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Atherosclerosis is a chronic inflammatory disease associated with lipid metabolism disorder. Autophagy is a catabolic process and contributes to maintaining cellular homeostasis. Substantial evidence suggests that defective autophagy is implicated in several diseases, including atherosclerosis, while increased autophagy mitigates atherosclerosis development. Thus, understanding the mechanisms of autophagy regulation and its association with atherosclerosis is vital to develop new therapies against atherosclerosis. Dietary bioactive compounds are non-nutrient natural compounds that include phenolics, flavonoids, and carotenoids. Importantly, these bioactive compounds possess anti-inflammatory, antioxidant, and antibacterial properties that may alleviate various chronic diseases. Recently, examining the effects of bioactive compounds on autophagy activity in atherogenesis has drawn considerable attention. The current review discusses the role of macrophage autophagy in the development and progression of atherosclerosis. We also summarize our current knowledge of the therapeutic potential of bioactive compounds on atherosclerosis and autophagy.

Funder: UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society) Cambridge Centre for Parkinson-Plus National Institute for Health Research Cambridge Biomedical Research Centre, Posttranslational modifications of proteins, such as acetylation, are essential for the regulation of diverse physiological processes, including metabolism, development and aging. Autophagy is an evolutionarily conserved catabolic process that involves the highly regulated sequestration of intracytoplasmic contents in double-membrane vesicles called autophagosomes, which are subsequently degraded after fusing with lysosomes. The roles and mechanisms of acetylation in autophagy control have emerged only in the last few years. In this review, we describe key molecular mechanisms by which previously identified acetyltransferases and deacetylases regulate autophagy. We highlight how p300 acetyltransferase controls mTORC1 activity to regulate autophagy under starvation and refeeding conditions in many cell types. Finally, we discuss how altered acetylation may impact various neurodegenerative diseases in which many of the causative proteins are autophagy substrates. These studies highlight some of the complexities that may need to be considered by anyone aiming to perturb acetylation under these conditions.

Application of novel methods in cancer therapy is important in terms of management and treatment of the life-threatening disorder. It appears that autophagy is a potential target in cancer therapy, as a variety of drugs targeting autophagy have shown great potential in reducing the viability and proliferation of cancer cells. Autophagy is primarily a catabolic process which provides energy during starvation. Besides, this process contributes to the degradation of aged or potentially toxic components and organelles. On the other hand, the source of a variety of naturally occurring anti-tumor drugs are flavonoids which have high anti-tumor activity. Luteolin is a polyphenolic flavone with the great pharmacological effects such as anti-diabetic, hepatoprotective, antioxidant, anti-inflammation, and anti-tumor. At the present review, we demonstrate how luteolin affects on autophagy process to induce anti-tumor activity.

Autophagy is a major catabolic process that maintains cell metabolism by degrading damaged organelles and other dysfunctional proteins via the lysosome. Abnormal regulation of this process has been known to be involved in the progression of pathophysiological diseases, such as cancer and neurodegenerative disorders. Although the mechanisms for the regulation of autophagic pathways are relatively well known, the precise regulation of this pathway in the treatment of cancer remains largely unknown. It is still complicated whether the regulation of autophagy is beneficial in improving cancer. Many studies have demonstrated that autophagy plays a dual role in cancer by suppressing the growth of tumors or the progression of cancer development, which seems to be dependent on unknown characteristics of various cancer types. This review summarizes the key targets involved in autophagy and malignant transformation. In addition, the opposing tumor-suppressive and oncogenic roles of autophagy in cancer, as well as potential clinical therapeutics utilizing either regulators of autophagy or combinatorial therapeutics with anti-cancer drugs have been discussed.

Macroautophagy is a conserved catabolic process observed in all eukaryotic cells, during which selected cellular components are transported to and broken down within lysosomes. The process starts with the capture of unnecessary material into autophagosomes, which is followed by autophagosome-lysosome fusion to generate autolysosomes that degrade the cargo. In the past quarter-century, our knowledge about autophagosome formation almost exponentially increased, while the later steps were much less studied. This fortunately changed in the past few years, with more and more publications focusing on the fate of the completed autophagosome. In this review, we aspire to summarize the current knowledge about the molecular mechanisms of autophagosome-lysosome fusion.

As an important form of selective autophagy in cells, ER-phagy (endoplasmic reticulum-selective autophagy), the autophagic degradation of endoplasmic reticulum (ER), degrades ER membranes and proteins to maintain cellular homeostasis. The relationship between ER-phagy and human diseases, including neurodegenerative disorders, cancer, and other metabolic diseases has been unveiled by extensive research in recent years. Starting with the catabolic process of ER-phagy and key mediators in this pathway, this paper reviews the advances in the mechanism of ER-phagy and its diseases relevance. We hope to provide some enlightenment for further study on ER-phagy and the development of novel therapeutic strategies for related diseases.

Autophagy is the main catabolic process by which cells recycle cytoplasmic components and superfluous or damaged organelles to preserve metabolic homeostasis under normal conditions and promote survival under stress. As a tightly regulated and dynamic process, autophagy has critical roles in development and cell differentiation, immune function, organismal health and lifespan. Accumulating findings suggest that defective or dysregulated autophagy accelerates ageing and increases susceptibility to diseases, such as neurodegenerative disorders and cancer, among others. This virtual issue of the FEBS Journal on Autophagy includes a collection of articles that present recent advances on the regulation of autophagy and provide a view of its complex roles in physiological and pathological contexts.

Fibrosis occurs in most human organs including the liver, lung, heart and kidney, and is crucial for the progression of most chronic diseases. As an indispensable catabolic process for intracellular quality control and homeostasis, autophagy occurs in most mammalian cells and is implicated in many biological processes including fibrogenesis. Although advances have been made in understanding autophagy process, the potential role of autophagy in fibrotic diseases remains controversial and has recently attracted a great deal of attention. In the current review, we summarize the commonalities of autophagy affecting different types of fibrosis in different organs, including the liver, lung, heart, and kidney as well as in cystic fibrosis, systematically outline the contradictory results and highlight the distinct role of autophagy during the various stages of fibrosis. In summary, the exact role autophagy plays in fibrogenesis depends on specific cell types and different stimuli, and identifying and evaluating the pathogenic contribution of autophagy in fibrogenesis will promote the discovery of novel therapeutic strategies for the clinical management of these fibrotic diseases.

Background. Autophagy is a catabolic process that depends on the lysosome. It is usually used to maintain cellular homeostasis, survival and development by degrading abnormal substances and dysfunctional organelles, especially when the cell is exposed to starvation or other stresses. Increasing studies have reported that autophagy is associated with various eye diseases, of which aging is one of the important factors. Objective. To summarize the functional and regulatory role of autophagy in ocular diseases with aging, and discuss the possibility of autophagy-targeted therapy in age-related diseases. Methods. PubMed searches were performed to identify relevant articles published mostly in the last 5 years. The key words were used to retrieve including “autophagy”, “aging”, “oxidative stress AND autophagy”, “dry eye AND autophagy”, “corneal disease AND autophagy”, “glaucoma AND autophagy”, “cataract AND autophagy”, “AMD AND autophagy”, “cardiovascular diseases AND autophagy”, “diabetes AND autophagy”. After being classified and assessed, the most relevant full texts in English were chosen. Results. Apart from review articles, more than two research articles for each age-related eye diseases related to autophagy were retrieved. We only included the most relevant and recent studies for summary and discussion. Conclusion. Autophagy has both protective and detrimental effects on the progress of age-related eye diseases. Different types of studies based on certain situations in vitro showed distinct results, which do not necessarily coincide with the actual situation in human bodies completely. It means the exact role and regulatory function of autophagy in ocular diseases remains largely unknown. Although autophagy as a potential therapeutic target has been proposed, many problems still need to be solved before it applies to clinical practice.

Introduction: Autophagy is one of the most conserved clearance systems through which eukaryotes manage to handle dysfunctional and excess organelles and macromolecules. This catabolic process has not only a role in the maintenance of basal turnover of cellular components, but it is also essential in cells adaptation to stress conditions. In the last decades, defects in autophagic machinery have been identified as a feature in neurodegenerative diseases. In this context, mass spectrometry-based proteomics has become an important tool in the comprehensive analysis of proteins involved in the autophagic flux.Area covered: In this review, we discuss recent contributions of proteomic techniques in the study of defective autophagy related to neurodegenerative illness. Particular emphasis is given to the identification of i) shared autophagic markers between different disorders, which support common pathological mechanisms; ii) unique autophagic signature, which could aid to discriminate among diseases.Expert opinion: Proteomic approaches are valuable in the identification of alterations of components to the autophagic process at different steps of the process. The investigation of autophagic defects associated with neurological disorders is crucial in order to unravel all the potential mechanism leading to neurodegeneration and propose effective therapeutic strategies targeting autophagy.

Autophagy is a dynamic and complicated catabolic process. Imaging autophagic flux can clearly advance knowledge of its pathophysiology significance. While the most common way autophagy is imaged relies on fluorescent protein-based probes, this method requires substantial genetic manipulation that severely restricts the application. Small fluorescent probes capable of tracking autophagic flux with good spatiotemporal resolution are highly demanable. Methods: In this study, we developed a small-molecule fluorogenic probe (AFG-1) that facilitates real-time imaging of autophagic flux in both intact cells and live mice. AFG-1 is inspired by the cascading nitrosative and acidic microenvironments evolving during autophagy. It operates over two sequential steps. In the first step, AFG-1 responds to the up-regulated peroxynitrite at the initiation of autophagy by its diphenylamino group being oxidatively dearylated to yield a daughter probe. In the second step, the daughter probe responds to the acidic autolysosomes at the late stage of autophagy by being protonated. Results: This pathway-dependent mechanism has been confirmed first by sequentially sensing ONOO- and acid in aqueous solution, and then by imaging autophagic flux in live cells. Furthermore, AFG-1 has been successfully applied to visualize autophagic flux in real-time in live mice following brain ischemic injury, justifying its robustness. Conclusion: Due to the specificity, easy operation, and the dynamic information yielded, AFG-1 should serve as a potential tool to explore the roles of autophagy under various pathological settings.

Potential constraints on protocell size are developed from simple entropic considerations. To do that, two new different indexes as measures of their structural and dynamic order were developed and applied to an elemental model of the heterotrophic protocell. According to our results, cell size should be a key factor determining the potential of these primitive systems to evolve and consequently to support life. Our analyses also suggest that the size of the optimal vesicles could be constrained to have radii in the interval $$ (R_{\text{S}} \le R \le R_{\text{D}} ) $$ , where the two extreme limits $$ R_{\text{S}} $$ and $$ R_{\text{D}} $$ represent the states of maximum structural order (largest accumulation of substrate inside the vesicle) and the maximum flux of entropy production, respectively. According to the above criteria, the size of the optimum vesicles falls, approximately, in the same spatial range estimated for biological living cells assuming plausible values for the second-order rate constant involved in the catabolic process. Furthermore, the existence of very small vesicles could be seriously affected by the limited efficiency, far from the theoretical limits, with which these catabolic processes may proceed in a prebiotic system.

Although macroautophagy/autophagy has been proposed as a critical defense mechanism against HIV-1 by targeting viral components for degradation, its contribution as a catabolic process in providing optimal anti-HIV-1 immunity has never been addressed. The failure to restore proper antiviral CD8A/CD8 T-cell immunity, especially against HIV-1, is still the major limitation of current antiretroviral therapies. Consequently, it is of clinical imperative to provide new strategies to enhance the function of HIV-1-specific CD8A T-cells in patients under antiretroviral treatments (ART). Here, we investigated whether targeting autophagy activity could be an optional solution to make this possible. Our data show that, after both polyclonal and HIV-1-specific activation, CD8A T-cells from ART displayed reduced autophagy-dependent degradation of lysosomal contents when compared to naturally HIV-1 protected elite controllers (EC). We further confirmed in EC, by using specific BECN1 gene silencing and lysosomal inhibitors, the critical role of active autophagy in superior CD8A T-cell protection against HIV-1. More importantly, we found that an IL21 treatment was effective in rescuing the antiviral CD8A T-cell immunity from ART in an autophagy-dependent manner. Finally, we established that IL21-dependent rescue occurred due to the enhanced degradation of endogenous lipids via autophagy, referred to as lipophagy, which fueled the cellular rates of mitochondrial beta-oxidation. In summary, our data show that autophagy/lipophagy can be considered as a therapeutic tool to elicit functional antiviral CD8 T-cell responses. Our results also provide additional insights toward the development of improved T-cell-based prevention and cure strategies against HIV-1. Abbreviations: ART: patients under antiretroviral therapy; BaF: bafilomycin A1; BECN1: beclin 1; CEF: cytomegalo-, Epstein-Barr- and flu-virus peptide pool; Chloro.: chloroquine; EC: elite controllers; FAO: fatty acid beta-oxidation; HIVneg: HIV-1-uninfected control donors; IFNG/IFN-γ: interferon gamma; IL21: interleukin 21; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; PBMC: peripheral blood mononuclear cells; SQSTM1: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1.

AMP-activated protein kinase (AMPK) signaling provides a key cellular regulatory system that maintains the balance between energy consumption and production. The heterotrimeric AMPK complex comprising catalytic (α) and regulatory (β and γ) subunits responds to reduced glucose levels by inducing the evolutionarily conserved catabolic process, autophagy, which recycles cytoplasmic content. The protective roles of autophagy induction against a variety of diseases, such as neurodegeneration, has made AMPK activation a promising strategy for therapeutic treatment of various diseases. In this chapter, we describe how AMPK can be induced and how this activates different components of the autophagic machinery. We then review various classes of AMPK activators and the evidence for their capacity to induce autophagy and ameliorate aggregate-prone protein accumulation in cellular and animal models of neurodegeneration.

https://pubs.rsc.org/en/content/articlelanding/2020/cs/d0cs00913j Autophagy is an adaptive catabolic process functioning to promote cell survival in the event of inappropriate living conditions such as nutrient shortage and to cope with diverse cytotoxic insults. It is regarded as one of the key survival mechanisms of living organisms. Cells undergo autophagy to accomplish the lysosomal digestion of intracellular materials including damaged proteins, organelles, and foreign bodies, in a bulk, non-selective or a cargo-specific manner. Studies in the past decades have shed light on the association of autophagy pathways with various diseases and also highlighted the therapeutic value of autophagy modulation. Hence, it is crucial to develop effective approaches for monitoring intracellular autophagy dynamics, as a comprehensive account of methodology establishment is far from complete. In this review, we aim to provide an overview of the major current fluorescence-based techniques utilized for visualizing, sensing or measuring autophagic activities in cells or tissues, which are categorized firstly by targets detected and further by the types of fluorescence tools. We will mainly focus on the working mechanisms of these techniques, put emphasis on the insight into their roles in biomedical science and provide perspectives on the challenges and future opportunities in this field.

Autophagy is a catabolic process that maintains cellular homeostasis and plays crucial roles during development, adaptation to stress, and immune response. Dysfunctional autophagy has been linked to several human pathologies, ranging from cancer to neurodegenerative and inflammatory diseases. During the past two decades, advances have been made in our understanding of the molecular mechanisms underlying the formation of autophagosome, the double-membrane organelle that represents the hallmark morphological feature of autophagy. Autophagosomes, that sequester cytoplasmic material and ultimately fuse with lysosomes, are generated by the hierarchical recruitment of at least 15 autophagy-related (ATG) proteins. In addition to this canonical mode of autophagy, it is now well established that autophagosomes can also be formed without the entire set of ATGs. This alternate cellular process is termed “noncanonical autophagy.” Here we review recent findings regarding the molecular regulation of these noncanonical forms of autophagy and discuss their potential implications in physiology and physiopathology.

Autophagy is a catabolic process that removes aggregated proteins and damaged organelles via lysosomal degradation. Increasing evidence suggests that dysfunction of autophagy is associated with a variety of human pathologies, including aging, cancer, neurodegenerative diseases, heart diseases, diabetes, and other metabolic diseases. Current research suggests that the regulation of autophagy may be a novel target for the treatment of these diseases. For this purpose, it is essential to have a deep understanding on the molecular details of autophagy and its regulatory network in each of the disease contexts. Over the years, a variety of chemical autophagy inducers and inhibitors has been developed. The application of these autophagy regulators can assist us in the exploration of the mechanism and therapeutic potential of autophagy regulation. In this chapter, we summarize the recent advances in chemical autophagy regulators to provide methodological support for autophagy research.

The longhorned tick, Haemaphysalis longicornis (Acari: Ixodidae), is a hard tick and a vector for severe fever with thrombocytopenia syndrome (SFTS) virus. The number of patients infected with SFTS is rapidly increasing. Recently, the invertebrate pathogen Metarhizium anisopliae JEF-290 was reported to be useful to control the tick as an alternative to chemical acaricides, which are not easily applicable in human living areas where the tick is widely spread. In this study, we analyzed how the tick and the fungal pathogen interact at the transcriptional level. Field-collected tick nymphs were treated with JEF-290 conidia at 1 × 108 conidia/ml. In the early stage of infection with 2.5% mortality, the infected ticks were subjected to RNA sequencing, and non-infected ticks and fungal masses served as controls. Fungus and tick genes were mostly up-regulated at the early stage of infection. In the gene set enrichment analysis of the infecting fungus, catabolic processes that included lipids, phospholipids, and detoxification processes, the response to oxidative stress, and toxic substances were significantly up-regulated. In this fungal up-regulation, various lipase, antioxidant enzyme, and hydrolase genes were highly transcribed. The gene set enrichment analysis of the infected tick showed that many peptide synthesis processes including translation, peptide metabolism, ribonucleotide metabolism, and energy production processes that included ATP generation and ADP metabolism were significantly up-regulated. Structurally, mitochondria and ribosome subunit genes in ticks were highly transcribed to upregulate these processes. Together these results indicate that JEF-290 initiates process that infects the tick while the tick actively defends against the fungal attack. This work provides background to improve our understanding of the early stage of fungal infection in longhorned tick.

Autophagy is a ubiquitous catabolic process, which causes cellular bulk degradation through vesicular engulfment of obsolete, damaged or harmful cytoplasmic components. While autophagy regulates cellular homeostasis during development and in youth, there is mounting evidence that autophagy becomes increasingly dysfunctional with age. Recent work in Caenorhabditis elegans even suggests that late-life dysfunctional autophagy exhibits detrimental effects that drive the ageing process. Other studies link elevated autophagy closely to increased health and longevity. This review aims to put these apparently opposing views into perspective and define our current understanding of the role of autophagy during ageing.

Radiotherapy is an important component of cancer treatment modalities. With the rapid development of three-dimensional conformal, intensity-modulated, image-guided radiotherapy and the efficacy of radiotherapy continues to improve. Autophagy, as a catabolic process, is characterized by the formation of a double-membrane vesicle. Radiotherapy is known to induce autophagy in both cancer and normal cells. Here, we reviewed the interaction of radiotherapy and autophagy in the process of cancer treatment. The potential role of autophagy modification in enhancing radiotherapy treatment will also be reviewed.

Autophagy is a catabolic process, which involves recycling of cellular elements and it seems to play a major role in etiopathogenesis of cancers. Autophagy is thought to buffer metabolic stress, thereby aiding in cell survival. Also, it is found that inhibiting autophagy under deficient nutrition can restore cell death to apoptosis. Therefore, autophagy plays a dual role in cancer therapeutics. Globally oral cancer is a major concern of numerous deaths, so comprehensive work needs to be undertaken in the field of its progression and to determine positive treatment modalities. There exists a serious dearth of knowledge to understand and comprehend the process of autophagy, and it is beyond doubt that further research in this field would bring forth several new methods of cancer prevention and treatment.

Autophagy, the catabolic process that recycles damaged organelles or macromolecules in response to cellular stresses, plays a critical role in cellular metabolism. Autophagy modulates both glucose ...

Our understanding of the molecular basis of aging has greatly increased over the past few decades. In this review, we provide an overview of the key signaling pathways associated with aging, and whose modulation has been shown to extend lifespan in a range of model organisms. We also describe how these pathways converge onto autophagy, a catabolic process that functions to recycle dysfunctional cellular material and maintains energy homeostasis. Finally, we consider various approaches of therapeutically modulating these longevity pathways, highlighting exercise as a potent geroprotector.

Background and Purpose— Stroke-induced acute severe body weight (BW) loss is associated with a high rate of mortality during a critical poststroke period. Several interventions to reduce weight loss, however, have not been successful. Currently, the biological significance of this extraordinary catabolic process is not well understood. Spleen-derived monocytes/macrophages (MMs) are the major immune cells recruited to the injured brain. The trafficking of MMs has been shown to be important for tissue repair and recovery. The purpose of the study is to investigate whether the BW reduction is essential for MM-mediated immune response for mice to survive and whether a corticosterone-mediated catabolic event underlies the processes. Methods— C57BL/6 male mice (12-week-old) were subjected to transient middle cerebral artery occlusion. BW, total MMs, and their Ly-6C high and Ly-6C low subsets were determined in the spleen, blood, and the brain in poststroke mice. Poststroke survival rate and MM subsets were determined in mice with adrenalectomy, sham-adrenalectomy, and adrenalectomy mice supplemented with corticosterone. Results— Stroke reduced BW with a maximum reduction at day 3 poststroke (17.2±5.2%). The reduction at day 3 was positively linked to injury severity and selective depletion of MMs, but no other types of immune cells, in the spleen. Notably, the splenic MM depletion was significantly greater in mice with severe BW reduction (≥18% at day 3). In the blood, stroke depleted circulating MMs to a similar degree in animals with moderate and severe BW loss. Ly-6C+ monocyte infiltration in the poststroke brain was greater in mice with severe BW loss. Blocking the catabolic process by adrenalectomy significantly increased poststroke mortality, but the mortality was partially rescued by corticosterone supplement in adrenalectomy mice. Conclusions— Stroke-induced BW loss facilitates MM-mediated immune response, and the adrenal corticosterone-mediated catabolic process is necessary for poststroke survival. Visual Overview— An online visual overview is available for this article.

Autophagy is a highly evolutionarily-conserved catabolic process facilitating the development and survival of organisms which have undergone favorable and/or stressful conditions, in particular the plant. Accumulating evidence has implicated that autophagy is involved in growth and development, as well as responses to various stresses in plant. Similarly, phytohormones also play a pivotal role in the response to various stresses in addition to the plant growth and development. However, the relationship between autophagy and phytohormones still remains poorly understood. Here, we review advances in the crosstalk between them upon various environmental stimuli. We also discuss how autophagy coordinates the phytohormones to regulate plant growth and development. We propose that unraveling the regulatory role(s) of autophagy in modulating the homeostasis of phytohormones would benefit crop breeding and improvement under variable environments, in particular under suboptimal conditions.

Autophagy is a catabolic process whose activation may help cancer cells to adapt to cellular stress although, in some instances, it can induce cell death. Autophagy stimulation or inhibition has been considered an opportunity to treat cancer, especially in combination with anticancer therapies, although autophagy manipulation may be viewed as controversial. Thus, whether to induce or to inhibit autophagy may be the best option in the different cancer patients is still matter of debate. Her we will recapitulate the possible advantages or disadvantages of manipulating autophagy in cancer, not only with the aim to obtain cancer cell death and disable oncogenes, but also to evaluate its interplay with the immune response which is fundamental for the success of anticancer therapies.

Viral pathogens often exploit host cell regulatory and signaling pathways to ensure an optimal environment for growth and survival. Several studies have suggested that 5′-adenosine monophosphate-activated protein kinase (AMPK), an intracellular serine/threonine kinase, plays a significant role in the modulation of infection. Traditionally, AMPK is a key energy regulator of cell growth and proliferation, host autophagy, stress responses, metabolic reprogramming, mitochondrial homeostasis, fatty acid β-oxidation and host immune function. In this review, we highlight the modulation of host AMPK by various viruses under physiological conditions. These intracellular pathogens trigger metabolic changes altering AMPK signaling activity that then facilitates or inhibits viral replication. Considering the COVID-19 pandemic, understanding the regulation of AMPK signaling following infection can shed light on the development of more effective therapeutic strategies against viral infectious diseases.

Autophagy is a catabolic process that facilitates nutrient recycling via degradation of damaged organelles and proteins through lysosomal mediated degradation. Alterations in this complex, and tightly regulated process, lead to disease. Autophagy is widely accepted as cytoprotective against neurodegenerative diseases and a variety of clinical interventions are moving forward to increase autophagy as a therapeutic intervention. Autophagy has both positive and negative roles in cancer and this has led to controversy over whether or how autophagy manipulation should be attempted in cancer therapy. Nevertheless, cancer is the disease where most current activity in trying to manipulate autophagy for therapy is taking place and dozens of clinical trials are using autophagy inhibition with Chloroquine or Hydroxychloroquine in combination with other drugs for the treatment of multiple neoplasms. Here, we review recent literature implicating autophagy in neurodegenerative diseases and cancer and highlight some of the opportunities, controversies and potential pitfalls of therapeutically targeting autophagy., Highlights • Autophagy is a complex process that can be pharmacologically targeted at multiple steps. • Autophagy protects against neurodegeneration and enhanced autophagy decreases pathogenesis of neurodegenerative diseases. • Autophagy is both pro and anti-tumorigenic depending on the stage of tumorigenesis and mutational and oncogenic background. • Clinical trials are ongoing to increase autophagy in neurodegenerative diseases and inhibit autophagy to treat cancer.

Autophagy is a conserved catabolic process of the cell, which has been described to be involved in the development of various viral diseases. However, the role of autophagy in Orf virus (ORFV) replication remains unknown. In this study, we provide the first evidence that ORFV infection triggered autophagy in primary ovine fetal turbinate cells (OFTu) based on the appearance of abundant double- and single-membrane vesicles, the accumulation of LC3 fluorescent puncta, the enhancement of LC3-I/-II conversion, and autophagic flux. Moreover, modulation of ORFV-induced autophagy by rapamycin (RAPA), Earle's balanced salts solution (EBSS), chloroquine (CQ) or 3-methyladenime (3-MA) does not affect virus production. In conclusion, these results suggest that autophagy can be induced in host cells by ORFV infection, but which maybe not essential for ORFV replication.

Autophagy is a catabolic process by which cells can dispose of damaged content and intracellular microorganisms. Recent evidence implicates autophagy as a crucial repair process necessary to recover from critical illness-induced organ failure. Withholding parenteral nutrition in the acute phase of critical illness activates autophagy and enhances recovery. Several registered drugs have autophagy-stimulating properties, but all lack specificity and none has been investigated in critically ill patients for this purpose. ispartof: Critical Care vol:21 issue:1 pages:209- ispartof: location:England status: published

Autophagy ensures cellular homeostasis by the degradation of long-lived proteins, damaged organelles and pathogens. This catabolic process provides essential cellular building blocks upon nutrient deprivation. Cellular metabolism, especially mitochondrial respiration, has a significant influence on autophagic flux, and complex I function is required for maximal autophagy. In Parkinson’s disease mitochondrial function is frequently impaired and autophagic flux is altered. Thus, dysfunctional organelles and protein aggregates accumulate and cause cellular damage. In order to investigate the interdependency between mitochondrial function and autophagy, novel tool compounds are required. Herein, we report the discovery of a structurally novel autophagy inhibitor (Authipyrin) using a high content screening approach. Target identification and validation led to the discovery that Authipyrin targets mitochondrial complex I directly, leading to the potent inhibition of mitochondrial respiration as well as autophagy. Special Issue: SI

Autophagy constitutes an evolutionarily conserved catabolic process that contributes to the clearance of damaged cellular components in response to a variety of stress conditions. Additionally, it plays a variety of physiological and pathophysiological roles in maintaining cell homeostasis. Recently, the critical role of autophagy during cellular senescence has been supported by evidences demonstrating the reversal of senescence by the reestablishment of autophagy. As considerable attention has been directed toward understanding the molecular mechanisms underlying senescence and autophagy, a method to accurately quantify autophagy during senescence is critical to understand its role in senescence and senescence-related diseases. In this chapter, we describe the use of CYTO-ID® green dye and DQ™ Red BSA to monitor the autophagic flux as an accurate method to quantify autophagic activity. This technique relies on the specificity of CYTO-ID® green dye in staining autophagosome and the cleavage of the self-quenched DQ™ Red BSA protease substrates in an acidic compartment. In particular, herein we describe protocols to quantify autophagy during senescence.

Since the discovery of autophagy in the mid-2000s, the interest in autophagy-related processes within the scientific community has been burgeoning. Countless authors have investigated its function in cellular homeostasis, but arguably of higher importance is its role during pathology. Although primarily a catabolic process, in cancer cells autophagy has numerous downstream effects, being observed to be both pro- and anti-apoptotic. One of the primary factors mediating this differential role of autophagy is the accumulation or sequestration of reactive oxygen species (ROS). Until recently, despite its increasing popularity in the Western world, the efficacy of herbal supplements has been largely anecdotal. Herein, we reviewed the ten most commonly studied herbs in cancer research and their impact on ROS regulation, on the activation and inhibition of autophagy, and ultimately on cancer cell death.

Autophagy is a ubiquitous catabolic process by which damaged or harmful intracellular components are delivered to the lysosomes for self-digestion and recycling. It is critical in cancer treatment. Therapy-induced autophagy predominantly acts as a pro-survival mechanism, but progressive autophagy can lead to non-apoptotic cell death, also known as autophagic cell death. Plants or herbs contain various natural compounds that are widely used in the treatment of many types of malignancies. Emerging evidence indicates that phytochemicals targeting the autophagic pathway are promising agents for cancer treatment. However, these compounds play different roles in autophagy. In this review, we discussed the role of autophagy in cancer development and therapy, and focussed on elucidating the anti-cancer activities of autophagic modulators, especially phytochemicals. Notably, we described a novel premise that the dynamic role of phytochemicals should be evaluated in regulation of autophagy in cancer.

Autophagy is a dynamic catabolic process that plays a major role in sequestering and recycling cellular components in multiple physiological and pathophysiological conditions. Despite recent progress in our understanding of the autophagic process there is still a shortage of robust methods for monitoring autophagy in live cells. Flow cytometry, a reliable and unbiased method for quantitative collection of data in a high-throughput manner, was recently utilized to monitor autophagic activity in live and fixed mammalian cells. In this article we summarize the advantages and potential pitfalls of the use of flow cytometry to study autophagy.

Macroautophagy, hereafter autophagy, is a catabolic process by which cells remove protein aggregates and damaged organelles for recycling. This process is important for maintaining cellular homeost...

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.

Autophagy is a catabolic process used by eukaryotic cells to maintain or restore cellular and organismal homeostasis. A better understanding of autophagy in plant biology could lead to an improvement of the recycling processes of plant cells and thus contribute, for example, towards reducing the negative ecological consequences of nitrogen-based fertilizers in agriculture. It may also help to optimize plant adaptation to adverse biotic and abiotic conditions through appropriate plant breeding or genetic engineering to incorporate useful traits in relation to this catabolic pathway. In this review, we describe useful protocols for studying autophagy in the plant cell, taking into account some specificities of the plant model.

© 2018 Elsevier Ltd Autophagy is a catabolic process, which mediates degradation of cellular components and has important roles in health and disease. Therefore, small molecule modulators of autophagy are in great demand. Herein, we describe a phenotypic high-content screen for autophagy inhibitors, which led to the discovery of a dimethoxypyridine-based class of autophagy inhibitors, which derive from previously reported, natural product-inspired MAP4K4 inhibitors. Comprehensive structure-activity relationship studies led to a potent compound, and biological validation experiments indicated that the mode of action was upstream or independent of mTOR.

In this short chapter, some aspects of immunometabolism of dendritic cells and T cells are briefly sketched. The dichotomous function of dendritic cells is associated with two different metabolic pathways. While resting dendritic cells use fatty acid oxidation to fuel the mitochondrial oxidative phosphorylation pathway, activated immunostimulatory dendritic cells typically switch to aerobic glycolysis, the Otto Warburg metabolism. In contrast to the metabolism of immunostimulatory dendritic cells, an inherently catabolic process, the Krebs cycle and fatty acid oxidation, plays a significant role in the development of tolerogenic dendritic cells.

During senescence of leaf tissues and fruits, chlorophylls are degraded following a catabolic process that transforms the molecule of chlorophyll into final colorless, non-fluorescent chlorophyll catabolites (NCCs) and non-fluorescent dioxibilane chlorophyll catabolites (NDCCs). These compounds have been characterized in different vegetal species showing several structural constraints and defined functional groups at three peripheral positions. Information regarding the NCC profile of fruits is scarce, and at the moment NDCCs have not been described in fruits. Characterization of NCCs and NDCCs in ripened quince fruits (Cydonia oblonga, Miller) was analyzed by HPLC–ESI-MS, describing four chlorophyll breakdown products (two NCCs and two NDCCs) by considering their chromatographic properties, UV-spectrum and MS profile, and was compared, if possible, with NCC/NDCC standards. Co-NCC1 and Co-NDCC2 are equal to the catabolites identified in senescence leaves of maize and barley, respectively, while the catabolites Co-NCC2 and Co-NDCC1 are new structures but closely related to the previous ones. This is the first time that NDCCs are tentatively identified in a fruit tissue, which presents a NCC/NDCC profile dominated by the series of dioxibilin-type chlorophyll catabolites, an additional proof that the chlorophyll pathway is similar in leaves and fruits.

Autophagy is a conserved catabolic process that delivers the cytosol and cytosolic constituents to the lysosome. Its fundamental role is to maintain cellular homeostasis and to protect cells from varying insults, including misfolded proteins and damaged organelles. Beyond these roles, the highly specialized cells of the brain have further adapted autophagic pathways to suit their distinct needs. In this review, we briefly summarize our current understanding of the different forms of autophagy and then offer a closer look at how these pathways impact neuronal and glial functions. The emerging evidence indicates that not only are autophagy pathways essential for neural health, but they have a direct impact on developmental and neurodegenerative processes. Taken together, as we unravel the complex roles autophagy pathways play, we will gain the necessary insight to modify these pathways to protect the human brain and treat neurodegenerative diseases.

Previous studies showed that liver dysfunction develops soon after severe burn, and this is associated with activation of endoplasmic reticulum (ER) stress. Autophagy is a catabolic process to maintain cellular organelle balance; ER stress is associated with autophagy signaling cascades. We thus sought to determine whether autophagy signals were associated with damage in the liver after burn, and further whether burn-associated ER stress activates autophagy signals in hepatocytes.C57BL/6 male mice received a 25% total body surface area full-thickness scald burn, and liver was harvested at 24 h after burn. HepG2 cells were stimulated with an ER stress inducer thapsigargin (TG) for 24 h to mimic ER stress in vitro. Terminal deoxyuridine nick-end labeling staining was performed on histologic sections of liver. Autophagy was assessed by immunoblotting. Statistical analysis was performed using the Student t-test and significance was accepted at P 0.05.Terminal deoxyuridine nick-end labeling positive-stained hepatocytes increased in burned animals with a significant elevation of caspase 3 activity (P 0.05). Hepatic autophagy-related (ATG) protein 3, ATG5 and light chain (LC) 3B elevated significantly in burn animals as well (P 0.05). Expression of Beclin-1, LC3A, and LC3B increased in HepG2 cells in response to TG, similar to the response seen in vivo. Cytosolic adenosine triphosphate dropped significantly, and adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) were phosphorylated as well in response to TG (P 0.05).ER stress, which occurs in hepatocytes after severe injury, is associated with autophagy and liver damage after severe burn. In response to ER stress, activated autophagy is associated with adenosine monophosphate-activated protein kinase and mammalian target target of rapamycin pathway.

3027 Background: Autophagy is a catabolic process triggered in cells during periods of stress to enable their survival. Established tumors utilize autophagy to survive periods of metabolic or hypoxic stress. Inhibition of early stage autophagy can rescue cancer cells, while inhibition of late stage autophagy will lead to cell death due to accumulation of damaged organelles. The antimalarial drugs CQ and HCQ inhibit late phase autophagy. The goal of our study is to assess the safety, tolerability and activity of combining CQ/HCQ with CG in advanced solid tumor patients who either progressed on other therapies or in whom CG is a therapeutic option. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ, later substituted with HCQ, in combination with CG in patients with previously treated advanced solid tumors. Secondary objectives were to determine ORR, PFS and OS. A starting dose of 50 mg of CQ/HCQ was used in conjunction with CG, and increased in increments of 50 mg in each dose cohort. Grade 3 or greater toxicity that is treatment-related, and was not self-limited, or controlled in less than 7 days was considered dose limiting toxicity (DLT). Results: Twenty-three patients were enrolled with a median follow up of 6 months. HCQ 100 mg was found to be the MTD in combination with CG with ≥Grade 3 thrombocytopenia and/or neutropenia as dose-limiting. Median OS was 11 months, and the 1- and 3- year overall survival rates were 30% and 7%, respectively. Median progression free survival was 5 months and the 6-, 12-, and 18-months progression-free survivals were 48%, 21% and 14%, respectively (Table). Conclusions: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537. [Table: see text]