Journal articles on the topic 'Autophagy'
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1
Sakai, Shinsuke, Takeshi Yamamoto, Yoshitsugu Takabatake, Atsushi Takahashi, Tomoko Namba-Hamano, Satoshi Minami, Ryuta Fujimura, et al. "Proximal Tubule Autophagy Differs in Type 1 and 2 Diabetes." Journal of the American Society of Nephrology 30, no. 6 (April 30, 2019): 929–45. http://dx.doi.org/10.1681/asn.2018100983.
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BackgroundEvidence of a protective role of autophagy in kidney diseases has sparked interest in autophagy as a potential therapeutic strategy. However, understanding how the autophagic process is altered in each disorder is critically important in working toward therapeutic applications.MethodsUsing cultured kidney proximal tubule epithelial cells (PTECs) and diabetic mouse models, we investigated how autophagic activity differs in type 1 versus type 2 diabetic nephropathy. We explored nutrient signals regulating starvation-induced autophagy in PTECs and used autophagy-monitoring mice and PTEC-specific autophagy-deficient knockout mice to examine differences in autophagy status and autophagy’s role in PTECs in streptozotocin (STZ)-treated type 1 and db/db type 2 diabetic nephropathy. We also examined the effects of rapamycin (an inhibitor of mammalian target of rapamycin [mTOR]) on vulnerability to ischemia-reperfusion injury.ResultsAdministering insulin or amino acids, but not glucose, suppressed autophagy by activating mTOR signaling. In db/db mice, autophagy induction was suppressed even under starvation; in STZ-treated mice, autophagy was enhanced even under fed conditions but stagnated under starvation due to lysosomal stress. Using knockout mice with diabetes, we found that, in STZ-treated mice, activated autophagy counteracts mitochondrial damage and fibrosis in the kidneys, whereas in db/db mice, autophagic suppression jeopardizes kidney even in the autophagy-competent state. Rapamycin-induced pharmacologic autophagy produced opposite effects on ischemia-reperfusion injury in STZ-treated and db/db mice.ConclusionsAutophagic activity in PTECs is mainly regulated by insulin. Consequently, autophagic activity differs in types 1 and 2 diabetic nephropathy, which should be considered when developing strategies to treat diabetic nephropathy by modulating autophagy.
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Gordon, P. B., H. Høyvik, and P. O. Seglen. "Prelysosomal and lysosomal connections between autophagy and endocytosis." Biochemical Journal 283, no. 2 (April 15, 1992): 361–69. http://dx.doi.org/10.1042/bj2830361.
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In isolated rat hepatocytes electroloaded with [14C]sucrose, autophaged sugar accumulated in lysosomes under control conditions, and in prelysosomal autophagic vacuoles (amphisomes) in the presence of asparagine, an inhibitor of autophagic-lysosomal fusion. Endocytic uptake of the sucrose-cleaving enzyme invertase resulted in rapid and complete degradation of autophaged sucrose in both amphisomes and lysosomes. Pre-accumulated sucrose was degraded equally well in both compartments, regardless of amphisomal-lysosomal flux inhibition by asparagine, suggesting that endocytic entry into the autophagic pathway can take place both at the lysosomal and at the amphisomal level. The completeness of sucrose degradation by endocytosed invertase furthermore indicates that all lysosomes involved in autophagy can also engage in endocytosis. Endocytosed invertase reached the amphisomes even when autophagy was blocked by 3-methyladenine, and autophaged sucrose reached this compartment even when endocytic influx was blocked by vinblastine, suggesting that amphisomes may exhibit some degree of permanence independently of either pathway.
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Chueh, Kuang-Shun, Jian-He Lu, Tai-Jui Juan, Shu-Mien Chuang, and Yung-Shun Juan. "The Molecular Mechanism and Therapeutic Application of Autophagy for Urological Disease." International Journal of Molecular Sciences 24, no. 19 (October 4, 2023): 14887. http://dx.doi.org/10.3390/ijms241914887.
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Autophagy is a lysosomal degradation process known as autophagic flux, involving the engulfment of damaged proteins and organelles by double-membrane autophagosomes. It comprises microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy. Macroautophagy consists of three stages: induction, autophagosome formation, and autolysosome formation. Atg8-family proteins are valuable for tracking autophagic structures and have been widely utilized for monitoring autophagy. The conversion of LC3 to its lipidated form, LC3-II, served as an indicator of autophagy. Autophagy is implicated in human pathophysiology, such as neurodegeneration, cancer, and immune disorders. Moreover, autophagy impacts urological diseases, such as interstitial cystitis /bladder pain syndrome (IC/BPS), ketamine-induced ulcerative cystitis (KIC), chemotherapy-induced cystitis (CIC), radiation cystitis (RC), erectile dysfunction (ED), bladder outlet obstruction (BOO), prostate cancer, bladder cancer, renal cancer, testicular cancer, and penile cancer. Autophagy plays a dual role in the management of urologic diseases, and the identification of potential biomarkers associated with autophagy is a crucial step towards a deeper understanding of its role in these diseases. Methods for monitoring autophagy include TEM, Western blot, immunofluorescence, flow cytometry, and genetic tools. Autophagosome and autolysosome structures are discerned via TEM. Western blot, immunofluorescence, northern blot, and RT-PCR assess protein/mRNA levels. Luciferase assay tracks flux; GFP-LC3 transgenic mice aid study. Knockdown methods (miRNA and RNAi) offer insights. This article extensively examines autophagy’s molecular mechanism, pharmacological regulation, and therapeutic application involvement in urological diseases.
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López-Alonso, Inés, Alina Aguirre, Adrián González-López, Álvaro F. Fernández, Laura Amado-Rodríguez, Aurora Astudillo, Estefanía Batalla-Solís, and Guillermo M. Albaiceta. "Impairment of autophagy decreases ventilator-induced lung injury by blockade of the NF-κB pathway." American Journal of Physiology-Lung Cellular and Molecular Physiology 304, no. 12 (June 15, 2013): L844—L852. http://dx.doi.org/10.1152/ajplung.00422.2012.
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Excessive lung stretch triggers lung inflammation by activation of the NF-κB pathway. This route can be modulated by autophagy, an intracellular proteolytic system. Our objective was to study the impact of the absence of autophagy in a model of ventilator-induced lung injury. Mice lacking Autophagin-1/ATG4B ( Atg4b −/−), a critical protease in the autophagic pathway, and their wild-type counterparts were studied in baseline conditions and after mechanical ventilation. Lung injury, markers of autophagy, and activation of the inflammatory response were evaluated after ventilation. Mechanical ventilation increased autophagy and induced lung injury in wild-type mice. Atg4b −/− animals showed a decreased lung injury after ventilation, with less neutrophilic infiltration than their wild-type counterparts. As expected, autophagy was absent in mutant animals, resulting in the accumulation of p62 and ubiquitinated proteins. Activation of the canonical NF-κB pathway was present in ventilated wild-type, but not Atg4b-deficient, animals. Moreover, these mutant mice showed an accumulation of ubiquitinated IκB. High-pressure ventilation partially restored the autophagic response in Atg4b −/− mice and abolished the differences between genotypes. In conclusion, impairment of autophagy results in an ameliorated inflammatory response to mechanical ventilation and decreases lung injury. The accumulation of ubiquitinated IκB may be responsible for this effect.
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Zolotova, S. A., and S. V. Palyanov. "The role of autophagy in cardiac damage." Scientific Bulletin of the Omsk State Medical University 3, no. 1 (2023): 71–83. http://dx.doi.org/10.61634/2782-3024-2023-9-71-83.
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Autophagy is one of the mechanisms ensuring cell homeostasis on the one hand, and on the other hand, it is a way of utilizing damaged cell structures through their autolysis in the autophagosome for reuse in cell metabolism. Autophagy is usually considered as an adaptive process allowing cells to survive under conditions of stress, nutrient deficiency and hypoxia. However, under certain circumstances autophagy can be the cause of cell death. Cell death accompanied by autophagy activation and autophagosome accumulation has been classified as programmed cell death type II. However, compared to detailed information on the adaptive role of autophagy, its involvement in cell death has been poorly understood. Autophagic cell death can be divided into two groups, namely: (1) autophagic cell death with increased autophagy activity; (2) autophagic cell death with decreased autophagy processes. In the first scenario, autophagy is excessively activated, causing uncontrolled autolysis of cellular structures and cell death. A similar scenario is observed in cell death caused by excessive degradation of damaged organelles in lysosomes. Of particular interest is a specific form of autophagy in which damaged mitochondria are excessively eliminated from the cell - mitophagy. Autophagic cell death is characteristic of diabetic cardiomyopathy. The second variant, characterized by reduced autophagy processes, is observed in doxorubicin-induced cardiomyopathy, autophagy during ischemia/reperfusion and autophagic cell death in lysosomal accumulation diseases. In this scenario, the final step of autophagy is usually disrupted, and an imbalance between autophagosome formation and lysosomal activity leads to massive autophagosome accumulation, which subsequently causes cellular dysfunction and death. Dysregulation of autophagy causes a unique form of cell death, called autosis, with certain morphological and biochemical features that differ from other forms of cell death, such as apoptosis and necrosis. In autosis, Na+/K+ ATPase plays a special role, which by physically interacting with Beclin 1 can promote autophagic cell death. The principles of therapeutic intervention aimed at preventing autophagic death of cardiomyocytes depend on the specific mechanisms of autophagy. For example, the use of Na+/K+-ATPase inhibitors, such as cardiac glycosides, provides a cardioprotective effect by inhibiting autophagy, while the use of trehalose and 3,4-dimethoxychalcon, can optimize autophagy processes and reduce the intensity of excessive autophagosome accumulation. Thus, the study of mechanisms of autophagy and search for new approaches in pharmacocorrection and pharmacoprophylaxis of autophagic cell death are actual directions of modern scientific research. The aim of the review is to present the concept of autophagic cell death in some heart diseases.
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Yang, Fan, Haoran Hu, Wenjing Yin, Guangyi Li, Ting Yuan, Xuetao Xie, and Changqing Zhang. "Autophagy Is Independent of the Chondroprotection Induced by Platelet-Rich Plasma Releasate." BioMed Research International 2018 (July 24, 2018): 1–11. http://dx.doi.org/10.1155/2018/9726703.
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Background. Platelet-rich plasma (PRP) has been shown to be a promising therapeutic agent against osteoarthritis (OA), whereas its chondroprotection mechanism is not fully elucidated. Autophagy is considered an important biological process throughout the development of OA. Therefore, the objective of the present study is to investigate the role of autophagy in the chondroprotection and compare the effects of releasate between L-PRP and P-PRP. Methods. PRP were prepared from rat blood. Rat chondrocytes pretreated in the presence or absence of interleukin-1 beta (IL-1β) were incubated with PRP releasate. The expressions of OA-related genes and autophagy-related genes were determined by RT-PCR and western blot, respectively. Autophagic bodies were assessed by transmission electron microscopy and the autophagy flux was monitored under the confocal microscopy. The effect of PRP on autophagy was further investigated in the milieu of autophagy activator, rapamycin, or autophagy inhibition by downregulation of Atg5. The effect of PRP on cartilage repair and autophagy was also evaluated in an OA rat model. Results. In vitro, PRP releasate increased the expression of the anabolic genes, COL2 and Aggrecan, and decreased the expression of the catabolic genes, whereas the expression of autophage markers, Atg5 and Beclin-1, as well as the ratio of LC3 II/LC3 I, was not significantly altered in normal or IL-1β-treated chondrocytes. Similar expression pattern was found following the activation (rapamycin) or inhibition (Atg5 silencing) of autophagy. In vivo, PRP releasate ameliorated posttraumatic cartilage degeneration while the expression of LC3 was comparable to that in the vehicle treatment group. Conclusions. PRP releasate promoted the anabolic gene expression, relieved inflammatory stress in chondrocytes, and ameliorated cartilage degeneration, but autophagy was independent of these processes.
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Li, Jiarou, and Hongliang Wang. "Autophagy-dependent ferroptosis in infectious disease." Journal of Translational Internal Medicine 11, no. 4 (December 1, 2023): 355–62. http://dx.doi.org/10.2478/jtim-2023-0099.
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Abstract Autophagy is the initial defense response of the host against pathogens. Autophagy can be either non-selective or selective. It selectively targets the degradation of autophagic substrates through the sorting and transportation of autophagic receptor proteins. However, excessive autophagy activity will trigger cell death especially ferroptosis, which was characterized by the accumulation of lipid peroxide and free iron. Several certain types of selective autophagy degrade antioxidant systems and ferritin. Here, we summarized the latest researches of autophagy in infection and discuss the regulatory mechanisms and signaling pathways of autophagy-dependent ferroptosis.
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Ko, Su-Hyuk, Gilberto Gonzalez, Zhijie Liu, and Lizhen Chen. "Axon Injury-Induced Autophagy Activation Is Impaired in a C. elegans Model of Tauopathy." International Journal of Molecular Sciences 21, no. 22 (November 13, 2020): 8559. http://dx.doi.org/10.3390/ijms21228559.
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Autophagy is a conserved pathway that plays a key role in cell homeostasis in normal settings, as well as abnormal and stress conditions. Autophagy dysfunction is found in various neurodegenerative diseases, although it remains unclear whether autophagy impairment is a contributor or consequence of neurodegeneration. Axonal injury is an acute neuronal stress that triggers autophagic responses in an age-dependent manner. In this study, we investigate the injury-triggered autophagy response in a C. elegans model of tauopathy. We found that transgenic expression of pro-aggregant Tau, but not the anti-aggregant Tau, abolished axon injury-induced autophagy activation, resulting in a reduced axon regeneration capacity. Furthermore, axonal trafficking of autophagic vesicles were significantly reduced in the animals expressing pro-aggregant F3ΔK280 Tau, indicating that Tau aggregation impairs autophagy regulation. Importantly, the reduced number of total or trafficking autophagic vesicles in the tauopathy model was not restored by the autophagy activator rapamycin. Loss of PTL-1, the sole Tau homologue in C. elegans, also led to impaired injury-induced autophagy activation, but with an increased basal level of autophagic vesicles. Therefore, we have demonstrated that Tau aggregation as well as Tau depletion both lead to disruption of injury-induced autophagy responses, suggesting that aberrant protein aggregation or microtubule dysfunction can modulate autophagy regulation in neurons after injury.
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Kasprowska-Liśkiewicz, Daniela. "The cell on the edge of life and death: Crosstalk between autophagy and apoptosis." Postępy Higieny i Medycyny Doświadczalnej 71 (September 21, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.4672.
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Recently, the crosstalk between autophagy and apoptosis has attracted broader attention. Basal autophagy serves to maintain cell homeostasis, while the upregulation of this process is an element of stress response that enables the cell to survive under adverse conditions. Autophagy may also determine the fate of the cell through its interactions with cell death pathways. The protein networks that control the initiation and the execution phase of these two processes are highly interconnected. Several scenarios for the crosstalk between autophagy and apoptosis exist. In most cases, the activation of autophagy represents an attempt of the cell to cope with stress, and protects the cell from apoptosis or delays its initiation. Generally, the simultaneous activation of pro-survival and pro-death pathways is prevented by the mutual inhibitory crosstalk between autophagy and apoptosis. But in some circumstances, autophagy or the proteins of the core autophagic machinery may promote cellular demise through excessive self-digestion (so-called “autophagic cell death”) or by stimulating the activation of other cell death pathways. It is controversial whether cells actually die via autophagy, which is why the term “autophagic cell death” has been under intense debate lately. This review summarizes the recent findings on the multilevel crosstalk between autophagy and apoptosis in aspects of common regulators, mutual inhibition of these processes, the stimulation of apoptosis by autophagy or autophagic proteins and finally the role of autophagy as a death-execution mechanism.
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Körholz, Katharina, Johannes Ridinger, Damir Krunic, Sara Najafi, Xenia F. Gerloff, Karen Frese, Benjamin Meder, et al. "Broad-Spectrum HDAC Inhibitors Promote Autophagy through FOXO Transcription Factors in Neuroblastoma." Cells 10, no. 5 (April 24, 2021): 1001. http://dx.doi.org/10.3390/cells10051001.
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Depending on context and tumor stage, deregulation of autophagy can either suppress tumorigenesis or promote chemoresistance and tumor survival. Histone deacetylases (HDACs) can modulate autophagy; however, the exact mechanisms are not fully understood. Here, we analyze the effects of the broad-spectrum HDAC inhibitors (HDACi) panobinostat and vorinostat on the transcriptional regulation of autophagy with respect to autophagy transcription factor activity (Transcription factor EB—TFEB, forkhead boxO—FOXO) and autophagic flux in neuroblastoma cells. In combination with the late-stage autophagic flux inhibitor bafilomycin A1, HDACis increase the number of autophagic vesicles, indicating an increase in autophagic flux. Both HDACi induce nuclear translocation of the transcription factors FOXO1 and FOXO3a, but not TFEB and promote the expression of pro-autophagic FOXO1/3a target genes. Moreover, FOXO1/3a knockdown experiments impaired HDACi treatment mediated expression of autophagy related genes. Combination of panobinostat with the lysosomal inhibitor chloroquine, which blocks autophagic flux, enhances neuroblastoma cell death in culture and hampers tumor growth in vivo in a neuroblastoma zebrafish xenograft model. In conclusion, our results indicate that pan-HDACi treatment induces autophagy in neuroblastoma at a transcriptional level. Combining HDACis with autophagy modulating drugs suppresses tumor growth of high-risk neuroblastoma cells. These experimental data provide novel insights for optimization of treatment strategies in neuroblastoma.
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Luo, Xiaomei, Wei Cheng, Shizhang Wang, Zhihong Chen, and Jieqiong Tan. "Autophagy Suppresses Invasiveness of Endometrial Cells through Reduction of Fascin-1." BioMed Research International 2018 (June 11, 2018): 1–9. http://dx.doi.org/10.1155/2018/8615435.
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Objective. Autophagy has been reported to be involved in the development of various disorders such as neurodegenerative and metabolic diseases and tumors. Autophagy activators and inhibitors are also potential therapeutics for these diseases. However, the mechanism of autophagic involvement in different diseases is not the same, and the role of autophagy in endometriosis (EM) has not yet been elucidated. This research investigated the mechanism by which autophagy acts in EM, with the aim of establishing a theoretical basis for its prevention and treatment through the targeted interference with autophagy. Methods. We used an RNA interference fragment targeting ATG5, the autophagy activator rapamycin, and the autophagy inhibitor 3-MA or overexpression of filopodia-related protein fascin-1, in conjunction with clonogenic assays, growth curves, and scratch assay to investigate the influence of autophagy on cellular growth, proliferation, and invasiveness. We collected specimens from 20 clinical cases of EM and investigated the protein expression of the autophagic marker LC3-II, the autophagic substrate p62, and fascin-1. Results. Rapamycin was able to inhibit the proliferation and colony formation of the endometriotic cell line CRL-7566, whereas the autophagy inhibitor 3-MA as well as the interference with the autophagy-related gene ATG5 had the opposite effect. More importantly, the autophagy activator rapamycin was able to inhibit the growth of filopodia in the endometriotic cells, and the overexpression of the fascin-1 restored the rapamycin-induced decrease of invasiveness. We found that the expression of the autophagy marker LC3-II was significantly reduced among the clinical EM specimens compared to the control group, while the expressions of fascin-1 and autophagic substrate p62 were increased. Conclusion. Our results indicate that the inhibition of autophagy and exogenous expression of fascin-1 may promote the invasiveness of endometrial cells. As a corollary, autophagy represents a potential target for the treatment of EM.
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Luhr, Morten, Maria Lyngaas Torgersen, Paula Szalai, Adnan Hashim, Andreas Brech, Judith Staerk, and Nikolai Engedal. "The kinase PERK and the transcription factor ATF4 play distinct and essential roles in autophagy resulting from tunicamycin-induced ER stress." Journal of Biological Chemistry 294, no. 20 (March 29, 2019): 8197–217. http://dx.doi.org/10.1074/jbc.ra118.002829.
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Endoplasmic reticulum (ER) stress is thought to activate autophagy via unfolded protein response (UPR)-mediated transcriptional up-regulation of autophagy machinery components and modulation of microtubule-associated protein 1 light chain 3 (LC3). The upstream UPR constituents pancreatic EIF2-α kinase (PERK) and inositol-requiring enzyme 1 (IRE1) have been reported to mediate these effects, suggesting that UPR may stimulate autophagy via PERK and IRE1. However, how the UPR and its components affect autophagic activity has not been thoroughly examined. By analyzing the flux of LC3 through the autophagic pathway, as well as the sequestration and degradation of autophagic cargo, we here conclusively show that the classical ER stressor tunicamycin (TM) enhances autophagic activity in mammalian cells. PERK and its downstream factor, activating transcription factor 4 (ATF4), were crucial for this induction, but surprisingly, IRE1 constitutively suppressed autophagic activity. TM-induced autophagy required autophagy-related 13 (ATG13), Unc-51–like autophagy-activating kinases 1/2 (ULK1/ULK2), and GABA type A receptor–associated proteins (GABARAPs), but interestingly, LC3 proteins appeared to be redundant. Strikingly, ATF4 was activated independently of PERK in both LNCaP and HeLa cells, and our further examination revealed that ATF4 and PERK regulated autophagy through separate mechanisms. Specifically, whereas ATF4 controlled transcription and was essential for autophagosome formation, PERK acted in a transcription-independent manner and was required at a post-sequestration step in the autophagic pathway. In conclusion, our results indicate that TM-induced UPR activates functional autophagy, and whereas IRE1 is a negative regulator, PERK and ATF4 are required at distinct steps in the autophagic pathway.
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Metz, Philippe, Abhilash Chiramel, Laurent Chatel-Chaix, Gualtiero Alvisi, Peter Bankhead, Rodrigo Mora-Rodríguez, Gang Long, Anne Hamacher-Brady, Nathan R. Brady, and Ralf Bartenschlager. "Dengue Virus Inhibition of Autophagic Flux and Dependency of Viral Replication on Proteasomal Degradation of the Autophagy Receptor p62." Journal of Virology 89, no. 15 (May 27, 2015): 8026–41. http://dx.doi.org/10.1128/jvi.00787-15.
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ABSTRACTAutophagic flux involves formation of autophagosomes and their degradation by lysosomes. Autophagy can either promote or restrict viral replication. In the case of Dengue virus (DENV), several studies report that autophagy supports the viral replication cycle, and describe an increase of autophagic vesicles (AVs) following infection. However, it is unknown how autophagic flux is altered to result in increased AVs. To address this question and gain insight into the role of autophagy during DENV infection, we established an unbiased, image-based flow cytometry approach to quantify autophagic flux under normal growth conditions and in response to activation by nutrient deprivation or the mTOR inhibitor Torin1. We found that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Early after infection, basal and activated autophagic flux was enhanced. However, during established replication, basal and Torin1-activated autophagic flux was blocked, while autophagic flux activated by nutrient deprivation was reduced, indicating a block to AV formation and reduced AV degradation capacity. During late infection AV levels increased as a result of inefficient fusion of autophagosomes with lysosomes. In addition, endolysosomal trafficking was suppressed, while lysosomal activities were increased. We further determined that DENV infection progressively reduced levels of the autophagy receptor SQSTM1/p62 via proteasomal degradation. Importantly, stable overexpression of p62 significantly suppressed DENV replication, suggesting a novel role for p62 as a viral restriction factor. Overall, our findings indicate that in the course of DENV infection, autophagy shifts from a supporting to an antiviral role, which is countered by DENV.IMPORTANCEAutophagic flux is a dynamic process starting with the formation of autophagosomes and ending with their degradation after fusion with lysosomes. Autophagy impacts the replication cycle of many viruses. However, thus far the dynamics of autophagy in case of Dengue virus (DENV) infections has not been systematically quantified. Therefore, we used high-content, imaging-based flow cytometry to quantify autophagic flux and endolysosomal trafficking in response to DENV infection. We report that DENV induced an initial activation of autophagic flux, followed by inhibition of general and specific autophagy. Further, lysosomal activity was increased, but endolysosomal trafficking was suppressed confirming the block of autophagic flux. Importantly, we provide evidence that p62, an autophagy receptor, restrict DENV replication and was specifically depleted in DENV-infected cells via increased proteasomal degradation. These results suggest that during DENV infection autophagy shifts from a proviral to an antiviral cellular process, which is counteracted by the virus.
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Papandreou, Margarita-Elena, and Nektarios Tavernarakis. "Selective Autophagy as a Potential Therapeutic Target in Age-Associated Pathologies." Metabolites 11, no. 9 (August 31, 2021): 588. http://dx.doi.org/10.3390/metabo11090588.
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Progressive accumulation of damaged cellular constituents contributes to age-related diseases. Autophagy is the main catabolic process, which recycles cellular material in a multitude of tissues and organs. Autophagy is activated upon nutrient deprivation, and oncogenic, heat or oxidative stress-induced stimuli to selectively degrade cell constituents and compartments. Specificity and accuracy of the autophagic process is maintained via the precision of interaction of autophagy receptors or adaptors and substrates by the intricate, stepwise orchestration of specialized integrating stimuli. Polymorphisms in genes regulating selective autophagy have been linked to aging and age-associated disorders. The involvement of autophagy perturbations in aging and disease indicates that pharmacological agents balancing autophagic flux may be beneficial, in these contexts. Here, we introduce the modes and mechanisms of selective autophagy, and survey recent experimental evidence of dysfunctional autophagy triggering severe pathology. We further highlight identified pharmacological targets that hold potential for developing therapeutic interventions to alleviate cellular autophagic cargo burden and associated pathologies.
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Nezis, Ioannis P., Bhupendra V. Shravage, Antonia P. Sagona, Trond Lamark, Geir Bjørkøy, Terje Johansen, Tor Erik Rusten, Andreas Brech, Eric H. Baehrecke, and Harald Stenmark. "Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis." Journal of Cell Biology 190, no. 4 (August 16, 2010): 523–31. http://dx.doi.org/10.1083/jcb.201002035.
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Autophagy is an evolutionarily conserved pathway responsible for degradation of cytoplasmic material via the lysosome. Although autophagy has been reported to contribute to cell death, the underlying mechanisms remain largely unknown. In this study, we show that autophagy controls DNA fragmentation during late oogenesis in Drosophila melanogaster. Inhibition of autophagy by genetically removing the function of the autophagy genes atg1, atg13, and vps34 resulted in late stage egg chambers that contained persisting nurse cell nuclei without fragmented DNA and attenuation of caspase-3 cleavage. The Drosophila inhibitor of apoptosis (IAP) dBruce was found to colocalize with the autophagic marker GFP-Atg8a and accumulated in autophagy mutants. Nurse cells lacking Atg1 or Vps34 in addition to dBruce contained persisting nurse cell nuclei with fragmented DNA. This indicates that autophagic degradation of dBruce controls DNA fragmentation in nurse cells. Our results reveal autophagic degradation of an IAP as a novel mechanism of triggering cell death and thereby provide a mechanistic link between autophagy and cell death.
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Kimura, Tomonori, Ashish Jain, Seong Won Choi, Michael A. Mandell, Kate Schroder, Terje Johansen, and Vojo Deretic. "TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity." Journal of Cell Biology 210, no. 6 (September 7, 2015): 973–89. http://dx.doi.org/10.1083/jcb.201503023.
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The present paradigms of selective autophagy in mammalian cells cannot fully explain the specificity and selectivity of autophagic degradation. In this paper, we report that a subset of tripartite motif (TRIM) proteins act as specialized receptors for highly specific autophagy (precision autophagy) of key components of the inflammasome and type I interferon response systems. TRIM20 targets the inflammasome components, including NLRP3, NLRP1, and pro–caspase 1, for autophagic degradation, whereas TRIM21 targets IRF3. TRIM20 and TRIM21 directly bind their respective cargo and recruit autophagic machinery to execute degradation. The autophagic function of TRIM20 is affected by mutations associated with familial Mediterranean fever. These findings broaden the concept of TRIMs acting as autophagic receptor regulators executing precision autophagy of specific cytoplasmic targets. In the case of TRIM20 and TRIM21, precision autophagy controls the hub signaling machineries and key factors, inflammasome and type I interferon, directing cardinal innate immunity response systems in humans.
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Shang, Chuquan, Bardes Hassan, Moinul Haque, Yuqi Song, Jing Li, Dongzhe Liu, Eva Lipke, Will Chen, Sylvie Giuriato, and Raymond Lai. "Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent." Cancers 13, no. 2 (January 7, 2021): 181. http://dx.doi.org/10.3390/cancers13020181.
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Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely Reporter Unresponsive (RU) and Reporter Responsive (RR), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.
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Shang, Chuquan, Bardes Hassan, Moinul Haque, Yuqi Song, Jing Li, Dongzhe Liu, Eva Lipke, Will Chen, Sylvie Giuriato, and Raymond Lai. "Crizotinib Resistance Mediated by Autophagy Is Higher in the Stem-Like Cell Subset in ALK-Positive Anaplastic Large Cell Lymphoma, and This Effect Is MYC-Dependent." Cancers 13, no. 2 (January 7, 2021): 181. http://dx.doi.org/10.3390/cancers13020181.
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Previously it was shown that autophagy contributes to crizotinib resistance in ALK-positive anaplastic large cell lymphoma (ALK + ALCL). We asked if autophagy is equally important in two distinct subsets of ALK + ALCL, namely Reporter Unresponsive (RU) and Reporter Responsive (RR), of which RR cells display stem-like properties. Autophagic flux was assessed with a fluorescence tagged LC3 reporter and immunoblots to detect endogenous LC3 alongside chloroquine, an autophagy inhibitor. The stem-like RR cells displayed significantly higher autophagic response upon crizotinib treatment. Their exaggerated autophagic response is cytoprotective against crizotinib, as inhibition of autophagy using chloroquine or shRNA against BECN1 or ATG7 led to a decrease in their viability. In contrast, autophagy inhibition in RU resulted in minimal changes. Since the differential protein expression of MYC is a regulator of the RU/RR dichotomy and is higher in RR cells, we asked if MYC regulates the autophagy-mediated cytoprotective effect. Inhibition of MYC in RR cells using shRNA significantly blunted crizotinib-induced autophagic response and effectively suppressed this cytoprotective effect. In conclusion, stem-like RR cells respond with rapid and intense autophagic flux which manifests with crizotinib resistance. For the first time, we have highlighted the direct role of MYC in regulating autophagy and its associated chemoresistance phenotype in ALK + ALCL stem-like cells.
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Nandi, Shyam S., Kenichi Katsurada, Neeru M. Sharma, Daniel R. Anderson, Sushil K. Mahata, and Kaushik P. Patel. "MMP9 inhibition increases autophagic flux in chronic heart failure." American Journal of Physiology-Heart and Circulatory Physiology 319, no. 6 (December 1, 2020): H1414—H1437. http://dx.doi.org/10.1152/ajpheart.00032.2020.
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This study elucidates that the improved cardiac extracellular matrix (ECM) remodeling and cardioprotective effect of matrix metalloprotease 9 (MMP9) inhibition in chronic heart failure (CHF) are via increased autophagic flux. Autophagy is cardioprotective; however, the mechanism of autophagy suppression in CHF is unknown. We for the first time demonstrated here that increased MMP9 suppressed cardiac autophagy and ablation of MMP9 increased cardiac autophagic flux in CHF rats. Restoring the physiological level of autophagy in the failing heart is a challenge, and our study addressed this challenge. The novelty and highlights of this report are as follows: 1) MMP9 regulates cardiomyocyte and fibroblast autophagy, 2) MMP9 inhibition protects CHF after myocardial infarction (MI) via increased cardiac autophagic flux, and 3) MMP9 inhibition increased cardiac autophagy via activation of AMP-activated protein kinase (AMPK)α, Beclin-1, Atg7 pathway and suppressed mechanistic target of rapamycin (mTOR) pathway.
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Yuan, Xi-Ming, Nargis Sultana, Nabeel Siraj, Liam J. Ward, Bijar Ghafouri, and Wei Li. "Autophagy Induction Protects against 7-Oxysterol-induced Cell Death via Lysosomal Pathway and Oxidative Stress." Journal of Cell Death 9 (January 2016): JCD.S37841. http://dx.doi.org/10.4137/jcd.s37841.
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7-Oxysterols are major toxic components in oxidized low-density lipoprotein and human atheroma lesions, which cause lysosomal membrane permeabilization (LMP) and cell death. Autophagy may function as a survival mechanism in this process. Here, we investigated whether 7-oxysterols mixed in an atheroma-relevant proportion induce autophagy, whether autophagy induction influences 7-oxysterol-mediated cell death, and the underlying mechanisms, by focusing on cellular lipid levels, oxidative stress, and LMP in 7-oxysterol-treated macrophages. We found that 7-oxysterols induced cellular lipid accumulation, autophagy dysfunction, and cell death in the form of both apoptosis and necrosis. Exposure to 7-oxysterols induced autophagic vacuole synthesis in the form of increased autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3) and LC3-phosphatidylethanolamine conjugate (LC3-II) and autophagic vacuole formation. This led to an accumulation of p62, indicating a reduction in autophagic vacuole degradation. Importantly, autophagy induction significantly reduced 7-oxysterol-mediated cell death by diminishing LMP and oxidative stress. Moreover, autophagy induction minimized cellular lipid accumulation induced by 7-oxysterols. These findings highlight the importance of autophagy in combating cellular stress, LMP, and cell death in atherosclerosis. Therefore, activation of the autophagy pathway may be a potential therapeutic strategy for prevention of necrotic core formation in atherosclerotic lesions.
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Taskaeva, Iuliia, and Nataliya Bgatova. "Ultrastructural and Immunofluorescent Analysis of Lithium Effects on Autophagy in Hepatocellular Carcinoma Cells." Asian Pacific Journal of Cancer Biology 3, no. 3 (November 13, 2018): 83–87. http://dx.doi.org/10.31557/apjcb.2018.3.3.83-87.
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Background: Hepatocellular carcinoma (HCC) is one of the most malignant cancers worldwide. The role of autophagy in the НСС development and progression is controversial and are still not well known. It has been shown that lithium induces autophagy and apoptosis, affects on proliferation and survival of various human malignancies. In this study we estimated lithium`s effects on autophagy in HCC in vivo.Materials and methods: Subcellular components and autophagic vacuoles were analyzed by transmission electron microscopy. The number of cells with LC3 and LAMP1 punctate was analyzed by double-immunofluorescence staining. Data are presented as mean ± standard deviation (SD). Mann–Whitney nonparametric tests were used to assess statistically significant differences at P < 0.05.Results: Lithium carbonate increased the numerical and volume density of autophagic vacuoles and autophagy marker LC3 beta. Therefore, lithium carbonate promotes enlarged autophagic vacuoles formation in HCC cells in vivo.Conclusion: Extended and unresolved autophagy induces cancer cell death by stimulating autophagic cell death. Thus, lithium-mediated autophagy can be an attractive approach in HCC chemotherapy.
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Lin, Long, Peiguo Yang, Xinxin Huang, Hui Zhang, Qun Lu, and Hong Zhang. "The scaffold protein EPG-7 links cargo–receptor complexes with the autophagic assembly machinery." Journal of Cell Biology 201, no. 1 (March 25, 2013): 113–29. http://dx.doi.org/10.1083/jcb.201209098.
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The mechanism by which protein aggregates are selectively degraded by autophagy is poorly understood. Previous studies show that a family of Atg8-interacting proteins function as receptors linking specific cargoes to the autophagic machinery. Here we demonstrate that during Caenorhabditis elegans embryogenesis, epg-7 functions as a scaffold protein mediating autophagic degradation of several protein aggregates, including aggregates of the p62 homologue SQST-1, but has little effect on other autophagy-regulated processes. EPG-7 self-oligomerizes and is degraded by autophagy independently of SQST-1. SQST-1 directly interacts with EPG-7 and colocalizes with EPG-7 aggregates in autophagy mutants. Mutations in epg-7 impair association of SQST-1 aggregates with LGG-1/Atg8 puncta. EPG-7 interacts with multiple ATG proteins and colocalizes with ATG-9 puncta in various autophagy mutants. Unlike core autophagy genes, epg-7 is dispensable for starvation-induced autophagic degradation of substrate aggregates. Our results indicate that under physiological conditions a scaffold protein endows cargo specificity and also elevates degradation efficiency by linking the cargo–receptor complex with the autophagic machinery.
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Wen, Hui-Ju, Zhilong Yang, You Zhou, and Charles Wood. "Enhancement of Autophagy during Lytic Replication by the Kaposi's Sarcoma-Associated Herpesvirus Replication and Transcription Activator." Journal of Virology 84, no. 15 (May 19, 2010): 7448–58. http://dx.doi.org/10.1128/jvi.00024-10.
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ABSTRACT Autophagy is one of two major degradation systems in eukaryotic cells. The degradation mechanism of autophagy is required to maintain the balance between the biosynthetic and catabolic processes and also contributes to defense against invading pathogens. Recent studies suggest that a number of viruses can evade or subvert the host cell autophagic pathway to enhance their own replication. Here, we investigated the effect of autophagy on the KSHV (Kaposi's sarcoma-associated herpesvirus) life cycle. We found that the inhibition of autophagy reduces KSHV lytic reactivation from latency, and an enhancement of autophagy can be detected during KSHV lytic replication. In addition, RTA (replication and transcription activator), an essential viral protein for KSHV lytic reactivation, is able to enhance the autophagic process, leading to an increase in the number of autophagic vacuoles, an increase in the level of the lipidated LC3 protein, and the formation of autolysosomes. Moreover, the inhibition of autophagy affects RTA-mediated lytic gene expression and viral DNA replication. These results suggest that RTA increases autophagy activation to facilitate KSHV lytic replication. This is the first report demonstrating that autophagy is involved in the lytic reactivation of KSHV.
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Choi, Soyoung, Hyejin Shin, Haengseok Song, and Hyunjung Jade Lim. "Suppression of autophagic activation in the mouse uterus by estrogen and progesterone." Journal of Endocrinology 221, no. 1 (January 17, 2014): 39–50. http://dx.doi.org/10.1530/joe-13-0449.
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Autophagy is a major cellular catabolic pathway tightly associated with cell survival. The involvement of autophagy in the prolonged survival of blastocysts in the uterus is well established, and it was assumed that ovarian steroid hormones – progesterone (P4) and estrogens – have important roles in the regulation of autophagy. However, information is scarce regarding whether these hormones regulate autophagy in certain hormone-responsive cellular systems. In this study, we investigated the effects of estrogen and P4 on autophagic response in the uteri of pregnant mice and in ovariectomized (OVX) mice treated with hormones. During pregnancy, autophagic response is high on days 1 and 2 when the uterus shows an inflammatory response to mating, but it subsides around the time of implantation. Dexamethasone treatment to day 1 pregnant mice reduced autophagy in the uterus. In OVX mouse uteri, estrogen or P4 reduces autophagic response within 6 h. Glycogen content in OVX uteri was increased by 3-methyladenine treatment, suggesting that autophagy is involved in glycogen breakdown in the hormone-deprived uterus. The classical nuclear receptor antagonists, ICI 182 780 or mifepristone, lead to the recovery of the autophagic response in OVX uteri. The suppression of autophagy by 17β-estradiol is inversely correlated with the accumulation of phospho-mouse target of rapamycin, and rapamycin treatment is moderately effective in the upregulation of autophagic response in OVX mouse uteri. Collectively, this study establishes that the uterine autophagy is induced in hormone-derived environment and is suppressed by hormone treatment. Uterine autophagy may have multiple functions as a responsive mechanism to acute inflammation and as an energy provider by breaking down glycogen under hormone deprivation.
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Herzog, Christian, Cheng Yang, Alexandrea Holmes, and Gur P. Kaushal. "zVAD-fmk prevents cisplatin-induced cleavage of autophagy proteins but impairs autophagic flux and worsens renal function." American Journal of Physiology-Renal Physiology 303, no. 8 (October 15, 2012): F1239—F1250. http://dx.doi.org/10.1152/ajprenal.00659.2011.
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Cisplatin injury to renal tubular epithelial cells (RTEC) is accompanied by autophagy and caspase activation. However, autophagy gradually decreases during the course of cisplatin injury. The role of autophagy and the mechanism of its decrease during cisplatin injury are not well understood. This study demonstrated that autophagy proteins beclin-1, Atg5, and Atg12 were cleaved and degraded during the course of cisplatin injury in RTEC and the kidney. zVAD-fmk, a widely used pancaspase inhibitor, blocked cleavage of autophagy proteins suggesting that zVAD-fmk would promote the autophagy pathway. Unexpectedly, zVAD-fmk blocked clearance of the autophagosomal cargo, indicating lysosomal dysfunction. zVAD-fmk markedly inhibited cisplatin-induced lysosomal cathepsin B and calpain activities and therefore impaired autophagic flux. In a mouse model of cisplatin nephrotoxicity, zVAD-fmk impaired autophagic flux by blocking autophagosomal clearance as revealed by accumulation of key autophagic substrates p62 and LC3-II. Furthermore, zVAD-fmk worsened cisplatin-induced renal dysfunction. Chloroquine, a lysomotropic agent that is known to impair autophagic flux, also exacerbated cisplatin-induced decline in renal function. These findings demonstrate that impaired autophagic flux induced by zVAD-fmk or a lysomotropic agent worsened renal function in cisplatin acute kidney injury (AKI) and support a protective role of autophagy in AKI. These studies also highlight that the widely used antiapoptotic agent zVAD-fmk may be contraindicated as a therapeutic agent for preserving renal function in AKI.
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Choi, Alexander J. S., and Stefan W. Ryter. "Autophagy in Inflammatory Diseases." International Journal of Cell Biology 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/732798.
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Autophagy provides a mechanism for the turnover of cellular organelles and proteins through a lysosome-dependent degradation pathway. During starvation, autophagy exerts a homeostatic function that promotes cell survival by recycling metabolic precursors. Additionally, autophagy can interact with other vital processes such as programmed cell death, inflammation, and adaptive immune mechanisms, and thereby potentially influence disease pathogenesis. Macrophages deficient in autophagic proteins display enhanced caspase-1-dependent proinflammatory cytokine production and the activation of the inflammasome. Autophagy provides a functional role in infectious diseases and sepsis by promoting intracellular bacterial clearance. Mutations in autophagy-related genes, leading to loss of autophagic function, have been implicated in the pathogenesis of Crohn's disease. Furthermore, autophagy-dependent mechanisms have been proposed in the pathogenesis of several pulmonary diseases that involve inflammation, including cystic fibrosis and pulmonary hypertension. Strategies aimed at modulating autophagy may lead to therapeutic interventions for diseases associated with inflammation.
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Wu, Junfang, and Marta M. Lipinski. "Autophagy in Neurotrauma: Good, Bad, or Dysregulated." Cells 8, no. 7 (July 10, 2019): 693. http://dx.doi.org/10.3390/cells8070693.
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Autophagy is a physiological process that helps maintain a balance between the manufacture of cellular components and breakdown of damaged organelles and other toxic cellular constituents. Changes in autophagic markers are readily detectable in the spinal cord and brain following neurotrauma, including traumatic spinal cord and brain injury (SCI/TBI). However, the role of autophagy in neurotrauma remains less clear. Whether autophagy is good or bad is under debate, with strong support for both a beneficial and detrimental role for autophagy in experimental models of neurotrauma. Emerging data suggest that autophagic flux, a measure of autophagic degradation activity, is impaired in injured central nervous systems (CNS), and interventions that stimulate autophagic flux may provide neuroprotection in SCI/TBI models. Recent data demonstrating that neurotrauma can cause lysosomal membrane damage resulting in pathological autophagosome accumulation in the spinal cord and brain further supports the idea that the impairment of the autophagy–lysosome pathway may be a part of secondary injury processes of SCI/TBI. Here, we review experimental work on the complex and varied responses of autophagy in terms of both the beneficial and detrimental effects in SCI and TBI models. We also discuss the existing and developing therapeutic options aimed at reducing the disruption of autophagy to protect the CNS after injuries.
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HAN, KYUNGREEM, JINWOONG KIM, and MOOYOUNG CHOI. "COMPUTER SIMULATIONS UNVEIL THE DYNAMICS OF AUTOPHAGY AND ITS IMPLICATIONS FOR THE CELLULAR QUALITY CONTROL." Journal of Biological Systems 22, no. 04 (November 11, 2014): 659–75. http://dx.doi.org/10.1142/s0218339014500260.
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Since the discovery of autophagy half a century ago, a number of physiological and molecular-level studies of autophagy have been carried out, revealing the basic mechanism and role of autophagy in the protein and organelle quality control. However, a reliable assessment method for the autophagy-mediated protein/organelle quality control with the help of an adequate mathematical model has not yet been reported. Based on the previous mathematical modeling of autophagy, we have carried out simulations to prove whether and how basal autophagy achieves substrate specificity and contributes to the cellular protein/organelle quality control. By means of numerical simulations, we probe the selective autophagic mode and observe that autophagic fluxes from abnormal protein/organelle are much greater than those from resident protein/organelle. Such a selective autophagic mode is found to correlate with the fractional abnormal protein/organelle concentration. Finally, it is shown that the fractional abnormal protein/organelle concentration against cellular damaging is efficiently controlled and regulated by suppression or promotion of the autophagosome formation rate. Mathematical modeling and numerical simulations allow one to analyze the autophagic protein/organelle quality control in a specific and quantitative manner and disclose that autophagy serves as a critical cellular quality control mechanism.
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Li, Cui, Sui, Huang, Huang, Fan, and Chu. "Autophagic Survival Precedes Programmed Cell Death in Wheat Seedlings Exposed to Drought Stress." International Journal of Molecular Sciences 20, no. 22 (November 16, 2019): 5777. http://dx.doi.org/10.3390/ijms20225777.
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Although studies have shown the concomitant occurrence of autophagic and programmed cell death (PCD) in plants, the relationship between autophagy and PCD and the factors determining this relationship remain unclear. In this study, seedlings of the wheat cultivar Jimai 22 were used to examine the occurrence of autophagy and PCD during polyethylene glycol (PEG)-8000-induced drought stress. Autophagy and PCD occurred sequentially, with autophagy at a relatively early stage and PCD at a much later stage. These findings suggest that the duration of drought stress determines the occurrence of PCD following autophagy. Furthermore, the addition of 3-methyladenine (3-MA, an autophagy inhibitor) and the knockdown of autophagy-related gene 6 (ATG6) accelerated PEG-8000-induced PCD, respectively, suggesting that inhibition of autophagy also results in PCD under drought stress. Overall, these findings confirm that wheat seedlings undergo autophagic survival under mild drought stress, with subsequent PCD only under severe drought.
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Ramachandran, Sharavan, Itishree S. Kaushik, and Sanjay K. Srivastava. "Pimavanserin: A Novel Autophagy Modulator for Pancreatic Cancer Treatment." Cancers 13, no. 22 (November 12, 2021): 5661. http://dx.doi.org/10.3390/cancers13225661.
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Pancreatic tumors exhibit high basal autophagy compared to that of other cancers. Several studies including those from our laboratory reported that enhanced autophagy leads to apoptosis in cancer cells. In this study, we evaluated the autophagy and apoptosis inducing effects of Pimavanserin tartrate (PVT). Autophagic effects of PVT were determined by Acridine Orange assay and Transmission Electron Microscopy analysis. Clinical significance of ULK1 in normal and pancreatic cancer patients was evaluated by R2 and GEPIA cancer genomic databases. Modulation of proteins in autophagy signaling was assessed by Western blotting and Immunofluorescence. Apoptotic effects of PVT was evaluated by Annexin-V/APC assay. Subcutaneous xenograft pancreatic tumor model was used to evaluate the autophagy-mediated apoptotic effects of PVT in vivo. Autophagy was induced upon PVT treatment in pancreatic ducal adenocarcinoma (PDAC) cells. Pancreatic cancer patients exhibit reduced levels of autophagy initiator gene, ULK1, which correlated with reduced patient survival. Interestingly, PVT induced the expression of autophagy markers ULK1, FIP200, Atg101, Beclin-1, Atg5, LC3A/B, and cleavage of caspase-3, an indicator of apoptosis in several PDAC cells. ULK1 agonist LYN-1604 enhanced the autophagic and apoptotic effects of PVT. On the other hand, autophagy inhibitors chloroquine and bafilomycin blocked the autophagic and apoptotic effects of PVT in PDAC cells. Notably, chloroquine abrogated the growth suppressive effects of PVT by 25% in BxPC3 tumor xenografts in nude mice. Collectively, our results indicate that PVT mediated pancreatic tumor growth suppression was associated with induction of autophagy mediated apoptosis.
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Trelford, Charles B., and Gianni M. Di Guglielmo. "Assessing methods to quantitatively validate TGFβ-dependent autophagy." Biology Open 9, no. 11 (November 9, 2020): bio055103. http://dx.doi.org/10.1242/bio.055103.
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ABSTRACTTransforming growth factor beta (TGFβ) promotes tumorigenesis by suppressing immune surveillance and inducing epithelial to mesenchymal transition (EMT). TGFβ may augment tumorigenesis by activating autophagy, which protects cancer cells from chemotherapy and promotes invasive and anti-apoptotic properties. Here, we assess how TGFβ1 modulates autophagy related (ATG) gene expression and ATG protein levels. We also assessed microtubule-associated protein light chain 3 (LC3) lipidation, LC3 puncta formation and autophagosome-lysosome co-localization in non-small cell lung cancer (NSCLC) cell lines. These experimental approaches were validated using pharmacological autophagy inhibitors (chloroquine and spautin-1) and an autophagy activator (MG132). We found that TGFβ1, chloroquine and MG132 had little effect on ATG protein levels but increased LC3 lipidation, LC3 puncta formation and autophagosome-lysosome co-localization. Since similar outcomes were observed using chloroquine and MG132, we concluded that several techniques employed to assess TGFβ-dependent autophagy may not differentiate between the activation of autophagy versus lysosomal inhibition. Thus, NSCLC cell lines stably expressing a GFP-LC3-RFP-LC3ΔG autophagic flux probe were used to assess TGFβ-mediated autophagy. Using this approach, we observed that TGFβ, MG132 and serum starvation increased autophagic flux, whereas chloroquine and spautin-1 decreased autophagic flux. Finally, we demonstrated that ATG5 and ATG7 are critical for TGFβ-dependent autophagy in NSCLC cells. The application of this model will fuel future experiments to characterize TGFβ-dependent autophagy, which is necessary to understand the molecular processes that link, TGFβ, autophagy and tumorigenesis.
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Fulda, Simone. "Targeting autophagy for the treatment of cancer." Biological Chemistry 399, no. 7 (June 27, 2018): 673–77. http://dx.doi.org/10.1515/hsz-2018-0105.
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Abstract Macroautophagy (herein termed autophagy) is evolutionarily highly conserved across eukaryotic cells and represents an intracellular catabolic process that targets damaged macromolecules and organelles for degradation. Autophagy is dysregulated in various human diseases including cancer. In addition, many drugs currently used for the treatment of cancer can engage autophagy, which typically promotes cancer cell survival by mitigating cellular stress. However, under certain circumstances activation of autophagy upon anticancer drug treatment can also trigger a lethal type of autophagy termed autophagic cell death (ACD). This may pave new avenues for exploiting the autophagic circuitry in oncology. This review presents the concept and some examples of anticancer drug-induced ACD.
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du Toit, André, Sholto De Wet, Jan-Hendrik Hofmeyr, Kristian Müller-Nedebock, and Ben Loos. "The Precision Control of Autophagic Flux and Vesicle Dynamics—A Micropattern Approach." Cells 7, no. 8 (August 3, 2018): 94. http://dx.doi.org/10.3390/cells7080094.
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Autophagy failure is implicated in age-related human disease. A decrease in the rate of protein degradation through the entire autophagy pathway, i.e., autophagic flux, has been associated with the onset of cellular proteotoxity and cell death. Although the precision control of autophagy as a pharmacological intervention has received major attention, mammalian model systems that enable a dissection of the relationship between autophagic flux and pathway intermediate pool sizes remain largely underexplored. Here, we make use of a micropattern-based fluorescence life cell imaging approach, allowing a high degree of experimental control and cellular geometry constraints. By assessing two autophagy modulators in a system that achieves a similarly raised autophagic flux, we measure their impact on the pathway intermediate pool size, autophagosome velocity, and motion. Our results reveal a differential effect of autophagic flux enhancement on pathway intermediate pool sizes, velocities, and directionality of autophagosome motion, suggesting distinct control over autophagy function. These findings may be of importance for better understanding the fine-tuning autophagic activity and protein degradation proficiency in different cell and tissue types of age-associated pathologies.
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Zhang, Juan, Qian Xiang, Man Wu, Yuan-Zhi Lao, Yan-Fang Xian, Hong-Xi Xu, and Zhi-Xiu Lin. "Autophagy Regulators in Cancer." International Journal of Molecular Sciences 24, no. 13 (June 30, 2023): 10944. http://dx.doi.org/10.3390/ijms241310944.
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Autophagy plays a complex impact role in tumor initiation and development. It serves as a double-edged sword by supporting cell survival in certain situations while also triggering autophagic cell death in specific cellular contexts. Understanding the intricate functions and mechanisms of autophagy in tumors is crucial for guiding clinical approaches to cancer treatment. Recent studies highlight its significance in various aspects of cancer biology. Autophagy enables cancer cells to adapt to and survive unfavorable conditions by recycling cellular components. However, excessive or prolonged autophagy can lead to the self-destruction of cancer cells via a process known as autophagic cell death. Unraveling the molecular mechanisms underlying autophagy regulation in cancer is crucial for the development of targeted therapeutic interventions. In this review, we seek to present a comprehensive summary of current knowledge regarding autophagy, its impact on cancer cell survival and death, and the molecular mechanisms involved in the modulation of autophagy for cancer therapy.
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Li, Xincong, Hanxiao Liu, Yijun Yu, Lan Ma, Chao Liu, and Leiying Miao. "Graphene Oxide Quantum Dots-Induced Mineralization via the Reactive Oxygen Species-Dependent Autophagy Pathway in Dental Pulp Stem Cells." Journal of Biomedical Nanotechnology 16, no. 6 (June 1, 2020): 965–74. http://dx.doi.org/10.1166/jbn.2020.2934.
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As an important recycling and degradation system, autophagy is considered to be critical in regulating stem cell differentiation. It has been shown that graphene oxide quantum dots (GOQDs) are a robust biological labelling tool for stem cells with little cytotoxicity. In this study, we explored the role of autophagy in regulating the impact of GOQDs on the odontoblastic differentiation of DPSCs during autophagy. Western blotting and immunofluorescence staining were used to evaluate the autophagic activity of DPSCs. Quantitative PCR, alizarin red S staining, and alkaline phosphatase staining were used to examine DPSC odontoblastic differentiation. The impacts of ROS scavengers on autophagy induction and reactive oxygen species (ROS) levels were also measured. Lentiviral vectors carrying Beclin1 siRNA sequences, as well as autophagy inhibitors (3-MA and bafilomycin A1), were used to inhibit autophagy. Initial exposure to GOQDs increased autophagic activity and enhanced DPSC mineralization. Autophagy inhibition suppressed GOQD-induced odontoblastic differentiation. Moreover, GOQD treatment induced autophagy in a ROS-dependent manner. GOQDs promoted differentiation, which could be modulated via ROS-induced autophagy.
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Quiniou, G., O. Dinet, O. Cervantes, M. Verdet, G. Boschetti, C. Viret, S. Nancey, M. Faure, and A. Rozieres. "P047 The ATG16L1 T300A polymorphism in Crohn’s Disease patients leads to abnormal autophagy flux in dendritic cells." Journal of Crohn's and Colitis 15, Supplement_1 (May 1, 2021): S155—S156. http://dx.doi.org/10.1093/ecco-jcc/jjab076.176.
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Abstract Background Crohn’s disease is a chronic inflammatory bowel disease, whose pathogenesis is largely determined by an inappropriate immune response towards luminal microbiota in genetically susceptible hosts, affecting in particular genes involved in the autophagy process. The autophagy-related ATG16L1 T300A variant is one of the most frequently associated polymorphisms with susceptibility to Crohn’s disease, but the functional consequences of this polymorphism on the dynamic properties of the autophagy flux remains unknown. Methods Using dynamic monitoring of LC3 lipidation, a key protein marker of autophagy, we have quantitatively analysed the autophagic flux of human primary dendritic cells, which are very potent antigen-presenting cells whose function is critical in Crohn’s disease. Results The detailed analysis of the dynamic properties of the autophagic flux reveal that the maturation process in dendritic cells from healthy subjects is associated with a decrease of the velocity and the intensity on the autophagy flux although the turnover of autophagosome formation was maintained, demonstrating the capacity of resilience of the autophagy flux for a maintenance of functional autophagy during maturation process. Strikingly, the expression of the ATG16L1 T300A variant, but not NOD2 R702W variant, in dendritic cells from patients with Crohn’s disease is associated with a disorder of the autophagic flux dynamics in immature dendritic cells, that was not modulated upon maturation. The lack of adaptation of the autophagy flux in ATG16L1 T300A expressing dendritic cells of Crohn’s disease patients, during their maturation was not associated with altered phenotypic acquisition of maturation markers but highlighted a very specific autophagic flux signature. Conclusion Dendritic cells of Crohn’s patients expressing the autophagy-related ATG16L1 T300A have an altered autophagy flux, that could affect their function and contribute to the pathogenesis of Crohn’s disease.
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Tang, Daolin, Rui Kang, Kristen M. Livesey, Chun-Wei Cheh, Adam Farkas, Patricia Loughran, George Hoppe, et al. "Endogenous HMGB1 regulates autophagy." Journal of Cell Biology 190, no. 5 (September 6, 2010): 881–92. http://dx.doi.org/10.1083/jcb.200911078.
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Autophagy clears long-lived proteins and dysfunctional organelles and generates substrates for adenosine triphosphate production during periods of starvation and other types of cellular stress. Here we show that high mobility group box 1 (HMGB1), a chromatin-associated nuclear protein and extracellular damage-associated molecular pattern molecule, is a critical regulator of autophagy. Stimuli that enhance reactive oxygen species promote cytosolic translocation of HMGB1 and thereby enhance autophagic flux. HMGB1 directly interacts with the autophagy protein Beclin1 displacing Bcl-2. Mutation of cysteine 106 (C106), but not the vicinal C23 and C45, of HMGB1 promotes cytosolic localization and sustained autophagy. Pharmacological inhibition of HMGB1 cytoplasmic translocation by agents such as ethyl pyruvate limits starvation-induced autophagy. Moreover, the intramolecular disulfide bridge (C23/45) of HMGB1 is required for binding to Beclin1 and sustaining autophagy. Thus, endogenous HMGB1 is a critical pro-autophagic protein that enhances cell survival and limits programmed apoptotic cell death.
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Yang, Cheng, Varsha Kaushal, Sudhir V. Shah, and Gur P. Kaushal. "Autophagy is associated with apoptosis in cisplatin injury to renal tubular epithelial cells." American Journal of Physiology-Renal Physiology 294, no. 4 (April 2008): F777—F787. http://dx.doi.org/10.1152/ajprenal.00590.2007.
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Autophagy has emerged as another major “programmed” mechanism to control life and death much like “programmed cell death” is for apoptosis in eukaryotes. We examined the expression of autophagic proteins and formation of autophagosomes during progression of cisplatin injury to renal tubular epithelial cells (RTEC). Autophagy was detected as early as 2–4 h after cisplatin exposure as indicated by induction of LC3-I, conversion of LC3-I to LC3-II protein, and upregulation of Beclin 1 and Atg5, essential markers of autophagy. The appearance of cisplatin-induced punctated staining of autophagosome-associated LC3-II upon GFP-LC3 transfection in RTEC provided further evidence for autophagy. The autophagy inhibitor 3-methyladenine blocked punctated staining of autophagosomes. The staining of normal cells with acridine orange displayed green fluorescence with cytoplasmic and nuclear components in normal cells but displayed considerable red fluorescence in cisplatin-treated cells, suggesting formation of numerous acidic autophagolysosomal vacuoles. Autophagy inhibitors LY294002 or 3-methyladenine or wortmannin inhibited the formation of autophagosomes but induced apoptosis after 2–4 h of cisplatin treatment as indicated by caspase-3/7 and -6 activation, nuclear fragmentation, and cell death. This switch from autophagy to apoptosis by autophagic inhibitors further suggests that the preapoptotic lag phase after treatment with cisplatin is mediated by autophagy. At later stages of cisplatin injury, apoptosis was also found to be associated with autophagy, as autophagic inhibitors and inactivation of autophagy proteins Beclin 1 and Atg5 enhanced activation of caspases and apoptosis. Our results demonstrate that induction of autophagy mounts an adaptive response, suppresses cisplatin-induced apoptosis, and prolongs survival of RTEC.
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Hamano, Tadanori, Soichi Enomoto, Norimichi Shirafuji, Masamichi Ikawa, Osamu Yamamura, Shu-Hui Yen, and Yasunari Nakamoto. "Autophagy and Tau Protein." International Journal of Molecular Sciences 22, no. 14 (July 12, 2021): 7475. http://dx.doi.org/10.3390/ijms22147475.
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Neurofibrillary tangles, which consist of highly phosphorylated tau protein, and senile plaques (SPs) are pathological hallmarks of Alzheimer’s disease (AD). In swollen axons, many autophagic vacuoles are observed around SP in the AD brain. This suggests that autophagy function is disturbed in AD. We used a neuronal cellular model of tauopathy (M1C cells), which harbors wild type tau (4R0N), to assess the effects of the lysosomotrophic agent NH4Cl, and autophagy inhibitors chloroquine and 3 methyladenine (3MA). It was found that chloroquine, NH4Cl and 3MA markedly increased tau accumulation. Thus, autophagy lysosomal system disturbances disturbed the degradation mechanisms of tau protein. Other studies also revealed that tau protein, including aggregated tau, is degraded via the autophagy lysosome system. Phosphorylated and C terminal truncated tau were also reported to disturb autophagy function. As a therapeutic strategy, autophagy upregulation was suggested. Thus far, as autophagy modulators, rapamycin, mTOCR1 inhibitor and its analogues, lithium, metformin, clonidine, curcumin, nicotinamide, bexaroten, and torehalose have been proposed. As a therapeutic strategy, autophagic modulation may be the next target of AD therapeutics.
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Skendros, Panagiotis, and Ioannis Mitroulis. "Host Cell Autophagy in Immune Response to Zoonotic Infections." Clinical and Developmental Immunology 2012 (2012): 1–9. http://dx.doi.org/10.1155/2012/910525.
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Autophagy is a fundamental homeostatic process in which cytoplasmic targets are sequestered within double-membraned autophagosomes and subsequently delivered to lysosomes for degradation. Accumulating evidence supports the pivotal role of autophagy in host defense against intracellular pathogens implicating both innate and adaptive immunity. Many of these pathogens cause common zoonotic infections worldwide. The induction of the autophagic machinery by innate immune receptors signaling, such as TLRs, NOD1/2, and p62/SQSTM1 in antigen-presenting cells results in inhibition of survival and elimination of invading pathogens. Furthermore, Th1 cytokines induce the autophagic process, whereas autophagy also contributes to antigen processing and MHC class II presentation, linking innate to adaptive immunity. However, several pathogens have developed strategies to avoid autophagy or exploit autophagic machinery to their advantage. This paper focuses on the role of host cell autophagy in the regulation of immune response against intracellular pathogens, emphasizing on selected bacterial and protozoan zoonoses.
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Almansa-Gómez, Sergio, Francisco Prieto-Ruiz, José Cansado, and Marisa Madrid. "Autophagy Modulation as a Potential Therapeutic Strategy in Osteosarcoma: Current Insights and Future Perspectives." International Journal of Molecular Sciences 24, no. 18 (September 7, 2023): 13827. http://dx.doi.org/10.3390/ijms241813827.
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Autophagy, the process that enables the recycling and degradation of cellular components, is essential for homeostasis, which occurs in response to various types of stress. Autophagy plays an important role in the genesis and evolution of osteosarcoma (OS). The conventional treatment of OS has limitations and is not always effective at controlling the disease. Therefore, numerous researchers have analyzed how controlling autophagy could be used as a treatment or strategy to reverse resistance to therapy in OS. They highlight how the inhibition of autophagy improves the efficacy of chemotherapeutic treatments and how the promotion of autophagy could prove positive in OS therapy. The modulation of autophagy can also be directed against OS stem cells, improving treatment efficacy and preventing cancer recurrence. Despite promising findings, future studies are needed to elucidate the molecular mechanisms of autophagy and its relationship to OS, as well as the mechanisms underlying the functioning of autophagic modulators. Careful evaluation is required as autophagy modulation may have adverse effects on normal cells, and the optimization of autophagic modulators for use as drugs in OS is imperative.
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Choi, Suyun, and Hyeyoung Kim. "The Remedial Potential of Lycopene in Pancreatitis through Regulation of Autophagy." International Journal of Molecular Sciences 21, no. 16 (August 12, 2020): 5775. http://dx.doi.org/10.3390/ijms21165775.
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Autophagy is an evolutionarily conserved process that degrades damaged organelles and recycles macromolecules to support cell survival. However, in certain disease states, dysregulated autophagy can play an important role in cell death. In pancreatitis, the accumulation of autophagic vacuoles and damaged mitochondria and premature activation of trypsinogen are shown in pancreatic acinar cells (PACs), which are the hallmarks of impaired autophagy. Oxidative stress mediates inflammatory signaling and cytokine expression in PACs, and it also causes mitochondrial dysfunction and dysregulated autophagy. Thus, oxidative stress may be a mediator for autophagic impairment in pancreatitis. Lycopene is a natural pigment that contributes to the red color of fruits and vegetables. Due to its antioxidant activity, it inhibited oxidative stress-induced expression of cytokines in experimental models of acute pancreatitis. Lycopene reduces cell death through the activation of 5′-AMP-activated protein kinase-dependent autophagy in certain cells. Therefore, lycopene may ameliorate pancreatitis by preventing oxidative stress-induced impairment of autophagy and/or by directly activating autophagy in PACs.
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Cebollero, Eduardo, and Ramon Gonzalez. "Induction of Autophagy by Second-Fermentation Yeasts during Elaboration of Sparkling Wines." Applied and Environmental Microbiology 72, no. 6 (June 2006): 4121–27. http://dx.doi.org/10.1128/aem.02920-05.
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ABSTRACT Autophagy is a transport system mediated by vesicles, ubiquitous in eukaryotic cells, by which bulk cytoplasm is targeted to a lysosome or vacuole for degradation. In the yeast Saccharomyces cerevisiae, autophagy is triggered by nutritional stress conditions (e.g., carbon- or nitrogen-depleted medium). In this study we showed that there is induction of autophagy in second-fermentation yeasts during sparkling wine making. Two methods were employed to detect autophagy: a biochemical approach based on depletion of the protein acetaldehyde dehydrogenase Ald6p and a morphological strategy consisting of visualization of autophagic bodies and autophagosomes, which are intermediate vesicles in the autophagic process, by transmission electron microscopy. This study provides the first demonstration of autophagy in second-fermentation yeasts under enological conditions. The correlation between autophagy and yeast autolysis during sparkling wine production is discussed, and genetic engineering of autophagy-related genes in order to accelerate the aging steps in wine making is proposed.
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Li, Chunzheng, Chenyu Wei, Gongke Zhao, and Xianguang Yang. "Cancer cells remodeling and quality control are inextricably linked to autophagy." AIMS Molecular Science 10, no. 2 (2023): 109–26. http://dx.doi.org/10.3934/molsci.2023009.
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<abstract> <p>Autophagy is a normal cellular physiological process. As one of the cell degradation systems, it participates in the lysosomal pathway process of degrading damaged proteins and subcellular organelles to maintain cell metabolism and energy states. Moreover, autophagy is essential for regulating organelle quality control and cell homeostasis. In recent decades, a large number of studies have demonstrated that autophagy abnormalities are present in a variety of human malignancies and that autophagy plays a crucial role in all stages of tumor development. Multiple tumors interfere with autophagy's normal regulation and use autophagy's essential properties to restructure their proteome, reprogram their metabolism, and adapt to stress. This article primarily discusses how autophagy either promotes or inhibits cancer development, the significance of autophagy in maintaining cell genome stability, and the role of selective autophagy in the reshaping and quality control of tumor cells.</p> </abstract>
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Gorostieta-Salas, Elisa, Daniel Moreno-Blas, Cristian Gerónimo-Olvera, Bulmaro Cisneros, Felipe A. Court, and Susana Castro-Obregón. "Enhanced Activity of Exportin-1/CRM1 in Neurons Contributes to Autophagy Dysfunction and Senescent Features in Old Mouse Brain." Oxidative Medicine and Cellular Longevity 2021 (August 13, 2021): 1–22. http://dx.doi.org/10.1155/2021/6682336.
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Brain aging is characterized by dysfunctional autophagy and cellular senescence, among other features. While autophagy can either promote or suppress cellular senescence in proliferating cells, in postmitotic cells, such as neurons, autophagy impairment promotes cellular senescence. CRM1 (exportin-1/XPO1) exports hundreds of nuclear proteins into the cytoplasm, including the transcription factors TFEB (the main inducer of autophagy and lysosomal biogenesis genes) and STAT3, another autophagy modulator. It appears that CRM1 is a modulator of aging-associated senescence and autophagy, because pharmacological inhibition of CRM1 improved autophagic degradation in flies, by increasing nuclear TFEB levels, and because enhanced CRM1 activity is mechanistically linked to senescence in fibroblasts from Hutchinson–Gilford progeria syndrome patients and old healthy individuals; furthermore, the exogenous overexpression of CRM1 induced senescence in normal fibroblasts. In this work, we tested the hypothesis that impaired autophagic flux during brain aging occurs due to CRM1 accumulation in the brain. We found that CRM1 levels and activity increased in the hippocampus and cortex during physiological aging, which resulted in a decrease of nuclear TFEB and STAT3. Consistent with an autophagic flux impairment, we observed accumulation of the autophagic receptor p62/SQSTM1 in neurons of old mice, which correlated with increased neuronal senescence. Using an in vitro model of neuronal senescence, we demonstrate that CRM1 inhibition improved autophagy flux and reduced SA-β-gal activity by restoring TFEB nuclear localization. Collectively, our data suggest that enhanced CRM1-mediated export of proteins during brain aging perturbs neuronal homeostasis, contributing to autophagy impairment, and neuronal senescence.
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Acheampong, Atiako Kwame, Carly Shanks, Chia-Yi Cheng, G. Eric Schaller, Yasin Dagdas, and Joseph J. Kieber. "EXO70D isoforms mediate selective autophagic degradation of type-A ARR proteins to regulate cytokinin sensitivity." Proceedings of the National Academy of Sciences 117, no. 43 (October 13, 2020): 27034–43. http://dx.doi.org/10.1073/pnas.2013161117.
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The phytohormone cytokinin influences many aspects of plant growth and development, several of which also involve the cellular process of autophagy, including leaf senescence, nutrient remobilization, and developmental transitions. The Arabidopsis type-A response regulators (type-A ARR) are negative regulators of cytokinin signaling that are transcriptionally induced in response to cytokinin. Here, we describe a mechanistic link between cytokinin signaling and autophagy, demonstrating that plants modulate cytokinin sensitivity through autophagic regulation of type-A ARR proteins. Type-A ARR proteins were degraded by autophagy in an AUTOPHAGY-RELATED (ATG)5-dependent manner, and this degradation is promoted by phosphorylation on a conserved aspartate in the receiver domain of the type-A ARRs. EXO70D family members interacted with type-A ARR proteins, likely in a phosphorylation-dependent manner, and recruited them to autophagosomes via interaction of the EXO70D AIM with the core autophagy protein, ATG8. Consistently, loss-of-function exo70D1,2,3 mutants exhibited compromised targeting of type-A ARRs to autophagic vesicles, have elevated levels of type-A ARR proteins, and are hyposensitive to cytokinin. Disruption of both type-A ARRs and EXO70D1,2,3 compromised survival in carbon-deficient conditions, suggesting interaction between autophagy and cytokinin responsiveness in response to stress. These results indicate that the EXO70D proteins act as selective autophagy receptors to target type-A ARR cargos for autophagic degradation, demonstrating modulation of cytokinin signaling by selective autophagy.
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Zhang, Zhaozhi, Xudong Pan, Shaonan Yang, Aijun Ma, Kun Wang, Yuan Wang, Ting Li, and Shihai Liu. "miR-155 Promotes ox-LDL-Induced Autophagy in Human Umbilical Vein Endothelial Cells." Mediators of Inflammation 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/9174801.
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As an evolutionarily conserved metabolic process, autophagy is involved in the process of atherosclerosis (AS). MicroRNA-155 (miR-155), a multifunctional miRNA, plays an important role in many physiological and pathological conditions, including AS and autophagy. However, the effect of miR-155 on the regulation of autophagy in endothelial cells has not been reported to date. Therefore, the objective of our study was to investigate the role of miR-155 in autophagy induced by oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells (HUVECs). Our results demonstrated that ox-LDL induced autophagy in HUVECs and increased the expression of miR-155 significantly. Overexpression of miR-155 improved autophagic activity, whereas low expression of miR-155 inhibited autophagic activity. Therefore, the data demonstrated that miR-155 has a modulating effect on the autophagy of vascular endothelial cells.
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Pérez-Pérez, María Esther, and José L. Crespo. "Autophagy in Algae." Perspectives in Phycology 1, no. 2 (November 10, 2014): 93–101. http://dx.doi.org/10.1127/pip/2014/0012.
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Sakai, Mai, Zhiqian Yu, Ryo Hirayama, Masa Nakasato, Yoshie Kikuchi, Chiaki Ono, Hiroshi Komatsu, et al. "Deficient Autophagy in Microglia Aggravates Repeated Social Defeat Stress-Induced Social Avoidance." Neural Plasticity 2022 (February 16, 2022): 1–13. http://dx.doi.org/10.1155/2022/7503553.
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Major depressive disorder (MDD) is associated with repeated exposure to environmental stress. Autophagy is activated under various stress conditions that are associated with several diseases in the brain. This study was aimed at elucidating the autophagy signaling changes in the prefrontal cortex (PFC) under repeated social defeat (RSD) to investigate the involvement of microglial autophagy in RSD-induced behavioral changes. We found that RSD stress, an animal model of MDD, significantly induced initial autophagic signals followed by increased transcription of autophagy-related genes (Atg6, Atg7, and Atg12) in the PFC. Similarly, significantly increased transcripts of ATGs (Atg6, Atg7, Atg12, and Atg5) were confirmed in the postmortem PFC of patients with MDD. The protein levels of the prefrontal cortical LC3B were significantly increased, whereas p62 was significantly decreased in the resilient but not in susceptible mice and patients with MDD. This indicates that enhanced autophagic flux may alleviate stress-induced depression. Furthermore, we identified that FKBP5, an early-stage autophagy regulator, was significantly increased in the PFC of resilient mice at the transcript and protein levels. In addition, the resilient mice exhibited enhanced autophagic flux in the prefrontal cortical microglia, and the autophagic deficiency in microglia aggravated RSD-induced social avoidance, indicating that microglial autophagy involves stress-induced behavioral changes.
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Luo, Shuwei, Xifeng Li, Yan Zhang, Yunting Fu, Baofang Fan, Cheng Zhu, and Zhixiang Chen. "Cargo Recognition and Function of Selective Autophagy Receptors in Plants." International Journal of Molecular Sciences 22, no. 3 (January 20, 2021): 1013. http://dx.doi.org/10.3390/ijms22031013.
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Autophagy is a major quality control system for degradation of unwanted or damaged cytoplasmic components to promote cellular homeostasis. Although non-selective bulk degradation of cytoplasm by autophagy plays a role during cellular response to nutrient deprivation, the broad roles of autophagy are primarily mediated by selective clearance of specifically targeted components. Selective autophagy relies on cargo receptors that recognize targeted components and recruit them to autophagosomes through interaction with lapidated autophagy-related protein 8 (ATG8) family proteins anchored in the membrane of the forming autophagosomes. In mammals and yeast, a large collection of selective autophagy receptors have been identified that mediate the selective autophagic degradation of organelles, aggregation-prone misfolded proteins and other unwanted or nonnative proteins. A substantial number of selective autophagy receptors have also been identified and functionally characterized in plants. Some of the autophagy receptors in plants are evolutionarily conserved with homologs in other types of organisms, while a majority of them are plant-specific or plant species-specific. Plant selective autophagy receptors mediate autophagic degradation of not only misfolded, nonactive and otherwise unwanted cellular components but also regulatory and signaling factors and play critical roles in plant responses to a broad spectrum of biotic and abiotic stresses. In this review, we summarize the research on selective autophagy in plants, with an emphasis on the cargo recognition and the biological functions of plant selective autophagy receptors.