scholarly journals High Levels of ROS Impair Lysosomal Acidity and Autophagy Flux in Glucose-Deprived Fibroblasts by Activating ATM and Erk Pathways

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 761
Author(s):  
Seon Beom Song ◽  
Eun Seong Hwang
Keyword(s):  
Energy Homeostasis ◽  
Human Fibroblasts ◽  
Large Population ◽  
Glucose Deprivation ◽  
Autophagic Flux ◽  
Serine Threonine Kinase ◽  
Autophagy Flux ◽  
Extracellular Signal ◽  
The Status ◽  
High Level

Under glucose deprivation, cells heavily mobilize oxidative phosphorylation to maintain energy homeostasis. This leads to the generation of high levels of ATP, as well as reactive oxygen species (ROS), from mitochondria. In nutrient starvation, autophagy is activated, likely to facilitate resource recycling, but recent studies suggest that autophagy flux is inhibited in cells undergoing glucose deprivation. In this study, we analyzed the status of autophagic flux in glucose-deprived human fibroblasts. Although lysosomes increased in quantity due in part to an increase of biogenesis, a large population of them suffered low acidity in the glucose-deprived cells. Autophagosomes also accumulated due to poor autolysis in these cells. A treatment of antioxidants not only restored lysosomal acidity but also released the flux blockade. The inhibition of ataxia telangiectasia mutated (ATM) serine/threonine kinase, which is activated by ROS, also attenuated the impairment of lysosomal acidity and autophagic flux, suggesting an effect of ROS that might be mediated through ATM activation. In addition, the activity of extracellular signal-regulated kinase (Erk) increased upon glucose deprivation, but this was also compromised by a treatment of antioxidants. Furthermore, the Erk inhibitor treatment also alleviated the failure in lysosomal acidity and autophagic flux. These together indicate that, upon glucose deprivation, cells undergo a failure of autophagy flux through an impairment of lysosomal acidity and that a high-level ROS-induced activation of Erk and ATM is involved in this impairment.

scholarly journals Breaking Bad: Autophagy Tweaks the Interplay Between Glioma and the Tumor Immune Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuxiang Fan ◽  
Yubo Wang ◽  
Jian Zhang ◽  
Xuechao Dong ◽  
Pu Gao ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Mammalian Cells ◽  
Energy Homeostasis ◽  
Well Being ◽  
Therapy Resistance ◽  
Autophagic Flux ◽  
Immune Microenvironment ◽  
Dismal Prognosis ◽  
Tumor Immune Microenvironment ◽  
The Status

Though significant strides in tumorigenic comprehension and therapy modality have been witnessed over the past decades, glioma remains one of the most common and malignant brain tumors characterized by recurrence, dismal prognosis, and therapy resistance. Immunotherapy advance holds promise in glioma recently. However, the efficacy of immunotherapy varies among individuals with glioma, which drives researchers to consider the modest levels of immunity in the central nervous system, as well as the immunosuppressive tumor immune microenvironment (TIME). Considering the highly conserved property for sustaining energy homeostasis in mammalian cells and repeatedly reported links in malignancy and drug resistance, autophagy is determined as a cutting angle to elucidate the relations between glioma and the TIME. In this review, heterogeneity of TIME in glioma is outlined along with the reciprocal impacts between them. In addition, controversies on whether autophagy behaves cytoprotectively or cytotoxically in cancers are covered. How autophagy collapses from its homeostasis and aids glioma malignancy, which may depend on the cell type and the cellular context such as reactive oxygen species (ROS) and adenosine triphosphate (ATP) level, are briefly discussed. The consecutive application of autophagy inducers and inhibitors may improve the drug resistance in glioma after overtreatments. It also highlights that autophagy plays a pivotal part in modulating glioma and the TIME, respectively, and the intricate interactions among them. Specifically, autophagy is manipulated by either glioma or tumor-associated macrophages to conform one side to the other through exosomal microRNAs and thereby adjust the interactions. Given that some of the crosstalk between glioma and the TIME highly depend on the autophagy process or autophagic components, there are interconnections influenced by the status and well-being of cells presumably associated with autophagic flux. By updating the most recent knowledge concerning glioma and the TIME from an autophagic perspective enhances comprehension and inspires more applicable and effective strategies targeting TIME while harnessing autophagy collaboratively against cancer.

Necrostatin-1 Analog DIMO Exerts Cardioprotective Effect against Ischemia Reperfusion Injury by Suppressing Necroptosis via Autophagic Pathway in Rats

Pharmacology ◽  
2021 ◽  
Vol 106 (3-4) ◽  
pp. 189-201
Author(s):  
Shigang Qiao ◽  
Wen-jie Zhao ◽  
Huan-qiu Li ◽  
Gui-zhen Ao ◽  
Jian-zhong An ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemia Reperfusion Injury ◽  
Myocardial Infarct ◽  
Ischemia Reperfusion ◽  
Glucose Deprivation ◽  
Neonatal Rat ◽  
Ligand Docking ◽  
Autophagic Flux ◽  
Myocardial Infarct Size ◽  
Rat Cardiomyocytes

Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.

Deep AI Enabled Ubiquitous Wireless Sensing

2021 ◽  
Vol 54 (2) ◽  
pp. 1-35
Author(s):  
Chenning Li ◽  
Zhichao Cao ◽  
Yunhao Liu
Keyword(s):  
Great Success ◽  
Wireless Sensing ◽  
Ubiquitous Sensing ◽  
Sensing Systems ◽  
The Status ◽  
Sensing Model ◽  
High Level ◽  
Traditional Approaches ◽  
The Internet Of Things ◽  
High Level Feature

With the development of the Internet of Things (IoT), many kinds of wireless signals (e.g., Wi-Fi, LoRa, RFID) are filling our living and working spaces nowadays. Beyond communication, wireless signals can sense the status of surrounding objects, known as wireless sensing , with their reflection, scattering, and refraction while propagating in space. In the last decade, many sophisticated wireless sensing techniques and systems were widely studied for various applications (e.g., gesture recognition, localization, and object imaging). Recently, deep Artificial Intelligence (AI), also known as Deep Learning (DL), has shown great success in computer vision. And some works have initially proved that deep AI can benefit wireless sensing as well, leading to a brand-new step toward ubiquitous sensing. In this survey, we focus on the evolution of wireless sensing enhanced by deep AI techniques. We first present a general workflow of Wireless Sensing Systems (WSSs) which consists of signal pre-processing, high-level feature, and sensing model formulation. For each module, existing deep AI-based techniques are summarized, further compared with traditional approaches. Then, we provide a view of issues and challenges induced by combining deep AI and wireless sensing together. Finally, we discuss the future trends of deep AI to enable ubiquitous wireless sensing.

scholarly journals Preconditioning Mediated by Sublethal Oxygen—Glucose Deprivation-Induced Cyclooxygenase-2 Expression via the Signal Transducers and Activators of Transcription 3 Phosphorylation

2008 ◽  
Vol 28 (7) ◽  
pp. 1329-1340 ◽  
Author(s):  
Eun J Kim ◽  
Ami P Raval ◽  
Miguel A Perez-Pinzon
Keyword(s):  
Glucose Deprivation ◽  
Cyclooxygenase 2 ◽  
Serine Phosphorylation ◽  
Signaling Cascade ◽  
Oxygen Glucose Deprivation ◽  
Signal Transducers ◽  
Extracellular Signal ◽  
Cox 2 ◽  
Transcription 3 ◽  
Signal Transducers And Activators

The signal transducers and activators of transcription (STATs) were found to be essential for cardioprotection. However, their role in preconditioning (PC) neuroprotection remains undefined. Previously, our studies showed that PC mediated a signaling cascade that involves activation of epsilon protein kinase C (εPKC), extracellular signal-regulated kinase (ERK1/2), and cyclooxygenase-2 (COX-2) pathways. However, the intermediate pathway by which ERK1/2 activates COX-2 was not defined. In this study, we investigated whether the PC-induced signaling pathway requires phosphorylation of STAT isoforms for COX-2 expression. To mimic PC or lethal ischemia, mixed cortical neuron/astrocyte cell cultures were subjected to 1 and/or 4 h of oxygen—glucose deprivation (OGD), respectively. The results indicated serine phosphorylation of STAT3 after PC or εPKC activation. Inhibition of either εPKC or ERK1/2 activation abolished PC-induced serine phosphorylation of STAT3. Additionally, inhibition of STAT3 prevented PC-induced COX-2 expression and neuroprotection against OGD. Therefore, our findings suggest that PC signaling cascade involves STAT3 activation after εPKC and ERK1/2 activation. Finally, we show that STAT3 activation mediates COX-2 expression and ischemic tolerance.

Conspicuous consumption of luxury experiences: an experimental investigation of status perceptions on social media

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Carolin Siepmann ◽  
Lisa Carola Holthoff ◽  
Pascal Kowalczuk
Keyword(s):  
Social Media ◽  
Personal Characteristics ◽  
Conspicuous Consumption ◽  
Individual Characteristics ◽  
Luxury Goods ◽  
Content Type ◽  
The Status ◽  
Self Actualization ◽  
The Individual ◽  
High Level

Purpose As luxury goods are losing their importance for demonstrating status, wealth or power to others, individuals are searching for alternative status symbols. Recently, individuals have increasingly used conspicuous consumption and displays of experiences on social media to obtain affirmation. This study aims to analyze the effects of luxury and nonluxury experiences, as well as traditional luxury goods on status- and nonstatus-related dimensions. Design/methodology/approach After presenting the theoretical foundation, the authors conduct a study with 599 participants to compare status perceptions elicited by the conspicuous consumption of luxury goods, luxury experiences and nonluxury experiences. The authors investigate whether experiences that are visibly consumed on Instagram are replacing traditional luxury goods as the most important status symbols. Furthermore, the authors examine the effects of the content shown on nonstatus-related dimensions and analyze whether status perceptions differ between female and male social media communicators. Finally, the authors analyze how personal characteristics (self-esteem, self-actualization and materialism) influence the status perceptions of others on social media. Findings The results show that luxury goods are still the most important means of displaying status. However, especially for women, luxury experiences are also associated with a high level of social status. Thus, the results imply important gender differences in the perceptions of status- and nonstatus-related dimensions. Furthermore, the findings indicate that, in particular, the individual characteristics of self-actualization and materialism affect status perceptions depending on the posted content. Originality/value While the research has already considered some alternative forms of conspicuous consumption, little attention has been given to experiences as status symbols. However, with their growing importance as substitutes for luxury goods and the rise of social media, the desire to conspicuously consume experiences is increasing. The authors address this gap in the literature by focusing on the conspicuous display of luxury and nonluxury experiences on social media.

MANAGERS CAN ALSO RESIST CHANGES — CAN WE DEAL WITH THIS? AN EXPLORATORY STUDY FROM JAPAN

2013 ◽  
Vol 21 (04) ◽  
pp. 447-493
Author(s):  
BALÁZS VASZKUN
Keyword(s):  
Traditional Values ◽  
Traditional Management ◽  
Japanese Firms ◽  
Work Routines ◽  
The Status ◽  
Major Reform ◽  
Mass Recruitment ◽  
Dominant Coalition ◽  
High Level ◽  
Shed Light

Japan is going through a transformation, yet it is difficult to judge which model should be chosen as a direction to go in with corporate reforms. Badly needed initiatives seeking to replace outdated managerial habits by new best practices in Japanese firms are being jeopardized by organizational members whose goal is to maintain the status quo — in terms of both political power and everyday work routines. Yet managerial habits and behaviours need to change if Japanese firms are to be entrepreneurial and innovative. According to institutionalism, blocking new initiatives is normal, and societal support is needed for major reform attempts. The focus of this paper is to shed light on how society in Japan is divided when it comes to large firms altering practices with which they have been traditionally managed. Our proposition is that complex, multi-element reform packages — having a potentially opposing dominant coalition, which is the case of Japan — ought to be implemented following a well-defined, prioritized listing of elements. After examining an attitude survey carried out in Japan, our findings revealed two clusters with a particularly high level of support for traditional management. Moreover, out of the two, one appeared to be extremely passive and resistant to any sort of change. In order to fight general resistance and reform outdated practices, our survey shows that Japan could move further towards a system compensating performance rather than seniority and giving more chance to women, discarding mass-recruitment, slow promotion whilst also maintaining the most deeply-rooted traditional values such as job security, paternalism or harmony in corporate life.

scholarly journals SPINK1-induced amelioration of impaired autophagy contributes to suppression of trypsinogen activation in a model of acute pancreatitis

2020 ◽  
Author(s):  
Yuxiao Zhao ◽  
Jianlong Jia ◽  
Abdullah Shopit ◽  
Yang Liu ◽  
Jun Wang
Keyword(s):  
Acute Pancreatitis ◽  
In Vitro Model ◽  
Autophagic Flux ◽  
Trypsin Activity ◽  
Autophagy Flux ◽  
Trypsinogen Activation ◽  
Vitro Model ◽  
First Time ◽  
Induced Amelioration

AbstractSPINK1 has been regarded as a reversible trypsinogen inhibitor for the inappropriate activation of trypsin, a key step in the initiation of acute pancreatitis (AP). However, the mechanisms of its action remains largely unclear and controversial. Here, we reported an unexpected effects of SPINK1 on inhibiting trypsinogen activation through the regulation of impaired autophagy in cerulein-stimulated AR42J cells, a well-established in vitro model of acute pancreatitis. Firstly, we found that the impaired autophagic flux was induced and trypsinogen activity enhanced in the above setting. Then, we showed that SPINK1 overexpression could inhibit the level of increased autophagic activity, improving the hindered autophagy flux, and significantly decreased the trypsinogen activity, whereas shRNA-caused downregulation of SPINK1 exacerbated the impairment of autophagic flux and trypsin activity, in the same cerulein-processed cells. More importantly, the trypsinogen activation in this model could be ameliorated by 3-Methyladenine(3-MA), an autophagy inhibitor. Thus, this study revealed, possibly for the first time, that SPINK1 greatly blocked the trypsinogen activation possibly through the modulation of impaired autophagy in cerulein-induced in vitro model of acute pancreatitis.

scholarly journals Cadmium affects autophagy in the human intestinal cells Caco-2 through ROS-mediated ERK activation

2021 ◽  
Author(s):  
Myriam Mireault ◽  
Yong Xiao ◽  
Benoît Barbeau ◽  
Catherine Jumarie
Keyword(s):  
Critical Role ◽  
Toxic Metal ◽  
Glucose Deprivation ◽  
Intestinal Cells ◽  
Autophagic Flux ◽  
Erk Activation ◽  
Cell Monolayers ◽  
Nutritional Conditions ◽  
Human Intestinal Cells

Abstract Cadmium is a toxic metal that enters the food chain. Following oral ingestion, the intestinal epithelium has the capacity to accumulate high levels of this metal. We have previously shown that Cd induces ERK1/2 activation in differentiated but not proliferative human enterocytic-like Caco-2 cells. As autophagy is a dynamic process that plays a critical role in intestinal mucosa, we aimed the present study 1) to investigate the role of p-ERK1/2 in constitutive autophagy in proliferative Caco-2 cells and 2) to investigate whether Cd-induced activation of ERK1/2 modifies autophagic activity in postconfluent Caco-2 cell monolayers. Western blot analyses of ERK1/2 and autophagic markers (LC3, SQSTM1), and cellular staining with acridine orange showed that ERK1/2 and autophagic activities both decreased with time in culture. GFP-LC3 fluorescence was also associated with proliferative cells and the presence of a constitutive ERK1/2-dependent autophagic flux was demonstrated in proliferative but not in postconfluent cells. In the latter condition, serum and glucose deprivation triggered autophagy via a transient phosphorylation of ERK1/2, whereas Cd-modified autophagy via a ROS-dependent sustained activation of ERK1/2. Basal autophagy flux in proliferative cells and Cd-induced increases in autophagic markers in postconfluent cells both involved p-ERK1/2. Whether Cd blocks autophagic flux in older cell cultures remains to be clarified but our data suggest dual effects. Our results prompt further studies investigating the consequences that Cd-induced ERK1/2 activation and the related effect on autophagy may have on the intestinal cells, which may accumulate and trap high levels of Cd under some nutritional conditions. Graphical abstract

scholarly journals A Drosophila Toolkit for Imaging of HA-tagged Proteins Unveiled a Block in Autophagy Flux in the Last Instar Larval Fat Body

2021 ◽  
Author(s):  
Tadayoshi Murakawa ◽  
Tsuyoshi Nakamura ◽  
Kohei Kawaguchi ◽  
Futoshi Murayama ◽  
Ning Zhao ◽  
...  
Keyword(s):  
Fat Body ◽  
Autophagic Flux ◽  
Single Chain Variable Fragment ◽  
Single Chain ◽  
Autophagy Flux ◽  
Epitope Tag ◽  
Family Gene ◽  
Intensive Work ◽  
Transgenic Strains

For in vivo functional analysis of a protein of interest (POI), multiple transgenic strains with POI harboring different tags are needed but generation of these strains is still labor-intensive work. To overcome this, we developed a versatile Drosophila toolkit with a genetically encoded single-chain variable fragment for the HA epitope tag: HA Frankenbody. This system allows various analyses of HA-tagged POI in live tissues by simply crossing an HA Frankenbody fly with an HA-tagged POI fly. Strikingly, the GFP-mCherry tandem fluorescent-tagged HA Frankenbody revealed a block in autophagic flux and an accumulation of enlarged autolysosomes in the last instar larval and prepupal fat body. Autophagy was dispensable for the swelling of lysosomes, indicating that lysosomal activity is downregulated at this stage. Furthermore, forced activation of lysosomes by fat body-targeted overexpression of Mitf, the single MiTF/TFE family gene in Drosophila, suppressed the lysosomal swelling and resulted in pupal lethality. Collectively, we propose that downregulated lysosomal function in the fat body plays a role in the metamorphosis of Drosophila.

scholarly journals Linguistic culture and politics in France

enadakultura ◽  
2021 ◽  
Author(s):  
Natalia Revishvili
Keyword(s):  
French Revolution ◽  
French Language ◽  
National Politics ◽  
The Public ◽  
French Academy ◽  
Long Period ◽  
The Status ◽  
Classical Language ◽  
High Level ◽  
Public Instruction

The rise of the French national politics was taking place simultaneously with the rise of the French power and territories in Europe. The first evidence of the emergence of the French language distinguished from Latin is the text of the ‘’French’’ version of the 842-nd Strasbourg Oath. France is an example of how ideas and myths about a language become ideologies and how it forms a part of a language policy, along with language planning and language practices.The French language was being established over a long period of time. From the 17th century onwards, increasing attention was paid to this issue. It is especially interesting to establish a high level of French spelling, the expression of good spelling in the French language has become an object of social values. On October 19 and 20, 1794, the Public Instruction Committee introduced a new project to teach French to all. French became the language of writing before it set foot in education.The 17-th and 18-th centuries became a period of legalization of the French language. The greatest philosophers and writers of this time legalized the French language in poetry and fiction. At the same time, it became the language of scientific writing. French gained the status of the most brilliant language in Europe over the last two centuries through the French Academy and the French Revolution. It was a new ‘’classical“ language.

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