vehicles in real-time is questionable. Consequently, in this paper a fully distributed algorithm is proposed where vehicles in the vicinity of an intersection continuously cooperate with each other to develop a schedule that allows them to safely proceed through the intersection while incurring minimum delay. Unlike other distributed approaches described in the literature, the wireless communication constraints are considered in the design of the control algorithm. Specifically, the proposed algorithm requires vehicles heading to an intersection to communicate only with neighboring vehicles, while the lead vehicles on each approach lane share information to develop a complete intersection utilization schedule. The scheduling rotates between vehicles to identify higher traffic volumes and favor vehicles coming from heavier lanes to minimize the overall intersection delay. The simulated experiments show significant reductions in the average delay using the proposed approach compared to other methods reported in the literature and reduction in the maximum delay experienced by a vehicle especially in cases of heavy traffic demand levels.

Low proliferation and high apoptosis of osteoblastic cells on hydrophobic surface are associated with defective Ras signaling

International Nuclear Information System (INIS)

Chang, Eun-Ju; Kim, Hong-Hee; Huh, Jung-Eun; Kim, In-Ae; Seung Ko, Jea; Chung, Chong-Pyoung; Kim, Hyun-Man

2005-01-01

The hydrophobic (HPB) nature of most polymeric biomaterials has been a major obstacle in using those materials in vivo due to low compatibility with cells. However, there is little knowledge of the molecular detail to explain how surface hydrophobicity affects cell responses. In this study, we compared the proliferation and apoptosis of human osteoblastic MG63 cells adhered to hydrophilic (HPL) and hydrophobic surfaces. On the hydrophobic surface, less formation of focal contacts and actin stress fibers, a delay in cell cycle progression, and an increase in apoptosis were observed. By using fibroblast growth factor 1 (FGF1) as a model growth factor, we also investigated intracellular signaling pathways on hydrophilic and hydrophobic surfaces. The activation of Ras, Akt, and ERK by FGF1 was impaired in MG63 cells on the hydrophobic surface. The overexpression of constitutively active form of Ras and Akt rescued those cells from apoptosis and recovered cell cycle progression. Furthermore, their overexpression also restored the actin cytoskeletal organization on the hydrophobic surface. Finally, the proliferative, antiapoptotic, and cytoskeletal effects of constitutively active Ras in MG63 cells on the hydrophobic surface were blocked by wortmannin and PD98059 that inhibit Akt and ERK activation, respectively. Therefore, our results suggest that the activation of Ras and its downstream molecules Akt and ERK to an appropriate level is one of crucial elements in the determination of osteoblast cell responses. The Ras pathway may represent a cell biological target that should be considered for successful surface modification of biomaterials to induce adequate cell responses in the bone tissue

NF-κB signaling is activated and confers resistance to apoptosis in three-dimensionally cultured EGFR-mutant lung adenocarcinoma cells

International Nuclear Information System (INIS)

Sakuma, Yuji; Yamazaki, Yukiko; Nakamura, Yoshiyasu; Yoshihara, Mitsuyo; Matsukuma, Shoichi; Koizume, Shiro; Miyagi, Yohei

2012-01-01

Highlights: ► EGFR-mutant cells in 3D culture resist EGFR inhibition compared with suspended cells. ► Degradation of IκB and activation of NF-κB are observed in 3D-cultured cells. ► Inhibiting NF-κB enhances the efficacy of the EGFR inhibitor in 3D-cultured cells. -- Abstract: Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells in suspension undergo apoptosis to a greater extent than adherent cells in a monolayer when EGFR autophosphorylation is inhibited by EGFR tyrosine kinase inhibitors (TKIs). This suggests that cell adhesion to a culture dish may activate an anti-apoptotic signaling pathway other than the EGFR pathway. Since the microenvironment of cells cultured in a monolayer are substantially different to that of cells existing in three-dimension (3D) in vivo, we assessed whether two EGFR-mutant lung adenocarcinoma cell lines, HCC827 and H1975, were more resistant to EGFR TKI-induced apoptosis when cultured in a 3D extracellular matrix (ECM) as compared with in suspension. The ECM-adherent EGFR-mutant cells in 3D were significantly less sensitive to treatment with WZ4002, an EGFR TKI, than the suspended cells. Further, a marked degradation of IκBα, the inhibitor of nuclear factor (NF)-κB, was observed only in the 3D-cultured cells, leading to an increase in the activation of NF-κB. Moreover, the inhibition of NF-κB with pharmacological inhibitors enhanced EGFR TKI-induced apoptosis in 3D-cultured EGFR-mutant cells. These results suggest that inhibition of NF-κB signaling would render ECM-adherent EGFR-mutant lung adenocarcinoma cells in vivo more susceptible to EGFR TKI-induced cell death.

Exploring Class-Based Intersectionality

Science.gov (United States)

Block, David; Corona, Victor

2014-01-01

This paper argues that language, culture and identity researchers need to take the intersectionality of identity inscriptions seriously and, further to this, that an intersectional approach which emanates from an interest in social class provides a productive way to examine the lives and experience of individuals living in multicultural societies.…

Brucein D, a Naturally Occurring Tetracyclic Triterpene Quassinoid, Induces Apoptosis in Pancreatic Cancer through ROS-Associated PI3K/Akt Signaling Pathway

Directory of Open Access Journals (Sweden)

Zheng-Quan Lai

2017-12-01

Full Text Available Brucein D (BD, a major active quassinoid in Brucea javanica, has exhibited pronounced anticancer activities. However, the biologic mechanisms have not been fully explored. In this study, BD exhibited more potent cytotoxic effect on pancreatic cancer (PanCa cell lines, while exerted weaker cytotoxic effects on GES-1 cells (non-tumorigenic. BD was shown to elicit apoptosis through inducing both the intrinsic and extrinsic mitochondria-mediated caspase activations. Furthermore, the BD-induced apoptotic effects were dependent on the accumulated reactive oxygen species (ROS and inactivation of PI3K/Akt signaling pathway. Pretreatment with tempol completely prevented the cellular apoptosis induced by BD, and recovered the inactivation of AKT, which suggested ROS essentially involved in BD-elicited apoptosis and down-regulation of PI3K/Akt pathway. In addition, the results obtained from orthotopic xenograft in nude mice were congruent with those of the in vitro investigations. These results support the notion that BD held good potential to be further developed into an effective pharmaceutical agent for the treatment of PanCa.

Where to locate transit stops: Cross-intersection profiles of ultrafine particles and implications for pedestrian exposure.

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Choi, Wonsik; Ranasinghe, Dilhara; DeShazo, J R; Kim, Jae-Jin; Paulson, Suzanne E

2018-02-01

Epidemiological studies have shown that exposure to traffic-related pollutants increases incidence of adverse health outcomes. Transit users in cities across the globe commonly spend 15-45 min or more waiting at transit stops each day, often at locations with high levels of pollution from traffic. Here, we investigate the characteristics of concentration profiles of ultrafine particles (UFP) with 5 m spatial resolution across intersections, to determine the best place to site transit stops to minimize exposures. Cross-intersection UFP profiles were derived from 1744 profiles covering 90 m before and after each intersection center with a mobile monitoring platform. Measurements were made at 10 signalized intersections located at six urban sites, each with a distinct built environment, during both mornings and afternoons. Measurements were made within 1.5 m of the sidewalk and approximately at breathing height (1.5 m above ground level) to approximate sidewalk exposures. UFP profiles were strongly influenced by high emissions from vehicle stops and accelerations, and peaked within 30 m of intersection centers; from there concentrations decreased sharply with distance. Peak concentrations averaged about 90% higher than the minima along the block. They were accompanied by more frequent and larger transient concentration spikes, increasing the chance of people near the intersection being exposed to both short-term extremely high concentration spikes and higher average concentrations. The decays are somewhat larger before the intersection than after the intersection, however as siting transit stops after intersections is preferred for smooth traffic flow, we focus on after the intersection. Simple time-duration exposure calculations combined with breathing rates suggest moving a bus stop from 20 to 40-50 m after the intersection can reduce transit-users' exposure levels to total UFP substantially, in proportion to the reciprocal of the magnitude of elevation at

DHX15 is associated with poor prognosis in acute myeloid leukemia (AML) and regulates cell apoptosis via the NF-kB signaling pathway.

Science.gov (United States)

Pan, Lili; Li, Yang; Zhang, Hai-Ying; Zheng, Yi; Liu, Xiao-Li; Hu, Zheng; Wang, Yi; Wang, Jing; Cai, Yuan-Hua; Liu, Qiao; Chen, Wan-Ling; Guo, Ying; Huang, Yuan-Mao; Qian, Feng; Jin, Li; Wang, Jiucun; Wang, Shao-Yuan

2017-10-27

The role of DHX15 , a newly identified DEAH-box RNA helicase, in leukemogenesis remains elusive. Here, we identified a recurrent mutation in DHX15 (NM_001358:c.664C>G: p.(R222G)) in one familial AML patient and 4/240 sporadic AML patients. Additionally, DHX15 was commonly overexpressed in AML patients and associated with poor overall survival (OS) (P=0.019) and relapse-free survival (RFS) (P=0.032). In addition, we found a distinct expression pattern of DHX15 . DHX15 was highly expressed in hematopoietic stem cells and leukemia cells but was lowly expressed in mature blood cells. DHX15 was down-regulated when AML patients achieved disease remission or when leukemia cell lines were induced to differentiate. DHX15 silencing greatly inhibited leukemia cell proliferation and induced cell apoptosis and G1-phase arrest. In contrast, the restoration of DHX15 expression rescued cell viability and reduced cell apoptosis. In addition, we found that DHX15 was down-regulated when cell apoptosis was induced by ATO (arsenic trioxide); overexpression of DHX15 caused dramatic resistance to ATO-induced cell apoptosis, suggesting an important role for DHX15 in cell apoptosis. We further explored the mechanism of DHX15 in apoptosis and found that overexpression of DHX15 activated NF-kB transcription. Knockdown of DHX15 inhibited the nuclear translocation and activation of the NF-kB subunit P65 in leukemia cells. Several downstream targets of the NF-kB pathway were also down-regulated, and apoptosis-associated genes CASP3 and PARP were activated. In conclusion, this study represents the first demonstration that DHX15 plays an important role in leukemogenesis via the NF-kB signaling pathway and may serve as an independent prognostic marker for AML.

30 CFR 57.7055 - Intersecting holes.

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Intersecting holes. 57.7055 Section 57.7055... Jet Piercing Drilling-Surface and Underground § 57.7055 Intersecting holes. Holes shall not be drilled where there is a danger of intersecting a misfired hole or a hole containing explosives, blasting agents...

UpSet: Visualization of Intersecting Sets

Science.gov (United States)

Lex, Alexander; Gehlenborg, Nils; Strobelt, Hendrik; Vuillemot, Romain; Pfister, Hanspeter

2016-01-01

Understanding relationships between sets is an important analysis task that has received widespread attention in the visualization community. The major challenge in this context is the combinatorial explosion of the number of set intersections if the number of sets exceeds a trivial threshold. In this paper we introduce UpSet, a novel visualization technique for the quantitative analysis of sets, their intersections, and aggregates of intersections. UpSet is focused on creating task-driven aggregates, communicating the size and properties of aggregates and intersections, and a duality between the visualization of the elements in a dataset and their set membership. UpSet visualizes set intersections in a matrix layout and introduces aggregates based on groupings and queries. The matrix layout enables the effective representation of associated data, such as the number of elements in the aggregates and intersections, as well as additional summary statistics derived from subset or element attributes. Sorting according to various measures enables a task-driven analysis of relevant intersections and aggregates. The elements represented in the sets and their associated attributes are visualized in a separate view. Queries based on containment in specific intersections, aggregates or driven by attribute filters are propagated between both views. We also introduce several advanced visual encodings and interaction methods to overcome the problems of varying scales and to address scalability. UpSet is web-based and open source. We demonstrate its general utility in multiple use cases from various domains. PMID:26356912

Secoisolariciresinol diglucoside prevents the oxidative stress-induced apoptosis of myocardial cells through activation of the JAK2/STAT3 signaling pathway.

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Huang, Guiqiong; Huang, Xiaofang; Liu, Min; Hua, Yue; Deng, Bo; Jin, Wen; Yan, Wen; Tan, Zhangbin; Wu, Yifen; Liu, Bin; Zhou, Yingchun

2018-06-01

Myocardial cell apoptosis mediated by oxidative stress has previously been identified as a key process in ischemic heart disease. Secoisolariciresinol diglucoside (SDG), a polyphenolic plant lignan primarily found in flaxseed, has been demonstrated to effectively protect myocardial cells from apoptosis. In the present study, the role of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) was investigated in mediating the protective effect of SDG. Findings of the present study revealed that treatment with H2O2 reduced cell viability and induced apoptosis in H9C2 rat cardiomyocytes. However, SDG was able to reduce the effect of H2O2 in a dose‑dependent manner. H2O2 reduced the expression level of phosphorylated STAT3 and inhibited the levels of B‑cell lymphoma‑extra‑large and induced myeloid leukemia cell differentiation protein, which are the STAT3 target genes. Conversely, SDG rescued phosphorylation of STAT3 and increased the levels of STAT3 target genes. Treatment with SDG alone led to a dose‑dependent increased phosphorylation of JAK2 and STAT3, without activating Src. Furthermore, the anti‑apoptotic effects of SDG were partially abolished by a JAK2/STAT3 inhibitor. In addition, molecular docking revealed that SDG may bind to the protein kinase domain of JAK2, at a binding energy of ‑8.258 kcal/mol. Molecular dynamics simulations revealed that JAK2‑SDG binding was stable. In conclusion, activation of the JAK2/STAT3 signaling pathway contributed to the anti‑apoptotic activity of SDG, which may be a potential JAK2 activator.

Differential Gene Expression Patterns in Chicken Cardiomyocytes during Hydrogen Peroxide-Induced Apoptosis.

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Wan, Chunyun; Xiang, Jinmei; Li, Youwen; Guo, Dingzong

2016-01-01

Hydrogen peroxide (H2O2) is both an exogenous and endogenous cytotoxic agent that can reliably induce apoptosis in numerous cell types for studies on apoptosis signaling pathways. However, little is known of these apoptotic processes in myocardial cells of chicken, a species prone to progressive heart failure. Sequencing of mRNA transcripts (RNA-Seq) allows for the identification of differentially expressed genes under various physiological and pathological conditions to elucidate the molecular pathways involved, including cellular responses to exogenous and endogenous toxins. We used RNA-seq to examine genes differentially expressed during H2O2-induced apoptosis in primary cultures of embryonic chicken cardiomyocytes. Following control or H2O2 treatment, RNA was extracted and sequencing performed to identify novel transcripts up- or downregulated in the H2O2 treatment group and construct protein-protein interaction networks. Of the 19,268 known and 2,160 novel transcripts identified in both control and H2O2 treatment groups, 4,650 showed significant differential expression. Among them, 55.63% were upregulated and 44.37% downregulated. Initiation of apoptosis by H2O2 was associated with upregulation of caspase-8, caspase-9, and caspase-3, and downregulation of anti-apoptotic genes API5 and TRIA1. Many other differentially expressed genes were associated with metabolic pathways (including 'Fatty acid metabolism', 'Alanine, aspartate, and glutamate metabolism', and 'Biosynthesis of unsaturated fatty acids') and cell signaling pathways (including 'PPAR signaling pathway', 'Adipocytokine signaling pathway', 'TGF-beta signaling pathway', 'MAPK signaling pathway', and 'p53 signaling pathway'). In chicken cardiomyocytes, H2O2 alters the expression of numerous genes linked to cell signaling and metabolism as well as genes directly associated with apoptosis. In particular, H2O2 also affects the biosynthesis and processing of proteins and unsaturated fatty acids. These

Icariside II induces apoptosis in U937 acute myeloid leukemia cells: role of inactivation of STAT3-related signaling.

Directory of Open Access Journals (Sweden)

Sang-Hun Kang

Full Text Available BACKGROUND: The aim of this study is to determine anti-cancer effect of Icariside II purified from the root of Epimedium koreanum Nakai on human acute myeloid leukemia (AML cell line U937. METHODOLOGY/PRINCIPAL FINDINGS: Icariside II blocked the growth U937 cells in a dose- and time-dependent manner. In this anti-proliferation process, this herb compound rendered the cells susceptible to apoptosis, manifested by enhanced accumulation of sub-G1 cell population and increased the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL-positive cells. Icariside II was able to activate caspase-3 and cleaved poly (ADP-ribose polymerase (PARP in a time-dependent manner. Concurrently, the anti-apoptotic proteins, such as bcl-x(L and survivin in U937 cells, were downregulated by Icariside II. In addition, Icariside II could inhibit STAT3 phosphorylation and function and subsequently suppress the activation of Janus activated kinase 2 (JAK2, the upstream activators of STAT3, in a dose- and time-dependent manner. Icariside II also enhanced the expression of protein tyrosine phosphatase (PTP SH2 domain-containing phosphatase (SHP-1, and the addition of sodium pervanadate (a PTP inhibitor prevented Icariside II-induced apoptosis as well as STAT3 inactivation in STAT3 positive U937 cells. Furthermore, silencing SHP-1 using its specific siRNA significantly blocked STAT3 inactivation and apoptosis induced by Icariside II in U937 cells. CONCLUSIONS/SIGNIFICANCE: Our results demonstrated that via targeting STAT3-related signaling, Icariside II sensitizes U937 cells to apoptosis and perhaps serves as a potent chemotherapeutic agent for AML.

MHC class I cross-talk with CD2 and CD28 induces specific intracellular signalling and leads to growth retardation and apoptosis via a p56(lck)-dependent mechanism

DEFF Research Database (Denmark)

Ruhwald, M; Pedersen, Anders Elm; Claesson, M H

1999-01-01

Ligation of the major histocompatibility complex class I molecules (MHC-I) on human T lymphoma cells (Jurkat) initiates p56(lck)-dependent intracellular signalling events (phosphotyrosine kinase activity; [Ca(2+)](i)) and leads to augmented growth inhibition and apoptosis. MHC-I ligation in concert...... of apoptosis. In parallel experiments with the p56(lck)-negative Jurkat mutant cell, JCaM1.6, cross-linking neither influenced cell signalling nor cellular growth functions, indicating a cardinal role of the src kinases in signal transduction via MHC-I, CD2 and CD28 molecules. The results presented here...... with ligation of CD2 or CD28 augments, changes or modifies the pattern of activation. Ligation of MHC-I and CD2 alone resulted in growth inhibition, whereas CD28 ligation alone had no effect on cell proliferation. Ligation of MHC-I together with CD2 augmented growth inhibition and enhanced the level...

Pedestrians´and cyclists´effect on capacity of right turn movement at signalized intersections

DEFF Research Database (Denmark)

Jørgensen, N O; Aagaard, Pierre E.; Rysgaard, Rikke

1998-01-01

Observations from 4 intersections in Copenhagen are used to formulate a model for the delays which right turning car traffic experience due to straight ahead going pedestrians and cyclists. The empirical data are used to formulate a simulation model which allows estimation of delays in cases...

30 CFR 56.7055 - Intersecting holes.

Science.gov (United States)

2010-07-01

... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Intersecting holes. 56.7055 Section 56.7055... Piercing Drilling § 56.7055 Intersecting holes. Holes shall not be drilled where there is a danger of intersecting a misfired hole or a hole containing explosives blasting agents, or detonators. [56 FR 46508, Sept...

Traffic Signal Cycle Lengths

Data.gov (United States)

Town of Chapel Hill, North Carolina — Traffic signal location list for the town of Chapel Hill. This data set includes light cycle information as well as as intersection information.The Town of Chapel...

A mechanism for suppression of the CDP-choline pathway during apoptosis

OpenAIRE

Morton, Craig C.; Aitchison, Adam J.; Gehrig, Karsten; Ridgway, Neale D.

2013-01-01

Inhibition of the CDP-choline pathway during apoptosis restricts the availability of phosphatidylcholine (PtdCho) for assembly of membranes and synthesis of signaling factors. The N-terminal nuclear localization signal (NLS) in CTP:phosphocholine cytidylyltransferase (CCT)α is removed during apoptosis but the caspase(s) involved and the contribution to suppression of the CDP-choline pathway is unresolved. In this study we utilized siRNA silencing of caspases in HEK293 cells and caspase 3-defi...

Construction and analysis of a modular model of caspase activation in apoptosis

Directory of Open Access Journals (Sweden)

Ho Kenneth L

2008-12-01

Full Text Available Abstract Background A key physiological mechanism employed by multicellular organisms is apoptosis, or programmed cell death. Apoptosis is triggered by the activation of caspases in response to both extracellular (extrinsic and intracellular (intrinsic signals. The extrinsic and intrinsic pathways are characterized by the formation of the death-inducing signaling complex (DISC and the apoptosome, respectively; both the DISC and the apoptosome are oligomers with complex formation dynamics. Additionally, the extrinsic and intrinsic pathways are coupled through the mitochondrial apoptosis-induced channel via the Bcl-2 family of proteins. Results A model of caspase activation is constructed and analyzed. The apoptosis signaling network is simplified through modularization methodologies and equilibrium abstractions for three functional modules. The mathematical model is composed of a system of ordinary differential equations which is numerically solved. Multiple linear regression analysis investigates the role of each module and reduced models are constructed to identify key contributions of the extrinsic and intrinsic pathways in triggering apoptosis for different cell lines. Conclusion Through linear regression techniques, we identified the feedbacks, dissociation of complexes, and negative regulators as the key components in apoptosis. The analysis and reduced models for our model formulation reveal that the chosen cell lines predominately exhibit strong extrinsic caspase, typical of type I cell, behavior. Furthermore, under the simplified model framework, the selected cells lines exhibit different modes by which caspase activation may occur. Finally the proposed modularized model of apoptosis may generalize behavior for additional cells and tissues, specifically identifying and predicting components responsible for the transition from type I to type II cell behavior.

Exploring the impact of signal types and adjacent vehicles on drivers' choices after the onset of yellow

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Bao, Ji; Chen, Qun; Luo, Dandan; Wu, Yuli; Liang, Zuli

2018-06-01

Drivers' choices at signalized intersections may be made in great uncertainty after the onset of yellow, which creates potential hazards for road safety. These choices are analyzed and modeled based on field observations at three comparable signalized intersections in Changsha, China. The results show that intersections without monitoring devices widen the indecision zone, which can increase the risk of rear-end collisions and the uncertainty of drivers' decision-making. In addition, drivers are more likely to stop during the yellow interval at intersections equipped with a green signal countdown device (GSCD) than at those with a green signal flashing device (GSFD). Subsequently, according to the results of a binary logistic regression model (BLRM), drivers' decision making at the onset of the yellow indication is greatly influenced by the vehicle's spot speed, the distance to the stop line, and signal and monitoring devices. The presence of an adjacent vehicle with a short space headway can particularly motivate the following driver to make a go-decision after the first driver chooses to pass the intersection. However, a stop-decision by a driver in an adjacent lane can also prompt the following driver to stop.

Apoptotic cells can induce non-autonomous apoptosis through the TNF pathway

Science.gov (United States)

Pérez-Garijo, Ainhoa; Fuchs, Yaron; Steller, Hermann

2013-01-01

Apoptotic cells can produce signals to instruct cells in their local environment, including ones that stimulate engulfment and proliferation. We identified a novel mode of communication by which apoptotic cells induce additional apoptosis in the same tissue. Strong induction of apoptosis in one compartment of the Drosophila wing disc causes apoptosis of cells in the other compartment, indicating that dying cells can release long-range death factors. We identified Eiger, the Drosophila tumor necrosis factor (TNF) homolog, as the signal responsible for apoptosis-induced apoptosis (AiA). Eiger is produced in apoptotic cells and, through activation of the c-Jun N-terminal kinase (JNK) pathway, is able to propagate the initial apoptotic stimulus. We also show that during coordinated cell death of hair follicle cells in mice, TNF-α is expressed in apoptotic cells and is required for normal cell death. AiA provides a mechanism to explain cohort behavior of dying cells that is seen both in normal development and under pathological conditions. DOI: http://dx.doi.org/10.7554/eLife.01004.001 PMID:24066226

The signalling axis mediating neuronal apoptosis in response to [Pt(O,O'-acac)(γ-acac)(DMS)].

Science.gov (United States)

Muscella, Antonella; Calabriso, Nadia; Vetrugno, Carla; Fanizzi, Francesco Paolo; De Pascali, Sandra Angelica; Marsigliante, Santo

2011-06-01

It was previously shown that [Pt(O,O'-acac)(γ-acac)(DMS)] induces apoptosis in various cancer cells and exerts antimetastatic responses in vitro. In rats, [Pt(O,O'-acac)(γ-acac)(DMS)] reaches the central nervous system in quantities higher than cisplatin causing less excitotoxicity. The aim of the present paper was to investigate whether [Pt(O,O'-acac)(γ-acac)(DMS)] is able to exert cytotoxic effects on SH-SY5Y human neuroblastoma cell line, and to study the intracellular transduction mechanisms underlying these effects. Here we have demonstrated that [Pt(O,O'-acac)(γ-acac)(DMS)] was more effective than cisplatin in provoking apoptosis characterized by: (a) mitochondria depolarization, (b) decrease of Bcl-2 expression and increase of BAX expressions with cytosol-to-mitochondria translocation, (c) activation of caspase-7 and -9 and (d) generation of reactive oxygen species (ROS). [Pt(O,O'-acac)(γ-acac)(DMS)] provoked the activation of the following signalling kinases that were interacting with each other: PKC-δ and -ɛ, ERK1/2, p38MAPK, JNK1/2, NF-κB, c-src and FAK. We found that ROS generated by NADPH oxidase was responsible for the [Pt(O,O'-acac)(γ-acac)(DMS)]-mediated PKC-δ and -ɛ activation and consequential phosphorylation of all MAPKs. [Pt(O,O'-acac)(γ-acac)(DMS)]-induced mitochondrial apoptosis was blocked when p38MAPK and JNK1/2 were inhibited, whilst the effects on Bax/Bcl-2 mRNA and protein levels were blocked inhibiting NF-κB. NF-κB nuclear translocation was blocked inhibiting MEK1/2 activity. In addition to the induction of apoptosis [Pt(O,O'-acac)(γ-acac)(DMS)] downregulated pro-survival pathway. Survival inhibition started from mitochondrial ROS generation which induced c-src, FAK and Akt activation. In conclusion, our results suggest that [Pt(O,O'-acac)(γ-acac)(DMS)] may be considered a promising compound for the treatment of neuroblastoma. Further studies are warranted to explore in detail the therapeutic potential of this compound

Deployment and Field Evaluation of In-Vehicle Traffic Signal Advisory System (ITSAS

Directory of Open Access Journals (Sweden)

Joyoung Lee

2017-06-01

Full Text Available This research evaluates the impact of In-vehicle Signal Advisory System (ITSAS on signalized arterial. ITSAS provides individual drivers equipped with a mobile communication device with advisory speed information enabling to minimize the time delay and fuel consumption when crossing intersection. Given the instantaneous vehicular driving information, such as position, speed, and acceleration rate, ITSAS produces advisory speed information by taking into consideration the traffic signal changes at a downstream intersection. The advisory speed information includes not only an optimal speed range updated every 300-ft for individual drivers but also a descriptive message to warn drivers stop to ensure safety at the downstream intersection. Unlike other similar Connected Vehicles applications for intersection management, ITSAS does not require Roadside Equipment (RSE to disseminate the advisory speed information as it is designed to exploit commercial cellular network service (i.e., 3G and 4G-LTE. Thus, ITSAS can be easily plugged into existing traffic control management system to rapidly conduct its implementation without significant additional cost. This research presents the field evaluations of ITSAS on a signalized corridor in New Jersey, which discovered significant travel time savings for the equipped vehicle.

Relaxin attenuates aristolochic acid induced human tubular epithelial cell apoptosis in vitro by activation of the PI3K/Akt signaling pathway.

Science.gov (United States)

Xie, Xiang-Cheng; Zhao, Ning; Xu, Qun-Hong; Yang, Xiu; Xia, Wen-Kai; Chen, Qi; Wang, Ming; Fei, Xiao

2017-06-01

Aristolochic acid nephropathy remains a leading cause of chronic kidney disease (CKD), however few treatment strategies exist. Emerging evidence has shown that H2 relaxin (RLX) possesses powerful antifibrosis and anti-apoptotic properties, therefore we aimed to investigate whether H2 relaxin can be employed to reduce AA-induced cell apoptosis. Human proximal tubular epithelial (HK-2) cells exposed to AA-I were treated with or without administration of H2 RLX. Cell viability was examined using the WST-8 assay. Apoptotic morphologic alterations were observed using the Hoechst 33342 staining method. Apoptosis was detected using flow cytometry. The expression of caspase 3, caspase 8, caspase 9, ERK1/2, Bax, Bcl-2, and Akt proteins was determined by Western blot. Co-treatment with RLX reversed the increased apoptosis observed in the AA-I only treated group. RLX restored expression of phosphorylated Akt which found to be decreased in the AA-I only treated cells. RLX co-treatment led to a decrease in the Bax/Bcl-2 ratio as well as the cleaved form of caspase-3 compared to the AA-I only treated cells. This anti-apoptotic effect of RLX was attenuated by co-administration of the Akt inhibitor LY294002. The present study demonstrated H2 RLX can decrease AA-I induced apoptosis through activation of the PI3K/Akt signaling pathway.

Estimation of left-turning vehicle maneuvers for the assessment of pedestrian safety at intersections

Directory of Open Access Journals (Sweden)

Wael K.M. Alhajyaseen

2012-07-01

Full Text Available Improving pedestrian safety at intersections remains a critical issue. Although several types of safety countermeasures, such as reforming intersection layouts, have been implemented, methods have not yet been established to quantitatively evaluate the effects of these countermeasures before installation. One of the main issues in pedestrian safety is conflicts with turning vehicles. This study aims to develop an integrated model to represent the variations in the maneuvers of left-turners (left-hand traffic at signalized intersections that dynamically considers the vehicle reaction to intersection geometry and crossing pedestrians. The proposed method consists of four empirically developed stochastic sub-models, including a path model, free-flow speed profile model, lag/gap acceptance model, and stopping/clearing speed profile model. Since safety assessment is the main objective driving the development of the proposed model, this study uses post-encroachment time (PET and vehicle speed at the crosswalk as validation parameters. Preliminary validation results obtained by Monte Carlo simulation show that the proposed integrated model can realistically represent the variations in vehicle maneuvers as well as the distribution of PET and vehicle speeds at the crosswalk.

Effect of the Wnt/β-catenin signaling pathway on apoptosis, migration, and invasion of transplanted hepatocellular carcinoma cells after transcatheter arterial chemoembolization in rats.

Science.gov (United States)

Wang, Bao-Ming; Li, Nuo

2018-05-01

This study aims to investigate the influence of the Wnt/β-catenin signaling pathway on apoptosis, migration, and invasion of transplanted hepatocellular carcinoma (HCC) cells after transcatheter arterial chemoembolization (TACE) in rat models. A total of 80 rats were grouped into sham, TACE, Wnt-C59, and TACE + Wnt-C59 groups (n = 20). Ten days after model establishment, 10 rats in each group were executed to perform pathological examination and follow-up experiment, and the remaining 10 rats in each group were reared to observe the survival condition. RT-qPCR and Western blotting were applied to determine the expressions of Wnt1, β-catenin, cyclin D1, c-met, vimentin, E-cadherin, and vascular endothelial growth factor (VEGF). ELISA was performed to measure the serum alpha-fetoprotein (AFP) content of rats. Flow cytometry was used to evaluate cell apoptosis rate and transwell assay to examine cell migration and invasion. Compared with the TACE group, the Wnt-C59 and TACE + Wnt-C59 groups showed increased apoptosis and survival time (the TACE + Wnt-C59 group > the Wnt-C59 group). Compared with the sham group, the TACE + Wnt-C59 groups showed decreased cancer tissue weight and expressions of Wnt1, β-catenin, cyclin D1, vimentin, c-met, and VEGF, but increased E-cadherin expression. Compared with the TACE group, the Wnt-C59 and TACE + Wnt-C59 groups showed decreased AFP level, migration, and invasion (the TACE + Wnt-C59 group Wnt-C59 group). These findings indicate inhibition of the Wnt/β-catenin signaling pathway improves therapeutic effect on TACE via suppressing migration, invasion, and promoting apoptosis of transplanted HCC cells in rats. © 2017 Wiley Periodicals, Inc.

Safety effects of exclusive and concurrent signal phasing for pedestrian crossing.

Science.gov (United States)

Zhang, Yaohua; Mamun, Sha A; Ivan, John N; Ravishanker, Nalini; Haque, Khademul

2015-10-01

This paper describes the estimation of pedestrian crash count and vehicle interaction severity prediction models for a sample of signalized intersections in Connecticut with either concurrent or exclusive pedestrian phasing. With concurrent phasing, pedestrians cross at the same time as motor vehicle traffic in the same direction receives a green phase, while with exclusive phasing, pedestrians cross during their own phase when all motor vehicle traffic on all approaches is stopped. Pedestrians crossing at each intersection were observed and classified according to the severity of interactions with motor vehicles. Observation intersections were selected to represent both types of signal phasing while controlling for other physical characteristics. In the nonlinear mixed models for interaction severity, pedestrians crossing on the walk signal at an exclusive signal experienced lower interaction severity compared to those crossing on the green light with concurrent phasing; however, pedestrians crossing on a green light where an exclusive phase was available experienced higher interaction severity. Intersections with concurrent phasing have fewer total pedestrian crashes than those with exclusive phasing but more crashes at higher severity levels. It is recommended that exclusive pedestrian phasing only be used at locations where pedestrians are more likely to comply. Copyright © 2015. Published by Elsevier Ltd.

Noxa/Mcl-1 Balance Regulates Susceptibility of Cells to Camptothecin-Induced Apoptosis

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Yide Mei

2007-10-01

Full Text Available Although camptothecin (CPT has been reported to induce apoptosis in various cancer cells, the molecular details of this regulation remain largely unknown. In this study, we demonstrate that 131-113-only protein Noxa is upregulated during CPT-induced apoptosis, which is independent of p53. In addition, we show that phosphatidylinositol 3-kinase (PI3K/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay, cAMP response element binding protein (CREB knockdown experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. Moreover, blocking Noxa expression using specific small interfering ribonucleic acid (siRNA significantly reduces the apoptosis in response to CPT, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, antiapoptotic Mcl-1 was also upregulated through PI3K/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, Noxa was found to interact with Mcl-1 in the presence or absence of CPT. Knockdown of Mcl-1 expression by short hairpin ribonucleic acid (shRNA was shown to potentiate CPT-induced apoptosis. Consistently, ectopic overexpression of Mcl-1 rescued cells from apoptosis induced by CPT. Cells coexpressing Noxa, Mcl-1 at different ratio correlates well with the extent of apoptosis, suggesting that the balance between Noxa, Mcl-1 may determine the susceptibility of HeLa cells to CPT-induced apoptosis.

[Effect of ginseng polysaccharide-induced wnt/beta-catenin signal transduction pathway on apoptosis of human nasopharyngeal cancer cells CNE-2].

Science.gov (United States)

Fan, Jia-Ming; Liu, Ze-Hong; Li, Jing; Wang, Ya-Ping; Yang, Lv-Yuan; Huang, Jiang-Ju

2013-10-01

proliferation of CNE-2 cells and promote thier apoptosis. The obstruction of Wnt/beta-catenin signaling pathway may be an important mechanism for GPS to induce the apoptosis of human nasopharyngeal cancer cells CNE-2.

Monitoring conical intersections in the ring opening of furan by attosecond stimulated X-ray Raman spectroscopy

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Weijie Hua

2016-03-01

Full Text Available Attosecond X-ray pulses are short enough to capture snapshots of molecules undergoing nonadiabatic electron and nuclear dynamics at conical intersections (CoIns. We show that a stimulated Raman probe induced by a combination of an attosecond and a femtosecond pulse has a unique temporal and spectral resolution for probing the nonadiabatic dynamics and detecting the ultrafast (∼4.5 fs passage through a CoIn. This is demonstrated by a multiconfigurational self-consistent-field study of the dynamics and spectroscopy of the furan ring-opening reaction. Trajectories generated by surface hopping simulations were used to predict Attosecond Stimulated X-ray Raman Spectroscopy signals at reactant and product structures as well as representative snapshots along the conical intersection seam. The signals are highly sensitive to the changes in nonadiabatically coupled electronic structure and geometry.

Effect of Boron on Thymic Cytokine Expression, Hormone Secretion, Antioxidant Functions, Cell Proliferation, and Apoptosis Potential via the Extracellular Signal-Regulated Kinases 1 and 2 Signaling Pathway.

Science.gov (United States)

Jin, Erhui; Ren, Man; Liu, Wenwen; Liang, Shuang; Hu, Qianqian; Gu, Youfang; Li, Shenghe

2017-12-27

Boron is an essential trace element in animals. Appropriate boron supplementation can promote thymus development; however, a high dose of boron can lead to adverse effects and cause toxicity. The influencing mechanism of boron on the animal body remains unclear. In this study, we examined the effect of boron on cytokine expression, thymosin and thymopoietin secretion, antioxidant function, cell proliferation and apoptosis, and extracellular signal-regulated kinases 1 and 2 (ERK1/2) pathway in the thymus of rats. We found that supplementation with 10 and 20 mg/L boron to the drinking water significantly elevated levels of interleukin 2 (IL-2), interferon γ (IFN-γ), interleukin 4 (IL-4), and thymosin α1 in the thymus of rats (p boron had no apparent effect on many of the above indicators. In contrast, supplementation with 480 and 640 mg/L boron had the opposite effect on the above indicators in rats and elevated levels of pro-inflammatory cytokines, such as interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor α (TNF-α) (p boron to the drinking water had a U-shaped dose-effect relationship with thymic cytokine expression, hormone secretion, antioxidant function, cell proliferation, and apoptosis. Specifically, supplementation with 10 and 20 mg/L boron promoted thymocyte proliferation and enhanced thymic functions. However, supplementation with 480 and 640 mg/L boron inhibited thymic functions and increased the number of apoptotic thymocytes, suggesting that the effects of boron on thymic functions may be caused via the ERK1/2 signaling pathway.

ISR Intersection 1

CERN Multimedia

CERN PhotoLab

1974-01-01

The experimental apparatus used at intersection 1 by the CERN-Bologna Collaboration (experiment R105). It consists of two almost identical magnetic spectrometers centered at 90 degrees on opposite sides of the intersection region. In each spectrometer one can see magnetostrictive wire spark chambers, a magnet, more chambers and various hodoscopes of scintillation counters. Gas Cerenkov counters (almost invisible in the picture) are located in the gap of each magnet. On the left hand side, a matrix of 119 lead glass Cerenkov counters is located behind some concrete and iron shielding.

Molecular dynamics simulation of dislocation intersections in aluminum

International Nuclear Information System (INIS)

Li, M.; Chu, W.Y.; Qian, C.F.; Gao, K.W.; Qiao, L.J.

2003-01-01

The molecular dynamics method is used to simulate dislocation intersection in aluminum containing 1.6x10 6 atoms using embedded atom method (EAM) potential. The results show that after intersection between two right-hand screw dislocations of opposite sign there are an extended jog corresponding to a row of 1/3 vacancies in the intersected dislocation, and a trail of vacancies behind the moving dislocation. After intersection between screw dislocations of same sign, there are an extended jog corresponding to a row of 1/3 interstitials in the intersected dislocation, and a trail of interstitials behind the moving dislocation. After intersection between screw and edge dislocations with different Burgers vector, there are a constriction corresponding to one 1/3 vacancy in the edge dislocation, and no point-defects behind the screw dislocation. When a moving screw dislocation intersects an edge dislocation with the same Burgers vector, the point of intersection will split into two constrictions corresponding to one 1/3 vacancy and 1/3 interstitial, respectively. The moving screw dislocation can pass the edge dislocation only after the two constrictions, which can move along the line of intersection of the two slip planes, meet and annihilate

Traffic Safety of Older Drivers in Various Types of Road Intersections

Directory of Open Access Journals (Sweden)

Tomaž Tollazzi

2010-05-01

Full Text Available In industrialized countries people over 50 years of age represent a rapidly growing part of population. Their lifestyle is also becoming more active, which means that the percentage of older drivers in the population of all drivers is also increasing. Many different studies have shown that elderly drivers are more frequently involved in specific types of accidents, especially at intersections. In the past 15 years there was a trend of increasing popularity of roundabouts in Slovenia. Their introduction was generally supported by the arguments of increased traffic-flow capacity and traffic safety as well. The studies on which these arguments are based were performed with an “ideal” type of driver in mind; the one that fully understands new rules and reacts correctly in all situations that may occur at such intersections, where there are no light signals to guide them. An elderly person does not necessarily conform to that ideal and if the percentage of elderly drivers became significant, the premises of the above mentioned studies may not be correct anymore which in turn implies that their results could also be questioned. The present study concentrated on the evaluation of traffic safety of elderly drivers, at various types of intersection, from their own perspective. Various statistical analyses of obtained data were performed. The most important finding was that we may claim, with high degree of probability, that the average person of the age of over 60 feels more unsafe at double-lane roundabouts than they would feel had the same intersection been equipped with traffic lights. Elderly traffic participants will always cause more accidents or participate in them due to hazardous factors. Challenge, arising from many different studies and researches, is in studying what measures and solutions can reduce the risk for elderly participants. KEYWORDS: traffic safety, road intersections, roundabouts, elderly people, older drivers

MicroRNA-Mediated Down-Regulation of Apoptosis Signal-Regulating Kinase 1 (ASK1) Attenuates the Apoptosis of Human Mesenchymal Stem Cells (MSCs) Transplanted into Infarcted Heart.

Science.gov (United States)

Lee, Chang Youn; Shin, Sunhye; Lee, Jiyun; Seo, Hyang-Hee; Lim, Kyu Hee; Kim, Hyemin; Choi, Jung-Won; Kim, Sang Woo; Lee, Seahyung; Lim, Soyeon; Hwang, Ki-Chul

2016-10-20

Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs) has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic effect of stem cells. In the damaged heart, oxidative stress due to reactive oxygen species (ROS) production can cause the death of transplanted MSCs. Apoptosis signal-regulating kinase 1 (ASK1) has been implicated in the development of oxidative stress-related pathologic conditions. Thus, we hypothesized that down-regulation of ASK1 in human MSCs (hMSCs) might attenuate the post-transplantation death of MSCs. To test this hypothesis, we screened microRNAs (miRNAs) based on a miRNA-target prediction database and empirical data and investigated the anti-apoptotic effect of selected miRNAs on human adipose-derived stem cells (hASCs) and on rat myocardial infarction (MI) models. Our data indicated that miRNA-301a most significantly suppressed ASK1 expression in hASCs. Apoptosis-related genes were significantly down-regulated in miRNA-301a-enriched hASCs exposed to hypoxic conditions. Taken together, these data show that miRNA-mediated down-regulation of ASK1 protects MSCs during post-transplantation, leading to an increase in the efficacy of MSC-based cell therapy.

MicroRNA-Mediated Down-Regulation of Apoptosis Signal-Regulating Kinase 1 (ASK1 Attenuates the Apoptosis of Human Mesenchymal Stem Cells (MSCs Transplanted into Infarcted Heart

Directory of Open Access Journals (Sweden)

Chang Youn Lee

2016-10-01

Full Text Available Stem cell therapy using adult stem cells, such as mesenchymal stem cells (MSCs has produced some promising results in treating the damaged heart. However, the low survival rate of MSCs after transplantation is still one of the crucial factors that limit the therapeutic effect of stem cells. In the damaged heart, oxidative stress due to reactive oxygen species (ROS production can cause the death of transplanted MSCs. Apoptosis signal-regulating kinase 1 (ASK1 has been implicated in the development of oxidative stress-related pathologic conditions. Thus, we hypothesized that down-regulation of ASK1 in human MSCs (hMSCs might attenuate the post-transplantation death of MSCs. To test this hypothesis, we screened microRNAs (miRNAs based on a miRNA-target prediction database and empirical data and investigated the anti-apoptotic effect of selected miRNAs on human adipose-derived stem cells (hASCs and on rat myocardial infarction (MI models. Our data indicated that miRNA-301a most significantly suppressed ASK1 expression in hASCs. Apoptosis-related genes were significantly down-regulated in miRNA-301a-enriched hASCs exposed to hypoxic conditions. Taken together, these data show that miRNA-mediated down-regulation of ASK1 protects MSCs during post-transplantation, leading to an increase in the efficacy of MSC-based cell therapy.

Hydrogen-Rich Saline Attenuates Brain Injury Induced by Cardiopulmonary Bypass and Inhibits Microvascular Endothelial Cell Apoptosis Via the PI3K/Akt/GSK3β Signaling Pathway in Rats

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Keyan Chen

2017-10-01

Full Text Available Background/Aims: Cardiopulmonary bypass (CPB is prone to inducing brain injury during open heart surgery. A hydrogen-rich solution (HRS can prevent oxidation and apoptosis, and inhibit inflammation. This study investigated effects of HRS on brain injury induced by CPB and regulatory mechanisms of the PI3K/Akt/GSK3β signaling pathway. Methods: A rat CPB model and an in vitro cell hypoxia model were established. After HRS treatment, Rat behavior was measured using neurological deficit score; Evans blue (EB was used to assess permeability of the blood-brain barrier (BBB; HE staining was used to observe pathological changes; Inflammatory factors and brain injury markers were detected by ELISA; the PI3K/Akt/GSK3β pathway-related proteins and apoptosis were assessed by western blot, immunohistochemistry and qRT –PCR analyses of brain tissue and neurons. Results: After CPB, brain tissue anatomy was disordered, and cell structure was abnormal. Brain tissue EB content increased. There was an increase in the number of apoptotic cells, an increase in expression of Bax and caspase-3, a decrease in expression of Bcl2, and increases in levels of Akt, GSK3β, P-Akt, and P-GSK3β in brain tissue. HRS treatment attenuated the inflammatory reaction ,brain tissue EB content was significantly reduced and significantly decreased expression levels of Bax, caspase-3, Akt, GSK3β, P-Akt, and P-GSK3β in the brain. After adding the PI3K signaling pathway inhibitor, LY294002, to rat cerebral microvascular endothelial cells (CMECs, HRS could reduce activated Akt expression and downstream regulatory gene phosphorylation of GSK3β expression, and inhibit CMEC apoptosis. Conclusion: The PI3K/Akt/GSK3β signaling pathway plays an important role in the mechanism of CPB-induced brain injury. HRS can reduce CPB-induced brain injury and inhibit CMEC apoptosis through the PI3K/Akt/GSK3β signaling pathway.

Transcriptome analysis of Spodoptera frugiperda Sf9 cells reveals putative apoptosis-related genes and a preliminary apoptosis mechanism induced by azadirachtin.

Science.gov (United States)

Shu, Benshui; Zhang, Jingjing; Sethuraman, Veeran; Cui, Gaofeng; Yi, Xin; Zhong, Guohua

2017-10-16

As an important botanical pesticide, azadirachtin demonstrates broad insecticidal activity against many agricultural pests. The results of a previous study indicated the toxicity and apoptosis induction of azadirachtin in Spodoptera frugiperda Sf9 cells. However, the lack of genomic data has hindered a deeper investigation of apoptosis in Sf9 cells at a molecular level. In the present study, the complete transcriptome data for Sf9 cell line was accomplished using Illumina sequencing technology, and 97 putative apoptosis-related genes were identified through BLAST and KEGG orthologue annotations. Fragments of potential candidate apoptosis-related genes were cloned, and the mRNA expression patterns of ten identified genes regulated by azadirachtin were examined using qRT-PCR. Furthermore, Western blot analysis showed that six putative apoptosis-related proteins were upregulated after being treated with azadirachtin while the protein Bcl-2 were downregulated. These data suggested that both intrinsic and extrinsic apoptotic signal pathways comprising the identified potential apoptosis-related genes were potentially active in S. frugiperda. In addition, the preliminary results revealed that caspase-dependent or caspase-independent apoptotic pathways could function in azadirachtin-induced apoptosis in Sf9 cells.

Paris saponin-induced autophagy promotes breast cancer cell apoptosis via the Akt/mTOR signaling pathway.

Science.gov (United States)

Xie, Zhan-Zhi; Li, Man-Mei; Deng, Peng-Fei; Wang, Sheng; Wang, Lei; Lu, Xue-Ping; Hu, Liu-Bing; Chen, Zui; Jie, Hui-Yang; Wang, Yi-Fei; Liu, Xiao-Xiao; Liu, Zhong

2017-02-25

Paris saponins possess anticancer, anti-inflammatory, and antiviral effects. However, the anticancer effect of Paris saponins has not been well elucidated and the mechanisms underlying the potential function of Paris saponins in cancer therapy are needed to be further identify. In this study, we report that saponin compounds isolated from Paris polyphylla exhibited antitumor activity against breast cancer cell lines, MCF-7 and MDA-MB-231. Paris saponin XA-2 induced apoptosis in both cell lines, as evidenced by the activation of caspases and cleavage of Poly (ADP-ribose) polymerase. The ability of XA-2 to induce autophagy was confirmed by acridine orange staining, accumulation of autophagosome-bound Long chain 3 (LC3)-II, and measurement of autophagic flux. XA-2-induced autophagy was observed to promote apoptosis by the combined treatment of breast cancer cell lines with XA-2 and autophagy inhibitors 3-methyladenine and bafilomycin A1, respectively. Moreover, we report a decrease in the levels of Akt/mTOR signaling pathway proteins, such as the phosphorylated forms of Akt, mTOR, P70S6K, and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1). Taken together, these results provide important insights explaining the anticancer activity of Paris saponins and the potential development of XA-2 as a new therapeutic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Intersectional embodiment and power

DEFF Research Database (Denmark)

Elg, Camilla; Jensen, Sune Qvotrup

Through almost two decades the term ‘intersectionality' has gained influence in post colonial studies, gender studies, feminist theory and other research fields occupied with how social differences are distributed and how individuals are socially constructed  in stratified societies. The ‘interse......Through almost two decades the term ‘intersectionality' has gained influence in post colonial studies, gender studies, feminist theory and other research fields occupied with how social differences are distributed and how individuals are socially constructed  in stratified societies...... not seem to gain much attention in social stratification research in general. In our paper we will present our work on an embodied approach to intersectionality, which is inspired by Pierre Bourdieu and other thinkers of embodiment. We will argue for the importance of a focus on the embodiment of social...

Cache-Oblivious Red-Blue Line Segment Intersection

DEFF Research Database (Denmark)

Arge, Lars; Mølhave, Thomas; Zeh, Norbert

2008-01-01

We present an optimal cache-oblivious algorithm for finding all intersections between a set of non-intersecting red segments and a set of non-intersecting blue segments in the plane. Our algorithm uses $O(\\frac{N}{B}\\log_{M/B}\\frac{N}{B}+T/B)$ memory transfers, where N is the total number...... of segments, M and B are the memory and block transfer sizes of any two consecutive levels of any multilevel memory hierarchy, and T is the number of intersections....

Ghrelin ameliorates the human alveolar epithelial A549 cell apoptosis induced by lipopolysaccharide

International Nuclear Information System (INIS)

Huang, Chunrong; Zheng, Haichong; He, Wanmei; Lu, Guifang; Li, Xia; Deng, Yubin; Zeng, Mian

2016-01-01

Ghrelin is a gastric acyl-peptide that plays an inhibitory role in cell apoptosis. Herein we investigate the protective effects of ghrelin in LPS-induced apoptosis of human alveolar epithelial A549 cells, along with the possible molecular mechanisms. LPS exposure impaired cell viability and increased apoptosis of A549 cells significantly in concentration- and time-dependent manners embodied in increased Bax and cleaved caspase-3 production, coupled with decreased Bcl-2 levels. Simultaneously, LPS remarkably decreased the expression of phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinas (ERK) in A549 cells. However, ghrelin'pretreatment ameliorated LPS-caused alterations in the ratio of Bax/Bcl-2 and cleaved caspase-3 expression, whereas activated the PI3K/Akt and ERK signaling. These results demonstrate that ghrelin lightens LPS-induced apoptosis of human alveolar epithelial cells partly through activating the PI3K/Akt and ERK pathway and thereby might benefit alleviating septic ALI. -- Graphical abstract: Ghrelin ameliorates the human alveolar epithelial A549 cells apoptosis induced by lipopolysaccharide partly through activating the PI3K/Akt and ERK pathway. Display Omitted -- Highlights: •It has been observed that LPS insult significantly increased apoptosis in A549 cells. •Both Akt and ERK signaling are critical adapter molecules to mediate the ghrelin-mediated proliferative effect. •Ghrelin may have a therapeutic effect in the prevention of LPS-induced apoptosis.

Ghrelin ameliorates the human alveolar epithelial A549 cell apoptosis induced by lipopolysaccharide

Energy Technology Data Exchange (ETDEWEB)

Huang, Chunrong; Zheng, Haichong; He, Wanmei; Lu, Guifang; Li, Xia [Department of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080 (China); Deng, Yubin, E-mail: dengyub@mail.sysu.edu.cn [Research Center of Translational Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080 (China); Zeng, Mian, E-mail: zengmian2004@163.com [Department of Medical Intensive Care Unit, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080 (China)

2016-05-20

Ghrelin is a gastric acyl-peptide that plays an inhibitory role in cell apoptosis. Herein we investigate the protective effects of ghrelin in LPS-induced apoptosis of human alveolar epithelial A549 cells, along with the possible molecular mechanisms. LPS exposure impaired cell viability and increased apoptosis of A549 cells significantly in concentration- and time-dependent manners embodied in increased Bax and cleaved caspase-3 production, coupled with decreased Bcl-2 levels. Simultaneously, LPS remarkably decreased the expression of phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated kinas (ERK) in A549 cells. However, ghrelin'pretreatment ameliorated LPS-caused alterations in the ratio of Bax/Bcl-2 and cleaved caspase-3 expression, whereas activated the PI3K/Akt and ERK signaling. These results demonstrate that ghrelin lightens LPS-induced apoptosis of human alveolar epithelial cells partly through activating the PI3K/Akt and ERK pathway and thereby might benefit alleviating septic ALI. -- Graphical abstract: Ghrelin ameliorates the human alveolar epithelial A549 cells apoptosis induced by lipopolysaccharide partly through activating the PI3K/Akt and ERK pathway. Display Omitted -- Highlights: •It has been observed that LPS insult significantly increased apoptosis in A549 cells. •Both Akt and ERK signaling are critical adapter molecules to mediate the ghrelin-mediated proliferative effect. •Ghrelin may have a therapeutic effect in the prevention of LPS-induced apoptosis.

A study of pedestrian compliance with traffic signals for exclusive and concurrent phasing.

Science.gov (United States)

Ivan, John N; McKernan, Kevin; Zhang, Yaohua; Ravishanker, Nalini; Mamun, Sha A

2017-01-01

This paper describes a comparison of pedestrian compliance at traffic signals with two types of pedestrian phasing: concurrent, where both pedestrians and vehicular traffic are directed to move in the same directions at the same time, and exclusive, where pedestrians are directed to move during their own dedicated phase while all vehicular traffic is stopped. Exclusive phasing is usually perceived to be safer, especially by senior and disabled advocacy groups, although these safety benefits depend upon pedestrians waiting for the walk signal. This paper investigates whether or not there are differences between pedestrian compliance at signals with exclusive pedestrian phasing and those with concurrent phasing and whether these differences continue to exist when compliance at exclusive phasing signals is evaluated as if they had concurrent phasing. Pedestrian behavior was observed at 42 signalized intersections in central Connecticut with both concurrent and exclusive pedestrian phasing. Binary regression models were estimated to predict pedestrian compliance as a function of the pedestrian phasing type and other intersection characteristics, such as vehicular and pedestrian volume, crossing distance and speed limit. We found that pedestrian compliance is significantly higher at intersections with concurrent pedestrian phasing than at those with exclusive pedestrian phasing, but this difference is not significant when compliance at exclusive phase intersections is evaluated as if it had concurrent phasing. This suggests that pedestrians treat exclusive phase intersections as though they have concurrent phasing, rendering the safety benefits of exclusive pedestrian phasing elusive. No differences were observed for senior or non-senior pedestrians. Published by Elsevier Ltd.

Evaluation of Intersection Traffic Control Measures through Simulation

Science.gov (United States)

Asaithambi, Gowri; Sivanandan, R.

2015-12-01

Modeling traffic flow is stochastic in nature due to randomness in variables such as vehicle arrivals and speeds. Due to this and due to complex vehicular interactions and their manoeuvres, it is extremely difficult to model the traffic flow through analytical methods. To study this type of complex traffic system and vehicle interactions, simulation is considered as an effective tool. Application of homogeneous traffic models to heterogeneous traffic may not be able to capture the complex manoeuvres and interactions in such flows. Hence, a microscopic simulation model for heterogeneous traffic is developed using object oriented concepts. This simulation model acts as a tool for evaluating various control measures at signalized intersections. The present study focuses on the evaluation of Right Turn Lane (RTL) and Channelised Left Turn Lane (CLTL). A sensitivity analysis was performed to evaluate RTL and CLTL by varying the approach volumes, turn proportions and turn lane lengths. RTL is found to be advantageous only up to certain approach volumes and right-turn proportions, beyond which it is counter-productive. CLTL is found to be advantageous for lower approach volumes for all turn proportions, signifying the benefits of CLTL. It is counter-productive for higher approach volume and lower turn proportions. This study pinpoints the break-even points for various scenarios. The developed simulation model can be used as an appropriate intersection lane control tool for enhancing the efficiency of flow at intersections. This model can also be employed for scenario analysis and can be valuable to field traffic engineers in implementing vehicle-type based and lane-based traffic control measures.

Phosphodiesterase-5 inhibitor sildenafil preconditions adult cardiac myocytes against necrosis and apoptosis. Essential role of nitric oxide signaling.

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Das, Anindita; Xi, Lei; Kukreja, Rakesh C

2005-04-01

We investigated the effect of sildenafil in protection against necrosis or apoptosis in cardiomyocytes. Adult mouse ventricular myocytes were treated with sildenafil (1 or 10 microM) for 1 h before 40 min of simulated ischemia (SI). Necrosis was determined by trypan blue exclusion and lactate dehydrogenase release following SI alone or plus 1 or 18 h of reoxygenation (RO). Apoptosis was assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling assay and mitochondrial membrane potential measured using a fluorescent probe 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1). Sildenafil reduced necrosis as indicated by decrease in trypan blue-positive myocytes and leakage of lactate dehydrogenase compared with untreated cells after either SI or SI-RO. The number of terminal deoxynucleotidyl transferase-mediated nick end labeling-positive myocytes or loss of JC-1 fluorescence following SI and 18 h of RO was attenuated in the sildenafil-treated group with concomitant inhibition of caspase 3 activity. An early increase in Bcl-2 to Bax ratio with sildenafil treatment was also observed in myocytes after SI-RO. The increase of Bcl-2 expression by sildenafil was inhibited by nitric-oxide synthase (NOS) inhibitor, L-nitro-amino-methyl-ester. The drug also enhanced mRNA and protein content of inducible NOS (iNOS) and endothelial NOS (eNOS) in the myocytes. Sildenafil-induced protection against necrosis and apoptosis was absent in the myocytes derived from iNOS knock-out mice and was attenuated in eNOS knock-out myocytes. The up-regulation of Bcl-2 expression by sildenafil was also absent in iNOS-deficient myocytes. Reverse transcription-PCR, Western blots, and immunohistochemical assay confirmed the expression of phosphodiesterase-5 in mouse cardiomyocytes. These data provide strong evidence for a direct protective effect of sildenafil against necrosis and apoptosis through NO signaling pathway. The results may have possible

Berberine prevents nitric oxide-induced rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and p38 MAPK signaling.

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Zhou, Yan; Liu, Shi-Qing; Yu, Ling; He, Bin; Wu, Shi-Hao; Zhao, Qi; Xia, Shao-Qiang; Mei, Hong-Jun

2015-09-01

Chondrocyte apoptosis is an important mechanism involved in osteoarthritis (OA). Berberine (BBR), a plant alkaloid derived from Chinese medicine, is characterized by multiple pharmacological effects, such as anti-inflammatory and anti-apoptotic activities. This study aimed to evaluate the chondroprotective effect and underlying mechanisms of BBR on sodium nitroprusside (SNP)-stimulated chondrocyte apoptosis and surgically-induced rat OA model. The in vitro results revealed that BBR suppressed SNP-stimulated chondrocyte apoptosis as well as cytoskeletal remodeling, down-regulated expressions of inducible nitric oxide synthase (iNOS) and caspase-3, and up-regulated Bcl-2/Bax ratio and Type II collagen (Col II) at protein levels, which were accompanied by increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation and decreased phosphorylation of p38 mitogen-activated protein kinase (MAPK). Furthermore, the anti-apoptotic effect of BBR was blocked by AMPK inhibitor Compound C (CC) and adenosine-9-β-D-arabino-furanoside (Ara A), and enhanced by p38 MAPK inhibitor SB203580. In vivo experiment suggested that BBR ameliorated cartilage degeneration and exhibited an anti-apoptotic effect on articular cartilage in a rat OA model, as demonstrated by histological analyses, TUNEL assay and immunohistochemical analyses of caspase-3, Bcl-2 and Bax expressions. These findings suggest that BBR suppresses SNP-stimulated chondrocyte apoptosis and ameliorates cartilage degeneration via activating AMPK signaling and suppressing p38 MAPK activity.

Intersectionality - an intercategorical approach

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Emerek, Ruth

2017-01-01

The aim of this article is to demonstrate how to empirically uncover intersectional complexity by simple methods. The article is based on three examples of intercategorical complexity. Firstly, by discussing gender mainstreaming, it is shown that a narrow focus on categories without their interse...... of a study in partial analyses may reveal intersectionality. The examples show how interaction and interwoven categories can be included in intercategorical analyses of structural relationships....

From Cellular Attractor Selection to Adaptive Signal Control for Traffic Networks.

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Tian, Daxin; Zhou, Jianshan; Sheng, Zhengguo; Wang, Yunpeng; Ma, Jianming

2016-03-14

The management of varying traffic flows essentially depends on signal controls at intersections. However, design an optimal control that considers the dynamic nature of a traffic network and coordinates all intersections simultaneously in a centralized manner is computationally challenging. Inspired by the stable gene expressions of Escherichia coli in response to environmental changes, we explore the robustness and adaptability performance of signalized intersections by incorporating a biological mechanism in their control policies, specifically, the evolution of each intersection is induced by the dynamics governing an adaptive attractor selection in cells. We employ a mathematical model to capture such biological attractor selection and derive a generic, adaptive and distributed control algorithm which is capable of dynamically adapting signal operations for the entire dynamical traffic network. We show that the proposed scheme based on attractor selection can not only promote the balance of traffic loads on each link of the network but also allows the global network to accommodate dynamical traffic demands. Our work demonstrates the potential of bio-inspired intelligence emerging from cells and provides a deep understanding of adaptive attractor selection-based control formation that is useful to support the designs of adaptive optimization and control in other domains.

DESIGNING AN EFFECTIVE INTERSECTION USING CAD ENVIRONMENT

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CRISAN George-Horea

2017-05-01

Full Text Available Ensuring the safety and streamline in road traffic are very important aims, with regard to the nowadays people mobility level. Road infrastructure is an essential element that can meet these requirements. Thus, it is proposed to develop an effective model of intersection by using CAD software tools. This type of intersection can be successfully used on almost any category of roads, increasing road traffic safety, reducing passing times through the intersection and in the same time, reducing conflict points and increase the intersection capacity.

cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

International Nuclear Information System (INIS)

Bhattacharjee, Rajesh; Xiang, Wenpei; Wang, Yinna; Zhang, Xiaoying; Billiar, Timothy R.

2012-01-01

Highlights: ► cAMP blocks cell death induced by TNF and actinomycin D in cultured hepatocytes. ► cAMP blocks NF-κB activation induced by TNF and actinomycin D. ► cAMP blocks DISC formation following TNF and actinomycin D exposure. ► cAMP blocks TNF signaling at a proximal step. -- Abstract: Tumor necrosis factor α (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF + ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found that cAMP exerts its affect at the proximal level of TNF signaling by inhibiting the formation of the DISC

cAMP prevents TNF-induced apoptosis through inhibiting DISC complex formation in rat hepatocytes

Energy Technology Data Exchange (ETDEWEB)

Bhattacharjee, Rajesh [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States); Xiang, Wenpei [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States); Family Planning Research Institute, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People' s Republic of China (China); Wang, Yinna [Vascular Medicine Institute, University of Pittsburgh School of Medicine, 10051-5A BST 3, 3501 Fifth Avenue, Pittsburgh, PA 15261 (United States); Zhang, Xiaoying [Department of Medicine/Endocrinology Division, University of Pittsburgh Medical Center, 200 Lothrop St., Pittsburgh, PA 15213 (United States); Billiar, Timothy R., E-mail: billiartr@upmc.edu [Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213 (United States)

2012-06-22

Highlights: Black-Right-Pointing-Pointer cAMP blocks cell death induced by TNF and actinomycin D in cultured hepatocytes. Black-Right-Pointing-Pointer cAMP blocks NF-{kappa}B activation induced by TNF and actinomycin D. Black-Right-Pointing-Pointer cAMP blocks DISC formation following TNF and actinomycin D exposure. Black-Right-Pointing-Pointer cAMP blocks TNF signaling at a proximal step. -- Abstract: Tumor necrosis factor {alpha} (TNF) is a pleiotropic proinflammatory cytokine that plays a role in immunity and the control of cell proliferation, cell differentiation, and apoptosis. The pleiotropic nature of TNF is due to the formation of different signaling complexes upon the binding of TNF to its receptor, TNF receptor type 1 (TNFR1). TNF induces apoptosis in various mammalian cells when the cells are co-treated with a transcription inhibitor like actinomycin D (ActD). When TNFR1 is activated, it recruits an adaptor protein, TNF receptor-associated protein with death domain (TRADD), through its cytoplasmic death effector domain (DED). TRADD, in turn, recruits other signaling proteins, including TNF receptor-associated protein 2 (TRAF2) and receptor-associated protein kinase (RIPK) 1, to form a complex. Subsequently, this complex combines with FADD and procaspase-8, converts into a death-inducing signaling complex (DISC) to induce apoptosis. Cyclic AMP (cAMP) is a second messenger that regulates various cellular processes such as cell proliferation, gene expression, and apoptosis. cAMP analogues are reported to act as anti-apoptotic agents in various cell types, including hepatocytes. We found that a cAMP analogue, dibutyryl cAMP (db-cAMP), inhibits TNF + ActD-induced apoptosis in rat hepatocytes. The protein kinase A (PKA) inhibitor KT-5720 reverses this inhibitory effect of cAMP on apoptosis. Cytoprotection by cAMP involves down-regulation of various apoptotic signal regulators like TRADD and FADD and inhibition of caspase-8 and caspase-3 cleavage. We also found

Proteomics and pathway analysis identifies JNK signaling as critical for high linear energy transfer radiation-induced apoptosis in non-small lung cancer cells.

Science.gov (United States)

Ståhl, Sara; Fung, Eva; Adams, Christopher; Lengqvist, Johan; Mörk, Birgitta; Stenerlöw, Bo; Lewensohn, Rolf; Lehtiö, Janne; Zubarev, Roman; Viktorsson, Kristina

2009-05-01

During the past decade, we have witnessed an explosive increase in generation of large proteomics data sets, not least in cancer research. There is a growing need to extract and correctly interpret information from such data sets to generate biologically relevant hypotheses. A pathway search engine (PSE) has recently been developed as a novel tool intended to meet these requirements. Ionizing radiation (IR) is an anticancer treatment modality that triggers multiple signal transduction networks. In this work, we show that high linear energy transfer (LET) IR induces apoptosis in a non-small cell lung cancer cell line, U-1810, whereas low LET IR does not. PSE was applied to study changes in pathway status between high and low LET IR to find pathway candidates of importance for high LET-induced apoptosis. Such pathways are potential clinical targets, and they were further validated in vitro. We used an unsupervised shotgun proteomics approach where high resolution mass spectrometry coupled to nanoflow liquid chromatography determined the identity and relative abundance of expressed proteins. Based on the proteomics data, PSE suggested the JNK pathway (p = 6.10(-6)) as a key event in response to high LET IR. In addition, the Fas pathway was found to be activated (p = 3.10(-5)) and the p38 pathway was found to be deactivated (p = 0.001) compared with untreated cells. Antibody-based analyses confirmed that high LET IR caused an increase in phosphorylation of JNK. Moreover pharmacological inhibition of JNK blocked high LET-induced apoptotic signaling. In contrast, neither an activation of p38 nor a role for p38 in high LET IR-induced apoptotic signaling was found. We conclude that, in contrast to conventional low LET IR, high LET IR can trigger activation of the JNK pathway, which in turn is critical for induction of apoptosis in these cells. Thus PSE predictions were largely confirmed, and PSE was proven to be a useful hypothesis-generating tool.

Apoptosis transcriptional mechanism of feline infectious peritonitis virus infected cells.

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Shuid, Ahmad Naqib; Safi, Nikoo; Haghani, Amin; Mehrbod, Parvaneh; Haron, Mohd Syamsul Reza; Tan, Sheau Wei; Omar, Abdul Rahman

2015-11-01

Apoptosis has been postulated to play an important role during feline infectious peritonitis virus (FIPV) infection; however, its mechanism is not well characterized. This study is focused on apoptosis and transcriptional profiling of FIPV-infected cells following in vitro infection of CRFK cells with FIPV 79-1146 WSU. Flow cytometry was used to determine mode of cell death in first 42 h post infection (hpi). FIPV infected cells underwent early apoptosis at 9 hpi (p apoptosis at 12 hpi (p apoptosis cluster (80 down-regulated and 51 up-regulated) along with increase of apoptosis, p53, p38 MAPK, VEGF and chemokines/cytokines signaling pathways were probably involved in apoptosis process. Six of the de-regulated genes expression (RASSF1, BATF2, MAGEB16, PDCD5, TNFα and TRAF2) and TNFα protein concentration were analyzed by RT-qPCR and ELISA, respectively, at different time-points. Up-regulations of both pro-apoptotic (i.e. PDCD5) and anti-apoptotic (i.e. TRAF2) were detected from first hpi and continuing to deregulate during apoptosis process in the infected cells.

Suppression of survivin expression in glioblastoma cells by the Ras inhibitor farnesylthiosalicylic acid promotes caspase-dependent apoptosis.

Science.gov (United States)

Blum, Roy; Jacob-Hirsch, Jasmine; Rechavi, Gideon; Kloog, Yoel

2006-09-01

The Ras inhibitor farnesylthiosalicylic acid (FTS) has been shown to induce apoptosis in glioblastoma multiforme, but its mechanism of action was unknown. We show that FTS or dominant-negative Ras, by deregulating extracellular signal-regulated kinase and Akt signaling, decreases survivin gene transcripts in U87 glioblastoma multiforme, leading to disappearance of survivin protein and cell death. FTS affected both Ras-controlled regulators of survivin transcription and Ras-regulated survival signals. Thus, Ras inhibition by FTS resulted in release of the survivin "brake" on apoptosis and in activation of the mitochondrial apoptotic pathway: dephosphorylation of Bad, activation of Bax, release of cytochrome c, and caspase activation. FTS-induced apoptosis of U87 cells was strongly attenuated by forced expression of survivin or by caspase inhibitors. These results show that resistance to apoptosis in glioblastoma multiforme can be abolished by a single Ras inhibitor, which targets both survivin, a critical inhibitor of apoptosis, and the intrinsic mitochondrial apoptotic machinery.

Intersectionality and Critical Race Parenting

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DePouw, Christin

2018-01-01

This conceptual article employs critical race theory (CRT) as a theoretical framework to explore the importance of intersectionality in critical race parenting. In particular, I focus on intersectionality to understand better how Whiteness and racial power play out in intimate relationships within the family, particularly between White parents and…

Authenticity in Leadership: Intersectionality of Identities.

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Jones, Susan R

2016-12-01

This chapter situates leadership and the process of becoming a leader within an understanding of identity, particularly intersecting social identities and intersectionality. © 2016 Wiley Periodicals, Inc., A Wiley Company.

Inositol Hexaphosphate Inhibits Proliferation and Induces Apoptosis of Colon Cancer Cells by Suppressing the AKT/mTOR Signaling Pathway

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Małgorzata Kapral

2017-10-01

Full Text Available Abstract: AKT, a serine/threonine protein kinase and mammalian target of rapamycin (mTOR plays a critical role in the proliferation and resistance to apoptosis that are essential to the development and progression of colon cancer. Therefore, AKT/mTOR signaling pathway has been recognized as an attractive target for anticancer therapy. Inositol hexaphosphate (InsP6, a natural occurring phytochemical, has been shown to have both preventive and therapeutic effects against various cancers, however, its exact molecular mechanisms of action are not fully understood. The aim of the in vitro study was to investigate the anticancer activity of InsP6 on colon cancer with the focus on inhibiting the AKT1 kinase and p70S6K1 as mTOR effector, in relation to proliferation and apoptosis of cells. The colon cancer Caco-2 cells were cultured using standard techniques and exposed to InsP6 at different concentrations (1 mM, 2.5 mM and 5 mM. Cellular proliferative activity was monitored by 5-bromo-2′-deoxyuridine (BrdU incorporation into cellular DNA. Flow cytometric analysis was performed for cell cycle progression and apoptosis studies. Real-time RT-qPCR was used to validate mRNA levels of CDNK1A, CDNK1B, CASP3, CASP9, AKT1 and S6K1 genes. The concentration of p21 protein as well as the activities of caspase 3, AKT1 and p70S6K1 were determined by the ELISA method. The results revealed that IP6 inhibited proliferation and stimulated apoptosis of colon cancer cells. This effect was mediated by an increase in the expression of genes encoding p21, p27, caspase 3, caspase 9 as well a decrease in transcription of AKT1 and S6K1. InsP6 suppressed phosphorylation of AKT1 and p70S6K1, downstream effector of mTOR. Based on these studies it may be concluded that InsP6 can reduce proliferation and induce apoptosis through inhibition of the AKT/mTOR pathway and mTOR effector followed by modulation of the expression and activity of several key components of these pathways in

Noxa/Mcl-1 Balance Regulates Susceptibility of Cells to Camptothecin-Induced Apoptosis1

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Mei, Yide; Xie, Chongwei; Xie, Wei; Tian, Xu; Li, Mei; Wu, Mian

2007-01-01

Although camptothecin (CPT) has been reported to induce apoptosis in various cancer cells, the molecular details of this regulation remain largely unknown. In this study, we demonstrate that BH3-only protein Noxa is upregulated during CPT-induced apoptosis, which is independent of p53. In addition, we show that phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway is responsible for Noxa's induction. Luciferase assay and cAMP response element binding protein (CREB) knockdown experiments further demonstrate that CREB is involved in the transcriptional upregulation of Noxa. Moreover, blocking Noxa expression using specific small interfering ribonucleic acid (siRNA) significantly reduces the apoptosis in response to CPT, indicating that Noxa is an essential mediator for CPT-induced apoptosis. Interestingly, antiapoptotic Mcl-1 was also upregulated through PI3K/Akt signaling pathway upon CPT treatment. Using immunoprecipitation assay, Noxa was found to interact with Mcl-1 in the presence or absence of CPT. Knockdown of Mcl-1 expression by short hairpin ribonucleic acid (shRNA) was shown to potentiate CPT-induced apoptosis. Consistently, ectopic overexpression of Mcl-1 rescued cells from apoptosis induced by CPT. Cells coexpressing Noxa and Mcl-1 at different ratio correlates well with the extent of apoptosis, suggesting that the balance between Noxa and Mcl-1 may determine the susceptibility of HeLa cells to CPT-induced apoptosis. PMID:17971907

Hyperthermia: an effective strategy to induce apoptosis in cancer cells.

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Ahmed, Kanwal; Tabuchi, Yoshiaki; Kondo, Takashi

2015-11-01

Heat has been used as a medicinal and healing modality throughout human history. The combination of hyperthermia (HT) with radiation and anticancer agents has been used clinically and has shown positive results to a certain extent. However, the clinical results of HT treatment alone have been only partially satisfactory. Cell death following HT treatment is a function of both temperature and treatment duration. HT induces cancer cell death through apoptosis; the degree of apoptosis and the apoptotic pathway vary in different cancer cell types. HT-induced reactive oxygen species production are responsible for apoptosis in various cell types. However, the underlying mechanism of signal transduction and the genes related to this process still need to be elucidated. In this review, we summarize the molecular mechanism of apoptosis induced by HT, enhancement of heat-induced apoptosis, and the genetic network involved in HT-induced apoptosis.

Curcumin Analog DK1 Induces Apoptosis in Human Osteosarcoma Cells In Vitro through Mitochondria-Dependent Signaling Pathway

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Muhammad Nazirul Mubin Aziz