Bibliographies thématiques / Autophagy dysfunction

Littérature scientifique sur le sujet « Autophagy dysfunction »

Auteur : Grafiati
Publié le 10 mars 2023

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Articles de revues sur le sujet "Autophagy dysfunction"

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Lee, Jisun, Samantha Giordano et Jianhua Zhang. « Autophagy, mitochondria and oxidative stress : cross-talk and redox signalling ». Biochemical Journal 441, no 2 (21 décembre 2011) : 523–40. http://dx.doi.org/10.1042/bj20111451.

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Reactive oxygen and nitrogen species change cellular responses through diverse mechanisms that are now being defined. At low levels, they are signalling molecules, and at high levels, they damage organelles, particularly the mitochondria. Oxidative damage and the associated mitochondrial dysfunction may result in energy depletion, accumulation of cytotoxic mediators and cell death. Understanding the interface between stress adaptation and cell death then is important for understanding redox biology and disease pathogenesis. Recent studies have found that one major sensor of redox signalling at this switch in cellular responses is autophagy. Autophagic activities are mediated by a complex molecular machinery including more than 30 Atg (AuTophaGy-related) proteins and 50 lysosomal hydrolases. Autophagosomes form membrane structures, sequester damaged, oxidized or dysfunctional intracellular components and organelles, and direct them to the lysosomes for degradation. This autophagic process is the sole known mechanism for mitochondrial turnover. It has been speculated that dysfunction of autophagy may result in abnormal mitochondrial function and oxidative or nitrative stress. Emerging investigations have provided new understanding of how autophagy of mitochondria (also known as mitophagy) is controlled, and the impact of autophagic dysfunction on cellular oxidative stress. The present review highlights recent studies on redox signalling in the regulation of autophagy, in the context of the basic mechanisms of mitophagy. Furthermore, we discuss the impact of autophagy on mitochondrial function and accumulation of reactive species. This is particularly relevant to degenerative diseases in which oxidative stress occurs over time, and dysfunction in both the mitochondrial and autophagic pathways play a role.
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Spaulding, HR, C. Ballmann, JC Quindry, MB Hudson et JT Selsby. « Autophagy in the heart is enhanced and independent of disease progression in mus musculus dystrophinopathy models ». JRSM Cardiovascular Disease 8 (janvier 2019) : 204800401987958. http://dx.doi.org/10.1177/2048004019879581.

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Background Duchenne muscular dystrophy is a muscle wasting disease caused by dystrophin gene mutations resulting in dysfunctional dystrophin protein. Autophagy, a proteolytic process, is impaired in dystrophic skeletal muscle though little is known about the effect of dystrophin deficiency on autophagy in cardiac muscle. We hypothesized that with disease progression autophagy would become increasingly dysfunctional based upon indirect autophagic markers. Methods Markers of autophagy were measured by western blot in 7-week-old and 17-month-old control (C57) and dystrophic (mdx) hearts. Results Counter to our hypothesis, markers of autophagy were similar between groups. Given these surprising results, two independent experiments were conducted using 14-month-old mdx mice or 10-month-old mdx/Utrn± mice, a more severe model of Duchenne muscular dystrophy. Data from these animals suggest increased autophagosome degradation. Conclusion Together these data suggest that autophagy is not impaired in the dystrophic myocardium as it is in dystrophic skeletal muscle and that disease progression and related injury is independent of autophagic dysfunction.
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Miceli, Caterina, Yohan Santin, Nicola Manzella, Raffaele Coppini, Andrea Berti, Massimo Stefani, Angelo Parini, Jeanne Mialet-Perez et Chiara Nediani. « Oleuropein Aglycone Protects against MAO-A-Induced Autophagy Impairment and Cardiomyocyte Death through Activation of TFEB ». Oxidative Medicine and Cellular Longevity 2018 (2018) : 1–13. http://dx.doi.org/10.1155/2018/8067592.

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Age-associated diseases such as neurodegenerative and cardiovascular disorders are characterized by increased oxidative stress associated with autophagy dysfunction. Oleuropein aglycone (OA), the main polyphenol found in olive oil, was recently characterized as an autophagy inducer and a promising agent against neurodegeneration. It is presently unknown whether OA can have beneficial effects in a model of cardiac stress characterized by autophagy dysfunction. Here, we explored the effects of OA in cardiomyocytes with overexpression of monoamine oxidase-A (MAO-A). This enzyme, by degrading catecholamine and serotonin, produces hydrogen peroxide (H2O2), which causes oxidative stress, autophagic flux blockade, and cell necrosis. We observed that OA treatment counteracted the cytotoxic effects of MAO-A through autophagy activation, as displayed by the increase of autophagic vacuoles and autophagy-specific markers (Beclin1 and LC3-II). Moreover, the decrease in autophagosomes and the increase in autolysosomes, indicative of autophagosome-lysosome fusion, suggested a restoration of the defective autophagic flux. Most interestingly, we found that the ability of OA to confer cardioprotection through autophagy induction involved nuclear translocation and activation of the transcriptional factor EB (TFEB). Our data provide strong evidence of the beneficial effects of OA, suggesting its potential use as a nutraceutical agent against age-related pathologies involving autophagy dysfunction, including cardiovascular diseases.
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Dong, Qianqian, Wenjuan Xing, Feifei Su, Xiangyan Liang, Fei Tian, Feng Gao, Siwang Wang et Haifeng Zhang. « Tetrahydroxystilbene Glycoside Improves Microvascular Endothelial Dysfunction and Ameliorates Obesity-Associated Hypertension in Obese ZDF Rats Via Inhibition of Endothelial Autophagy ». Cellular Physiology and Biochemistry 43, no 1 (2017) : 293–307. http://dx.doi.org/10.1159/000480410.

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Aims: Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension. Methods: (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non-invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP–RFP–LC3. Results: Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy-associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins. Conclusion: Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy.
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Chen, Yan, Chengxing Xia, Chunwei Ye, Feineng Liu, Yitian Ou, Ruping Yan, Haifeng Wang et Delin Yang. « MT-12 inhibits the proliferation of bladder cells in vitro and in vivo by enhancing autophagy through mitochondrial dysfunction ». Open Life Sciences 17, no 1 (1 janvier 2022) : 710–25. http://dx.doi.org/10.1515/biol-2022-0082.

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Abstract Bladder cancer (BC) is one of the most common malignancies involving the urinary system. Our previous study demonstrated that cobra venom membrane toxin 12 (MT-12) could effectively inhibit BC cell growth and metastasis and induce apoptosis. However, the specific molecular mechanism remains unknown. In this study, we explored whether MT-12 inhibits BC cell proliferation by inducing autophagy cell death through mitochondrial dysfunction. As a result, MT-12 inhibited proliferation and colony formation in RT4 and T24 cells. In the BC xenograft mouse model, autophagy inhibitor 3-MA alleviated the inhibitory effect of MT-12 on tumor growth. In addition, immunostaining revealed downregulated autophagy in MT-12-treated RT4 and T24 cells. We also found that MT-12 led to dysfunctional mitochondria with decreased mitochondrial membrane potential, mtDNA abundance, and increased ROS production, ultimately inducing autophagic apoptosis via the ROS/JNK/P53 pathway. MT-12 inhibits BC proliferation in vitro and in vivo by enhancing autophagy. MT-12 induces mitochondrial dysfunction and decreases autophagy, leading to increased ROS production, which in turn activates the JNK/p53 pathway, leading to BC apoptosis.
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Gukovskaya, Anna S., et Ilya Gukovsky. « Autophagy and pancreatitis ». American Journal of Physiology-Gastrointestinal and Liver Physiology 303, no 9 (1 novembre 2012) : G993—G1003. http://dx.doi.org/10.1152/ajpgi.00122.2012.

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Acute pancreatitis is an inflammatory disease of the exocrine pancreas that carries considerable morbidity and mortality; its pathophysiology remains poorly understood. Recent findings from experimental models and genetically altered mice summarized in this review reveal that autophagy, the principal cellular degradative pathway, is impaired in pancreatitis and that one cause of autophagy impairment is defective function of lysosomes. We propose that the lysosomal/autophagic dysfunction is a key initiating event in pancreatitis and a converging point of multiple deranged pathways. There is strong evidence supporting this hypothesis. Investigation of autophagy in pancreatitis has just started, and many questions about the “upstream” mechanisms mediating the lysosomal/autophagic dysfunction and the “downstream” links to pancreatitis pathologies need to be explored. Answers to these questions should provide insight into novel molecular targets and therapeutic strategies for treatment of pancreatitis.
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Kang, Liang, Qian Xiang, Shengfeng Zhan, Yu Song, Kun Wang, Kangcheng Zhao, Shuai Li, Zengwu Shao, Cao Yang et Yukun Zhang. « Restoration of Autophagic Flux Rescues Oxidative Damage and Mitochondrial Dysfunction to Protect against Intervertebral Disc Degeneration ». Oxidative Medicine and Cellular Longevity 2019 (30 décembre 2019) : 1–27. http://dx.doi.org/10.1155/2019/7810320.

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Oxidative stress-induced mitochondrial dysfunction and nucleus pulposus (NP) cell apoptosis play crucial roles in the development of intervertebral disc degeneration (IDD). Increasing studies have shown that interventions targeting impaired autophagic flux can maintain cellular homeostasis by relieving oxidative damage. Here, we investigated the effect of curcumin (CUR), a known autophagy activator, on IDD in vitro and in vivo. CUR suppressed tert-butyl hydroperoxide- (TBHP-) induced oxidative stress and mitochondrial dysfunction and thereby inhibited human NP cell apoptosis, senescence, and ECM degradation. CUR treatment induced autophagy and enhanced autophagic flux in an AMPK/mTOR/ULK1-dependent manner. Notably, CUR alleviated TBHP-induced interruption of autophagosome-lysosome fusion and impairment of lysosomal function and thus contributed to the restoration of blocked autophagic clearance. These protective effects of CUR in TBHP-stimulated human NP cells resembled the effects produced by the autophagy inducer rapamycin, but the effects were partially eliminated by 3-methyladenine- and compound C-mediated inhibition of autophagy initiation or chloroquine-mediated obstruction of autophagic flux. Lastly, CUR also exerted a protective effect against puncture-induced IDD progression in vivo. Our results showed that suppression of excessive ROS production and mitochondrial dysfunction through enhancement of autophagy coupled with restoration of autophagic flux ameliorated TBHP-induced human NP cell apoptosis, senescence, and ECM degradation. Thus, maintenance of the proper functioning of autophagy represents a promising therapeutic strategy for IDD, and CUR might serve as an effective therapeutic agent for IDD.
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Ko, Su-Hyuk, Gilberto Gonzalez, Zhijie Liu et Lizhen Chen. « Axon Injury-Induced Autophagy Activation Is Impaired in a C. elegans Model of Tauopathy ». International Journal of Molecular Sciences 21, no 22 (13 novembre 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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Azuelos, Ilan, Boris Jung, Martin Picard, Feng Liang, Tong Li, Christian Lemaire, Christian Giordano, Sabah Hussain et Basil J. Petrof. « Relationship between Autophagy and Ventilator-induced Diaphragmatic Dysfunction ». Anesthesiology 122, no 6 (1 juin 2015) : 1349–61. http://dx.doi.org/10.1097/aln.0000000000000656.

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Abstract Background: Mechanical ventilation (MV) is associated with atrophy and weakness of the diaphragm muscle, a condition termed ventilator-induced diaphragmatic dysfunction (VIDD). Autophagy is a lysosomally mediated proteolytic process that can be activated by oxidative stress, which has the potential to either mitigate or exacerbate VIDD. The primary goals of this study were to (1) determine the effects of MV on autophagy in the diaphragm and (2) evaluate the impact of antioxidant therapy on autophagy induction and MV-induced diaphragmatic weakness. Methods: Mice were assigned to control (CTRL), MV (for 6 h), MV + N-acetylcysteine, MV + rapamycin, and prolonged (48 h) fasting groups. Autophagy was monitored by quantifying (1) autophagic vesicles by transmission electron microscopy, (2) messenger RNA levels of autophagy-related genes, and (3) the autophagosome marker protein LC3B-II, with and without administration of colchicine to calculate the indices of relative autophagosome formation and degradation. Force production by mouse diaphragms was determined ex vivo. Results: Diaphragms exhibited a 2.2-fold (95% CI, 1.8 to 2.5) increase in autophagic vesicles visualized by transmission electron microscopy relative to CTRL after 6 h of MV (n = 5 per group). The autophagosome formation index increased in the diaphragm alone (1.5-fold; 95% CI, 1.3 to 1.8; n = 8 per group) during MV, whereas prolonged fasting induced autophagosome formation in both the diaphragm (2.5-fold; 95% CI, 2.2 to 2.8) and the limb muscle (4.1-fold; 95% CI, 1.8 to 6.5). The antioxidant N-acetylcysteine further augmented the autophagosome formation in the diaphragm during MV (1.4-fold; 95% CI, 1.2 to 1.5; n = 8 per group) and prevented MV-induced diaphragmatic weakness. Treatment with the autophagy-inducing agent rapamycin also largely prevented the diaphragmatic force loss associated with MV (n = 6 per group). Conclusions: In this model of VIDD, autophagy is induced by MV but is not responsible for diaphragmatic weakness. The authors propose that autophagy may instead be a beneficial adaptive response that can potentially be exploited for therapy of VIDD.
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Luo, Li, Yonghong Liang, Yuanyuan Fu, Zhiyuan Liang, Jinfen Zheng, Jie Lan, Feihai Shen et Zhiying Huang. « Toosendanin Induces Hepatocyte Damage by Inhibiting Autophagic Flux via TFEB-Mediated Lysosomal Dysfunction ». Pharmaceuticals 15, no 12 (3 décembre 2022) : 1509. http://dx.doi.org/10.3390/ph15121509.

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Toosendanin (TSN) is a triterpenoid from the fruit or bark of Melia toosendan Sieb et Zucc, which has clear antitumor and insecticidal activities, but it possesses limiting hepatotoxicity in clinical application. Autophagy is a degradation and recycling mechanism to maintain cellular homeostasis, and it also plays an essential role in TSN-induced hepatotoxicity. Nevertheless, the specific mechanism of TSN on autophagy-related hepatotoxicity is still unknown. The hepatotoxicity of TSN in vivo and in vitro was explored in this study. It was found that TSN induced the upregulation of the autophagy-marker microtubule-associated proteins 1A/1B light chain 3B (LC3B) and P62, the accumulation of autolysosomes, and the inhibition of autophagic flux. The middle and late stages of autophagy were mainly studied. The data showed that TSN did not affect the fusion of autophagosomes and lysosomes but significantly inhibited the acidity, the degradation capacity of lysosomes, and the expression of hydrolase cathepsin B (CTSB). The activation of autophagy could alleviate TSN-induced hepatocyte damage. TSN inhibited the expression of transcription factor EB (TFEB), which is a key transcription factor for many genes of autophagy and lysosomes, such as CTSB, and overexpression of TFEB alleviated the autophagic flux blockade caused by TSN. In summary, TSN caused hepatotoxicity by inhibiting TFEB-lysosome-mediated autophagic flux and activating autophagy by rapamycin (Rapa), which could effectively alleviate TSN-induced hepatotoxicity, indicating that targeting autophagy is a new strategy to intervene in the hepatotoxicity of TSN.
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Thèses sur le sujet "Autophagy dysfunction"

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Otten, Elsje Gesina. « Molecular mechanisms of autophagy and the effect of autophagy dysfunction on mitochondrial function ». Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3953.

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Long lifespan of evolutionary higher organisms including humans is associated with the challenge to maintain viability of post mitotic cells, such as neurons, for decades. Autophagy is increasingly recognized as an important prosurvival pathway in oxidative and proteotoxic stress conditions. Autophagy degrades cytosolic macromolecules in response to starvation and is involved in the selective degradation of damaged/toxic organelles, such as mitochondria. With age autophagy function declines, and is also compromised in several neurodegenerative diseases. We identified a novel role for autophagy in the maintenance of mitochondrial health, specifically respiratory complex I. Intriguingly, galactose-induced cell death of autophagy deficient cells was rescued by preventing ROS production at complex I or bypassing complex I-linked respiration. We propose that aberrant ROS production via complex I in response to autophagy deficiency could be pathogenic and result in neurodegeneration and preventing this could be an interesting therapeutic target. Furthermore, we found that vertebrates have evolved mechanisms to induce autophagy in response to oxidative stress. This involves the oxidation of the autophagy receptor p62, which promotes autophagy flux and the clearance of autophagy cargo, resulting in increased stress resistance in mammalian cells and survival under stress in flies. In addition, we obtained data revealing an important role for redox-regulated cysteines in NDP52 for the degradation of mitochondria via mitophagy and tools were created to study the role of other autophagy receptors in autophagy initiation and selective autophagy.
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Simcox, Eve Michelle. « Degradation and degeneration : synergistic impact of autophagy and mitochondrial dysfunction in Parkinson's disease ». Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2430.

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The single greatest risk factor for the development of idiopathic Parkinson’s Disease is advancing age. The differences at the cellular level that cause some individuals to develop this highly debilitating disease over healthy ageing are not fully understood. Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD) since the drug MPTP, known to cause Parkinson’s like symptoms, was shown to invoke its deleterious effect through inhibition of Complex I (CI) of the mitochondrial electron transport chain. Since this discovery in the 1980s, several causative genes in the much rarer familial forms of PD have been shown to encode proteins which function within, or in association with mitochondria. Through inherited cases of the disorder the process through which mitochondria are removed, mitophagy, a specialized form of autophagy has also been associated with the pathogenesis that leads to en masse cell death in this disorder. This work explores the interplay between mitochondrial deficiencies, through complex I dysfunction, and changes to autophagic processes. The methodologies to enable these observations are also described in detail with the development of novel and specialized techniques necessary to answer many of the specific research questions. The mechanisms behind complex I deficiency’s impact upon cellular processes is also explored as part of this thesis. Mitochondria and autophagy are irrevocably linked through mitochondrial dynamics, to this end an exploration of the greater impact complex I dysfunction has upon mitochondrial motility, fission and fusion was investigated. As the most prevalent neurodegenerative movement disorder of old age, understanding the molecular changes that result in Parkinson's Disease is vital to increase knowledge and offer novel therapeutic targets. Parallel studies in human upper midbrain tissue and cybrid cell lines within this work have revealed significant changes to both autophagy and mitochondrial dynamics in response to complex I deficiency. Given that mitochondrial ‘health’ and autophagic regulation directly impact upon one another identifying how exactly these may contribute to neuronal loss will hopefully allow therapeutic modulation at a point of PD pathogenesis where cells can still be retained.
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Hansson, Eva-Maria. « Towards a mechanistic explanation of insulin resistance, which incorporates mTOR, autophagy, and mitochondrial dysfunction ». Thesis, Linköpings universitet, Institutionen för klinisk och experimentell medicin, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-54489.

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Type 2 diabetes is a global disease which affects an increasing number of peopleevery year. At the heart of the disease lies insulin resistance in the target tissues,primarily fat and muscle. The insulin resistance is caused by the failure of a complexsignalling network, and several mechanistic hypotheses for this failure havebeen proposed. Herein, we evaluate a hypothesis that revolves around the proteinmammalian target of rapamycin (mTOR) and its feedback signals to insulin receptorsubstrate-1 (IRS1). In particular, we have re-examined this hypothesis andrelevant biological data using a mathematical modelling approach. During the course of modelling we gained several important insights. For instance,the model was unable to reproduce the relation between the EC50-valuesin the dose-response curves for IRS1 and its serine residue 312 (Ser-312). Thisimplies that the presented hypothesis, where the phosphorylation of Ser-312 liesdownstream of the tyrosine phosphorylation of IRS1, is inconsistent with the provideddata, and that the hypothesis or the data might be incorrect. Similarly, wealso realized that in order to fully account for the information in the dose-responsedata, time curves needed to be incorporated into the model. A preliminary model is presented, which explains most of the data-sets, butstill is unable to describe all the details in the data. The originally proposed hypothesisas an explanation to the given data has been revised, and our analysisserves to exemplify that an evaluation of a mechanistic hypothesis by mere biochemicalreasoning often misses out on important details, and/or leads to incorrectconclusions. A model-based approach, on the other hand, can efficiently pin-pointsuch weaknesses, and if combined with a comprehensive understanding of biologicalvariation and generation of experimental data, mathematical modelling canprove to be a method of great potential in the search for mechanistic explanationsto the cause of insulin resistance in type 2 diabetics.
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Morgan-Bathke, Maria Elizabeth. « The Role of Autophagy in Salivary Gland Dysfunction Following Targeted Head and Neck Radiation ». Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/301532.

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Head and neck cancer is one of the most common cancers worldwide. The current standard of care for head and neck cancer includes surgical resection of the tumor followed by chemoradiation. This targeted head and neck radiation causes dysfunction of the salivary glands, which leads to xerostomia, mucositis, dysphagia, dental caries, and malnutrition. These side effects greatly decrease patient quality of life and increase their financial responsibility. Current therapies available to ameliorate these negative side effects are expensive, only provide short-term relief, and many of them have negative side effects of their own. Therefore, another therapy is needed to prevent salivary gland dysfunction or restore its function following targeted head and neck radiation. Autophagy is a homeostatic cellular mechanism that could be targeted as a therapeutic mechanism in the salivary glands following targeted head and neck radiation. Autophagy is a catabolic process necessary to maintain cellular homeostasis. It has been shown to play a beneficial role in a variety of disease states including diabetes mellitus, obesity, and cancer. The role of autophagy in the response of cancerous tissue to radiation has been vastly studied. However, the role autophagy plays in normal tissue response to radiation remains poorly understood and much more research in this area is needed.Atg5^(f/f);Aqp5-Cre mice have a conditional knockout of Atg5, a gene necessary for autophagy, in the salivary glands. These mice have unchanged baseline levels of apoptosis, proliferation, and stimulated salivary flow rates when compared to wild-type mice. Therefore, they are a useful model to investigate the role of autophagy in the response of the salivary glands to targeted head and neck radiation. These Atg5^(f/f);Aqp5-Cre autophagy-deficient mice display increased radiosensitivity following targeted head and neck radiation. Furthermore, post-therapy use of CCI-779, a rapalogue and inducer of autophagy, allowed for restoration of salivary gland function following targeted head and neck radiation. Taken together, these results implicate autophagy as playing a beneficial role in normal salivary function following radiation. Therefore, autophagy could be utilized by normal salivary gland tissue following targeted head and neck radiation to maintain salivary gland function.
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Workinger, Paul M., et Paul M. Workinger. « Familial Amyotrophic Lateral Sclerosis with a focus on C9orf72 Hexanucleotide GGGGCC Repeat Expansion Associated ALS with Frontotemporal Dementia ». Thesis, The University of Arizona, 2017. http://hdl.handle.net/10150/625350.

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Amyotrophic Lateral Sclerosis (ALS) is a rare and fatal neurodegenerative disorder resulting in the loss of motor neurons from the spinal cord and frontal cortex. The patterns of neurodegeneration, affected regions, age of onset, and time course of disease progression are all highly variable between and within variants of the disease. Familial ALS (fALS), inherited versions of ALS due to genetic changes, accounts for between 5-20% of all ALS cases, while the rest are sporadic, with either no causative mutation identified or no familial history of ALS. Recently, the discovery of C9orf72 hexanucleotide repeat expansions have been identified as one of the most common causes of familial ALS, with some patients presenting with dual phenotypes of ALS and frontotemporal dementia, leading to new hypotheses about the nature of neurodegenerative diseases. Despite the continued discovery of new ALS causative genes, little is known about the pathogenesis of the disease. While almost all variants include the presence of intracellular protein inclusions, the site of the protein plaques and involved proteins varies between genetic and phenotypic variants of this disease. Due to the lack of clear pathogenic mechanisms, several hypotheses have been developed to explain the process of neurodegeneration. Autophagy, the process of self-eating, leading to destruction of damaged or excess proteins and organelles, has been implicated as being altered in ALS. Multiple variants have demonstrated altered mitochondrial morphology and cellular energetic dynamics, which could explain previous observations that implicate the process of apoptosis in cellular death. Many of the involved proteins in ALS have functional roles for intracellular, nucleocytoplasmic, and axonal transport of various proteins or RNA. These three competing hypotheses are currently the most prominent hypotheses in the pathogenesis of ALS, and have largely been considered as separate and competing in past research. Is there a chance that the true pathogenesis leading to neuronal destruction via apoptosis involve all three hypotheses? Altered protein and RNA transport dynamics could lead to changes in cellular stress responses or overload autophagy pathways, leading to exacerbated cellular stress responses, leading to alterations in mitochondrial morphology and eventually cell death via apoptosis.
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FONTANA, FABRIZIO. « APOPTOSIS AND PARAPTOSIS, INVOLVING ENDOPLASMIC RETICULUM STRESS, AUTOPHAGY AND MITOCHONDRIAL DYSFUNCTION, ARE INDUCED BY DELTA-TOCOTRIENOL IN PROSTATE CANCER CELLS ». Doctoral thesis, Università degli Studi di Milano, 2020. http://hdl.handle.net/2434/699447.

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Castration resistant prostate cancer (CRPC) is the most aggressive form of prostate cancer with still limited therapeutic outcomes due to the development of resistance to standard treatments. Unraveling the molecular mechanisms at the basis of the pro-death activity of novel anticancer compounds is necessary to increase the treatment strategies for this pathology. Here, we demonstrated that δ-tocotrienol (δ-TT, a vitamin E derivative) can induce apoptosis in human CRPC cell lines (PC3 and DU145) through modulation of the endoplasmic reticulum (ER) stress-autophagy axis. In these cells, δ-TT also triggers paraptosis, a non-canonical cell death mechanism characterized by cytoplasmic vacuolation resulting from mitochondrial/ER swelling and requiring protein synthesis. Mechanistically, we observed that δ-TT downregulates OXPHOS protein levels and inhibits mitochondrial respiration in PC3 and DU145 cells, leading to reduced oxygen consumption, ATP depletion and AMPK activation. Moreover, δ-TT treatment resulted in Ca2+ homeostasis alteration and ROS production, followed not only by apoptosis/paraptosis but also by mitochondrial fission and mitophagy. Taken together, these data demonstrate that in CRPC δ-TT can trigger both apoptosis and paraptosis, involving ER stress and autophagy. In addition, they suggest that δ-TT specifically alters mitochondrial morphology and function, inducing Ca2+ overload- and oxidative stress-mediated cell death.
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Keane, Harriet. « Network pharmacology of the MPP+ cellular model of Parkinson's disease ». Thesis, University of Oxford, 2015. http://ora.ox.ac.uk/objects/uuid:1e18e521-c1a3-4f1b-9572-9c68e0f16c2f.

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Parkinson's disease (PD) is an incurable neurodegenerative motor disorder caused by the inexorable loss of dopamine neurones from the substantia nigra pars compacta. Cell loss is characterised by the perturbation of multiple physiological processes (including mitochondrial function, autophagy and dopamine homeostasis) and much of this pathophysiology can be reproduced in vitro using the mitochondrial toxin MPP+ (1-methyl-4-phenylpyridinium). It was hypothesised that MPP+ toxicity could be modelled using protein-protein interaction networks (PPIN) in order to better understand the interplay of systems-level processes that result in eventual cell death in MPP+ models and PD. Initially, MPP+ toxicity was characterised in the human, dopamine-producing cell line BE(2)-M17 and it was confirmed that the neurotoxin resulted in time and dose dependent apoptosis. A radio-label pulse-chase assay was developed and demonstrated that MPP+ induced decreased autophagic flux preceded cell death. Autophagic dysfunction was consistent with lysosome deacidification due to cellular ATP depletion. Pertinent PPINs were sampled from publically available data using a seedlist of proteins with validated roles in MPP+ toxicity. These PPINs were subjected to a series of analyses to identify potential therapeutic targets. Two topological methods based on betweenness centrality were used to identify target proteins predicted to be critical for the crosstalk between mitochondrial dysfunction and autophagy in the context of MPP+ toxicity. Combined knockdown of a subset of target proteins potentiated MPP+ toxicity and the combined resulted in cellular rescue. Neither of these effects was observed following single knockdown/overexpression confirming the need for multiple interventions. Cellular rescue occurred via an autophagic mechanism; prominent autophagosomes were formed and it was hypothesised that these structures allowed for the sequestration of damaged proteins. This thesis demonstrates the value of PPINs as a model for Parkinson's disease, from network creation through target identification to phenotypic benefit.
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Orr, Miranda, et Salvatore Oddo. « Autophagic/lysosomal dysfunction in Alzheimer's disease ». BioMed Central, 2013. http://hdl.handle.net/10150/610220.

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Autophagy serves as the sole catabolic mechanism for degrading organelles and protein aggregates. Increasing evidence implicates autophagic dysfunction in Alzheimer's disease (AD) and other neurodegenerative diseases associated with protein misprocessing and accumulation. Under physiologic conditions, the autophagic/lysosomal system efficiently recycles organelles and substrate proteins. However, reduced autophagy function leads to the accumulation of proteins and autophagic and lysosomal vesicles. These vesicles contain toxic lysosomal hydrolases as well as the proper cellular machinery to generate amyloid-beta, the major component of AD plaques. Here, we provide an overview of current research focused on the relevance of autophagic/lysosomal dysfunction in AD pathogenesis as well as potential therapeutic targets aimed at restoring autophagic/lysosomal pathway function.
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Gonçalves, Ana Catarina Martins. « Relação entre a infeção por Escherichia coli aderente-invasina e a doença de Crohn ». Master's thesis, [s.n.], 2013. http://hdl.handle.net/10284/4089.

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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas
A Doença de Crohn é uma doença inflamatória crónica que pode afetar qualquer parte do trato gastrointestinal, embora comprometa preferencialmente o íleo. Apesar da incessante investigação a sua etiologia e patogénese permanecem desconhecidas. Até ao momento várias hipóteses têm sido avançadas na compreensão desta doença. Contudo, a teoria atual considera que se trata de uma doença complexa multifatorial que ocorre em indivíduos com predisposição genética, e que determinados fatores ambientais e microbianos são responsáveis pelo desenvolvimento de uma resposta inume inadequada. O possível envolvimento de um organismo infecioso, em particular a Escherichia coli Aderente-Invasiva (AIEC), tem estado sob investigação. A análise da flora bacteriana associada à mucosa ileal revelou uma anormal colonização da AIEC nos pacientes com Doença de Crohn. Estas bactérias são capazes de aderir e invadir as células epiteliais intestinais, assim como, penetrar e replicar extensivamente no interior dos macrófagos, sem induzir a morte da célula hospedeira. Por outro lado, a permeabilidade intestinal está significativamente aumentada nos indivíduos com Doença de Crohn. A AIEC diminui a resistência elétrica transepitelial e altera a estrutura morfológica das junções celulares, o que pode contribuir para esse aumento de permeabilidade. Pensa-se que as células M poderão constituir um potencial alvo de entrada que permite a interação bacteriana com os macrófagos da lâmina própria. Estudos in vitro têm demonstrado que os macrófagos infetados produzem grandes quantidades de fator de necrose tumoral α, e induzem a formação de agregados de células muitos semelhantes aos granulomas epitelioides. Estas estruturas representam uma das marcas histológicas características da Doença de Crohn. Crohn's disease is a chronic inflammatory disease that can affect any part of the gastrointestinal tract, although preferably compromise the ileum. Despite ongoing research its etiology and pathogenesis remain unknown. So far several hypotheses have been advanced in the understanding of this disease. However, the current theory considers that it is a complex multifactorial disease that occurs in individuals with a genetic predisposition and certain environmental and microbial factors are responsible for developing a response immune inadequate. The possible involvement of an infectious organism, in particular adherent-invasive Escherichia coli (AIEC) has been under investigation. The analysis of the bacterial flora associated with ileal mucosa revealed an abnormal AIEC colonization in patients with Crohn's disease. These bacteria are able to adhere to and invade intestinal epithelial cells, as well as penetrate and replicate extensively within macrophages without inducing the death of the host cell. On the other hand, is significantly increased intestinal permeability in patients with Crohn's disease. The AIEC decreases the transepithelial electrical resistance changes and the morphological structure of cell junctions, which may contribute to this increased permeability. It is believed that M cells might constitute a potential target input which allows the bacterial interaction with macrophages in the lamina propria. In vitro studies have demonstrated that infected macrophages produce large quantities of tumor necrosis factor α, and induce the formation of cell aggregates similar to many epithelioid granulomas. These structures represent one of the marks histological features of Crohn's disease.
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MICELI, CATERINA. « Oleuropein aglycone induces protective autophagy : molecular mechanisms and therapeutic targets in pathological models of autophagy dysfunction ». Doctoral thesis, 2017. http://hdl.handle.net/2158/1076892.

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Macroautophagy, also referred to as autophagy, is an intracellular process aimed to degrade and recycle cytoplasmic components, including long-lived proteins and damaged organelles. Due to the pivotal role of autophagy in maintaining cellular proteostasis, its dysfunction is associated with a wide number of human diseases such as cancer, cardiomyopathies and neurodegenerative disorders. In these pathological conditions, autophagy is initially activated as a survival mechanism but subsequently becomes defective, leading to cell damage. Many recent studies aim to better understand why autophagy is compromised in pathological conditions. Consequently restoration of defective autophagy now appears as an important therapeutic strategy in disease contexts. Several small molecules acting as autophagy modulators, such as plant polyphenols, or natural compounds present in fruit and vegetables, have been proposed as potential therapeutic applications. Plant polyphenols are able to regulate autophagy through different pathways. In particular, resveratrol and epigallocatechin-3 gallate (EGCG) stimulate the autophagic pathway via CamKK-AMPK-mTOR signalling. Polyphenols can also activate the sirtuins (SIRT), family of class III histone deacetylases, which are also involved in autophagy modulation. SIRT-induction results in many cellular outcomes and is considered responsible for the epigenetic effects of polyphenols. Oleuropein is the main polyphenol found in the olive tree and its main product, olive oil. Our previous studies have highlighted the beneficial effects of oleuropein aglycone (OLE), both in neuroblastoma cell lines (N2a) and in TgCRND8 mice, a model of Aβ deposition. In the latter, food supplementation with OLE resulted in remarkable plaque reduction and in the reduction of cognitive impairment when compared to non-OLE fed littermates. These protective effects were strongly correlated to an increased activation of autophagy in OLE fed mice. In light of the benefits associated with the upregulation in autophagy, the aim of this thesis was to investigate the cellular and molecular effectors of OLE-induced autophagy in vitro, by use of cultured human neuroblastoma cells (SH-SY5Y) and in vivo, using our TgCRND8 mice. Our in vitro results showed that OLE supplementation induces a rapid release of Ca2+ from the endoplasmic reticulum stores which, in turn, activates CAMKKβ with subsequent phosphorylation and activation of AMPK. The interplay between AMPK activation and mTOR inhibition shown in the OLE-fed animal model supports the idea that autophagy activation by OLE proceeds through mTOR inhibition. SIRT1 activation, another mechanism that synergizes with OLE-induced Ca2+-CaMKKβ-AMPK-mTOR signalling was also found in N2a cells. Given our findings for OLE dependent promotion of autophagy in our in vitro and in vivo neurodegeneration models, we aimed to determine whether OLE promotion of autophagy is ubiquitous and could protect against other pathological conditions displaying autophagy dysfunction. We selected an in vitro model of cardiomyopathy characterized by overexpression of monoamine oxidase-A (MAO-A). It is well established that catecholamine and serotonin degradation by MAO-A produces H2O2, which then disrupts nuclear translocation of TFEB, a master regulator of autophagy, causing autophagosome accumulation and ultimately cell death. Using this model we have shown that OLE treatment counteracts the effects of the MAO-A/H2O2 axis by improving mitochondrial function and decreasing cell necrosis. We demonstrate that these protective outcomes are, at least in part, related to the activation in autophagy. Indeed, increased autophagy observed in cardiac cells treated with OLE was a measure of the increase in autophagic vacuoles and autophagy-specific marker (LC3II) expression. Double immunofluorescence imaging of RFP-GFP-LC3 after 6 h of OLE treatment showed an increase of the autophagic flux; in addition, nuclear translocation of TFEB in OLE-treated cells was also observed. Together these data suggest that OLE treatment evokes transcriptional regulation of autophagy. In conclusion, our findings demonstrate that the underlying molecular mechanism of OLE stimulated autophagy includes the activation of the Ca2+-CaMKK-AMPK-mTOR signalling pathway. The identified molecular underpinnings of OLE treatment are indeed similar to other plant polyphenols such as resveratrol and EGCG. We show further that SIRT1-activation could synergize to maintain OLE-induced autophagy. TFEB translocation to the nucleus supports the importance of the transcriptional regulation of autophagy, findings that warrent further investigation. The results of this thesis add to the growing knowledge base of the molecular mechanisms of OLE-induced autophagy and provide strong evidence that similar to other plant polyphenols OLE can be a potential therapeutic against age-related diseases associated with autophagy dysfunction, including neurodegeneration and cardiovascular diseases.
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Livres sur le sujet "Autophagy dysfunction"

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Autophagy Dysfunction in Alzheimer's Disease and Dementia. Elsevier, 2022. http://dx.doi.org/10.1016/c2020-0-02800-8.

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Hamano, Tadanori, et Tatsuro Mutoh. Autophagy Dysfunction in Alzheimer's Disease and Dementia. Elsevier Science & Technology Books, 2022.

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Hamano, Tadanori, et Tatsuro Mutoh. Autophagy Dysfunction in Alzheimer's Disease and Dementia. Elsevier Science & Technology, 2022.

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Nakamura, Tomohiro, et Stuart A. Lipton. Neurodegenerative Diseases as Protein Misfolding Disorders. Oxford University Press, 2016. http://dx.doi.org/10.1093/med/9780190233563.003.0002.

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Neurodegenerative diseases (NDDs) often represent disorders of protein folding. Rather than large aggregates, recent evidence suggests that soluble oligomers of misfolded proteins are the most neurotoxic species. Emerging evidence points to small, soluble oligomers of misfolded proteins as the cause of synaptic dysfunction and loss, the major pathological correlate to disease progression in many NDDs including Alzheimer’s disease. The protein quality control machinery of the cell, which includes molecular chaperones as found in the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS), and various forms of autophagy, can counterbalance the accumulation of misfolded proteins to some extent. Their ability to eliminate the neurotoxic effects of misfolded proteins, however, declines with age. A plausible explanation for the age-dependent deterioration of the quality control machinery involves compromise of these systems by excessive generation of reactive oxygen species (ROS), such as superoxide anion (O2-), and reactive nitrogen species (RNS), such as nitric oxide (NO). The resulting redox stress contributes to the accumulation of misfolded proteins. Here, we focus on aberrantly increased generation of NO-related species since this process appears to accelerate the manifestation of key neuropathological features, including protein misfolding. We review the chemical mechanisms of posttranslational modification by RNS such as protein S-nitrosylation of critical cysteine thiol groups and nitration of tyrosine residues, showing how they contribute to the pathogenesis of NDDs.
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Chapitres de livres sur le sujet "Autophagy dysfunction"

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Tao, Tao, et Huanbai Xu. « Autophagy and Obesity-Related Reproductive Dysfunction ». Dans Autophagy : Biology and Diseases, 463–66. Singapore : Springer Singapore, 2020. http://dx.doi.org/10.1007/978-981-15-4272-5_33.

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Otten, Elsje G., Diego Manni et Viktor I. Korolchuk. « Mitochondrial Degradation, Autophagy and Neurodegenerative Disease ». Dans Mitochondrial Dysfunction in Neurodegenerative Disorders, 255–78. Cham : Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-28637-2_11.

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Gustafsson, Åsa B. « Mitochondrial Dysfunction and Mitophagy : Physiological Implications in Cardiovascular Health ». Dans Biochemistry of Apoptosis and Autophagy, 197–217. Cham : Springer International Publishing, 2021. http://dx.doi.org/10.1007/978-3-030-78799-8_11.

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Zhang, Jianhua, et Victor Darley-Usmar. « Mitochondrial Dysfunction in Neurodegenerative Disease : Protein Aggregation, Autophagy, and Oxidative Stress ». Dans Mitochondrial Dysfunction in Neurodegenerative Disorders, 95–111. London : Springer London, 2011. http://dx.doi.org/10.1007/978-0-85729-701-3_6.

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Chatterjee, Sharmistha, Uday Hossain et Parames C. Sil. « Role of Oxidative Stress, Mitochondrial Dysfunction, and Autophagy in Cardiovascular Disease : Its Pathogenesis and Amelioration by Different Small Natural Molecules ». Dans Modulation of Oxidative Stress in Heart Disease, 457–87. Singapore : Springer Singapore, 2019. http://dx.doi.org/10.1007/978-981-13-8946-7_19.

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Kaira, Meenakshi, Abhilasha Ahlawat, Vaibhav Walia et Munish Garg. « Autophagic Dysfunction in Neurodegeneration ». Dans Quality Control of Cellular Protein in Neurodegenerative Disorders, 25–62. IGI Global, 2020. http://dx.doi.org/10.4018/978-1-7998-1317-0.ch002.

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Autophagy is a normal physiological process characterized by the degradation of complex cellular contents into a simpler one and reutilized them in biosynthetic pathways. Lysosomes are the cell organelle that participates in the process of autophagy. The brain is the most vulnerable organ in most lysosome disorders because neurons are inefficient in removing impaired organelles and waste materials. In the brain, autophagy suppresses the accumulation of ubiquitinated proteins that results in further damage to the neurons responsible for neurodegeneration. Autophagy mediates protective effects in age-related diseases. In the chapter, the authors describe the process of autophagy, the mechanism involved, and the implication of the autophagic pathways in the various neurodegenerative disorders.
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Wu, Lin, Yingmei Zhang et Jun Ren. « Aging, mitochondria, and autophagy ». Dans Mitochondrial Dysfunction and Nanotherapeutics, 221–36. Elsevier, 2021. http://dx.doi.org/10.1016/b978-0-323-85666-9.00005-x.

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Gupta, Rohan, Rashmi K. Ambasta et Pravir Kumar. « Mitochondrial dysfunction and autophagy in neurodegeneration ». Dans Mitochondrial Dysfunction and Nanotherapeutics, 139–78. Elsevier, 2021. http://dx.doi.org/10.1016/b978-0-323-85666-9.00019-x.

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Kinch, Michael. « Autophagy ». Dans Prescription for Change. University of North Carolina Press, 2016. http://dx.doi.org/10.5149/northcarolina/9781469630625.003.0011.

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The title of the chapter is a Greek term that literally translates into “eating oneself” and is representative of a trend of mergers and acquisitions that has subsumed the drug development enterprise over the past three decades and now fundamentally threatens our ability to develop new medicines. We begin with two examples of acquisitions by Eli Lilly & Company. One product resulted from an unexpected discovery by Pfizer scientists of a drug meant to treat angina that had the unexpected but not undesired effect of treating erectile dysfunction. The second acquisition, of New York-based Imclone, was the final step in a high profile controversy that led the jailing of its CEO and the celebrity Martha Stewart for insider trading. Despite these two acquisitions, Eli Lilly largely did not participate in the merger mania of the past few decades and we relate how this most innovative company fell through the rankings to become a middling contender. This waning resulted from the meteoric rise of Pfizer as one of the most aggressive purveyors of pharmaceutical industry consolidation and the unlikely rise of Valeant Pharmaceuticals, a company with a checkered history and ongoing woes.
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Mano, Tatsuo, et Atsushi Iwata. « Autophagy and Huntington’s disease ». Dans Autophagy Dysfunction in Alzheimer's Disease and Dementia, 245–59. Elsevier, 2022. http://dx.doi.org/10.1016/b978-0-323-89906-2.00001-0.

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Actes de conférences sur le sujet "Autophagy dysfunction"

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Zhu, X. « Relationship Between Autophagy-Lysosomes Pathway and Ventilator-Induced Diaphragmatic Dysfunction ». Dans American Thoracic Society 2020 International Conference, May 15-20, 2020 - Philadelphia, PA. American Thoracic Society, 2020. http://dx.doi.org/10.1164/ajrccm-conference.2020.201.1_meetingabstracts.a2622.

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Rodilla, Ananda Marina, Luis Korrodi-Gregório, Pilar Manuel-Manresa, Roberto Quesada, Ricardo Pérez-Tomás et Vanessa Soto-Cerrato. « Abstract A05 : Targeting autophagy through novel anionophores that induce lysosomal dysfunction ». Dans Abstracts : AACR Precision Medicine Series : Targeting the Vulnerabilities of Cancer ; May 16-19, 2016 ; Miami, FL. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1557-3265.pmccavuln16-a05.

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Hawkins, Arie, Ming Zhao, Michael F. Beers et Surafel Mulugeta. « Mistargeted SP-C I73T Mutant Protein Induces Autophagy Block, Mitochondrial Dysfunction, And Intrinsic Apoptosis ». Dans American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a5097.

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Vij, N., M. Bodas, G. Pehote, D. Silverberg et E. Gulbins. « Autophagy Augmentation Alleviates Cigarette Smoke Induced CFTR Dysfunction, Ceramide Accumulation and COPD-Emphysema Pathogenesis ». Dans American Thoracic Society 2019 International Conference, May 17-22, 2019 - Dallas, TX. American Thoracic Society, 2019. http://dx.doi.org/10.1164/ajrccm-conference.2019.199.1_meetingabstracts.a2832.

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Greven, J., Y. Shi, W. Guo, F. Bläsius, K. Horst, B. Relja, EM Buhl et F. Hildebrand. « Trauma-hemorrhage : Mitochondrial dysfunction, autophagy and apoptosis in pig liver 72 h post polytrauma ». Dans Deutscher Kongress für Orthopädie und Unfallchirurgie. Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0040-1717262.

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Abdelsalam, Shahenda Salaheldine, et Abdelali Agouni. « Protein Tyrosine Phosphatase (PTP) 1B Inhibition Improves Endoplasmic Reticulum Stress-Induced Apoptosis and Impaired Angiogenic Response in Endothelial Cells ». Dans Qatar University Annual Research Forum & Exhibition. Qatar University Press, 2021. http://dx.doi.org/10.29117/quarfe.2021.0110.

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Insulin is not only important for glucose homeostasis, but also plays a critical role in the activation of endothelial nitric oxide synthase (eNOS) to synthesize nitric oxide (NO) and keeping the endothelium functional. Conditions which result in insulin resistance, such as diabetes and obesity, cause impairment of endothelial function, a condition known as endothelial dysfunction that features a reduced release of NO. Protein tyrosine phosphatase (PTP) 1B, is a known negative regulator of insulin receptor, that has been implicated in the pathogenesis of insulin resistance and endothelial dysfunction. Owing to its critical location at the surface of the endoplasmic reticulum (ER), PTP1B has been found to play an important role in ER stress response. However, the role of ER stress in PTP1B-mediated endothelial dysfunction is not fully elucidated. Toa address this, ER stress was induced pharmacologically in endothelial cells using thapsigargin, in the presence or absence of either a small molecule inhibitor of PTP1B or silencing siRNA duplexes, followed by the assessment of the expression of key ER stress markers, angiogenic capacity and apoptotic signals. We report here, that PTP1B inhibition protected cells against ER stress and ER stress-induced impairment in eNOS activation and angiogenic capacity. PTP1B inhibition or silencing also protected against ER stress-induced endothelial cell apoptosis. Moreover, PTP1B blockade also suppressed ER stress-activated autophagy. Our data emphasize on the critical role of PTP1B in ER stress-mediated endothelial cell dysfunction and highlights the therapeutic potential of PTP1B inhibition against ER stress-mediated cell death and impairment of endothelial function to prevent cardiovascular disease in pathologies charactereized by the activation of ER stress such as diabetes.
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Figueroa, P. Lόpez de, U. Nogueira-Recalde, V. Calamia, FG Osorio, M. Lotz, C. Lόpez-Otín, FJ Blanco et B. Carames. « OP0008 Deficient autophagy induces chondrocyte dysfunction through lamin a/c accumulation in aging and osteoarthritis ». Dans Annual European Congress of Rheumatology, 14–17 June, 2017. BMJ Publishing Group Ltd and European League Against Rheumatism, 2017. http://dx.doi.org/10.1136/annrheumdis-2017-eular.3819.

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Chavez-Perez, Valery, Mary Strasberg-Rieber et Manuel Rieber. « Abstract 2907 : AMPK induction, lysosomal acidification and melanoma survival increased by p53 dysfunction are counteracted by inhibiting autophagy ». Dans Proceedings : AACR 106th Annual Meeting 2015 ; April 18-22, 2015 ; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-2907.

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Liang, Jiyong, Dexing Fang et Amy B. Heimberger. « Abstract 1492 : Chimeric antigen receptor (CAR) T cell donor dependent dysfunction modulation with activation of autophagy and inhibition of trogocytosis ». Dans Proceedings : AACR Annual Meeting 2021 ; April 10-15, 2021 and May 17-21, 2021 ; Philadelphia, PA. American Association for Cancer Research, 2021. http://dx.doi.org/10.1158/1538-7445.am2021-1492.

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Biel, Thomas, et Ashutosh Rao. « Abstract 1332 : Autophagic clearance of protein aggregates is impaired in cancer cells with dysfunctional mitochondria ». Dans Proceedings : AACR Annual Meeting 2018 ; April 14-18, 2018 ; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-1332.

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