Role of autophagy in cancer prevention, development and therapy

2013 ◽  
Vol 55 ◽  
pp. 133-151 ◽  
Author(s):  
G. Vignir Helgason ◽  
Tessa L. Holyoake ◽  
Kevin M. Ryan
Keyword(s):  
Quality Control ◽  
Clinical Trials ◽  
Cancer Prevention ◽  
Mammalian Cells ◽  
Physiological Role ◽  
Anticancer Therapy ◽  
Substantial Progress ◽  
Health And Disease ◽  
Made In

Autophagy is a process that takes place in all mammalian cells and ensures homoeostasis and quality control. The term autophagy [self (auto)-eating (phagy)] was first introduced in 1963 by Christian de Duve, who discovered the involvement of lysosomes in the autophagy process. Since then, substantial progress has been made in understanding the molecular mechanism and signalling regulation of autophagy and several reviews have been published that comprehensively summarize these findings. The role of autophagy in cancer has received a lot of attention in the last few years and autophagy modulators are now being tested in several clinical trials. In the present chapter we aim to give a brief overview of recent findings regarding the mechanism and key regulators of autophagy and discuss the important physiological role of mammalian autophagy in health and disease. Particular focus is given to the role of autophagy in cancer prevention, development and in response to anticancer therapy. In this regard, we also give an updated list and discuss current clinical trials that aim to modulate autophagy, alone or in combination with radio-, chemo- or targeted therapy, for enhanced anticancer intervention.

scholarly journals The Physiological Role of Mitophagy: New Insights into Phosphorylation Events

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Yuko Hirota ◽  
Dongchon Kang ◽  
Tomotake Kanki
Keyword(s):  
Oxidative Stress ◽  
Quality Control ◽  
Mitochondrial Dna ◽  
Control Systems ◽  
Mammalian Cells ◽  
Physiological Role ◽  
Acid Oxidation ◽  
Molecular Processes ◽  
Mitochondrial Quality Control

Mitochondria play an essential role in oxidative phosphorylation, fatty acid oxidation, and the regulation of apoptosis. However, this organelle also produces reactive oxygen species (ROS) that continually inflict oxidative damage on mitochondrial DNA, proteins, and lipids, which causes further production of ROS. To oppose this oxidative stress, mitochondria possess quality control systems that include antioxidant enzymes and the repair or degradation of damaged mitochondrial DNA and proteins. If the oxidative stress exceeds the capacity of the mitochondrial quality control system, it seems that autophagy degrades the damaged mitochondria to maintain cellular homeostasis. Indeed, recent evidence from yeast to mammals indicates that the autophagy-dependent degradation of mitochondria (mitophagy) contributes to eliminate dysfunctional, aged, or excess mitochondria. In this paper, we describe the molecular processes and regulatory mechanisms of mitophagy in yeast and mammalian cells.

Emerging roles of mitochondrial membrane dynamics in health and disease

2009 ◽  
Vol 390 (8) ◽  
Author(s):  
Anja Schäfer ◽  
Andreas S. Reichert
Keyword(s):  
Quality Control ◽  
Molecular Basis ◽  
Mitochondrial Membrane ◽  
Mitochondrial Dynamics ◽  
Physiological Role ◽  
Membrane Dynamics ◽  
Mitochondrial Morphology ◽  
Mitochondrial Quality Control ◽  
Health And Disease

Abstract Mitochondria are highly dynamic organelles forming a tubular network that is sustained by fusion and fission events. Impairment thereof leads to various neuropathies in humans, such as optic atrophy and Parkinson's disease. We have only begun to understand the molecular machineries facilitating fusion and fission of mitochondria and how these processes are regulated. The physiological role of mitochondrial dynamics and how it may be involved in maintaining mitochondrial functionality is still unclear. Here, we discuss current views in this emerging field focusing on the molecular basis of how mitochondrial morphology is regulated and how this may contribute to mitochondrial quality control.

scholarly journals The Lipocalin Apolipoprotein D Functional Portrait: A Systematic Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Diego Sanchez ◽  
Maria D. Ganfornina
Keyword(s):  
Systematic Review ◽  
Physiological Function ◽  
Physiological Role ◽  
Future Research ◽  
Lipid Management ◽  
Health And Disease ◽  
Apolipoprotein D ◽  
Extracellular Structures ◽  
Cellular Compartments

Apolipoprotein D is a chordate gene early originated in the Lipocalin protein family. Among other features, regulation of its expression in a wide variety of disease conditions in humans, as apparently unrelated as neurodegeneration or breast cancer, have called for attention on this gene. Also, its presence in different tissues, from blood to brain, and different subcellular locations, from HDL lipoparticles to the interior of lysosomes or the surface of extracellular vesicles, poses an interesting challenge in deciphering its physiological function: Is ApoD a moonlighting protein, serving different roles in different cellular compartments, tissues, or organisms? Or does it have a unique biochemical mechanism of action that accounts for such apparently diverse roles in different physiological situations? To answer these questions, we have performed a systematic review of all primary publications where ApoD properties have been investigated in chordates. We conclude that ApoD ligand binding in the Lipocalin pocket, combined with an antioxidant activity performed at the rim of the pocket are properties sufficient to explain ApoD association with different lipid-based structures, where its physiological function is better described as lipid-management than by long-range lipid-transport. Controlling the redox state of these lipid structures in particular subcellular locations or extracellular structures, ApoD is able to modulate an enormous array of apparently diverse processes in the organism, both in health and disease. The new picture emerging from these data should help to put the physiological role of ApoD in new contexts and to inspire well-focused future research.

scholarly journals The Role of Vitamin C in Cancer Prevention and Therapy: A Literature Review

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1894
Author(s):  
Marcelo Villagran ◽  
Jorge Ferreira ◽  
Miquel Martorell ◽  
Lorena Mardones
Keyword(s):  
Clinical Trials ◽  
Vitamin C ◽  
Cancer Prevention ◽  
Randomized Study ◽  
Regulation Of Gene Expression ◽  
Water Soluble ◽  
In Vitro Assays ◽  
High Concentration

Vitamin C is a water-soluble antioxidant associated with the prevention of the common cold and is also a cofactor of hydrolases that participate in the synthesis of collagen and catecholamines, and in the regulation of gene expression. In cancer, vitamin C is associated with prevention, progression, and treatment, due to its general properties or its role as a pro-oxidant at high concentration. This review explores the role of vitamin C in cancer clinical trials and the aspects to consider in future studies, such as plasmatic vitamin C and metabolite excretion recording, and metabolism and transport of vitamin C into cancer cells. The reviewed studies show that vitamin C intake from natural sources can prevent the development of pulmonary and breast cancer, and that vitamin C synergizes with gemcitabine and erlotinib in pancreatic cancer. In vitro assays reveal that vitamin C synergizes with DNA-methyl transferase inhibitors. However, vitamin C was not associated with cancer prevention in a Mendelian randomized study. In conclusion, the role of vitamin C in the prevention and treatment of cancer is still an ongoing area of research. It is necessary that new phase II and III clinical trials be performed to collect stronger evidence of the therapeutic role of vitamin C in cancer.

scholarly journals Mitochondrial Iron in Human Health and Disease

2019 ◽  
Vol 81 (1) ◽  
pp. 453-482 ◽  
Author(s):  
Diane M. Ward ◽  
Suzanne M. Cloonan
Keyword(s):  
Human Health ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Biological Functions ◽  
Mitochondrial Homeostasis ◽  
Innate Immune Signaling ◽  
Mitochondrial Iron ◽  
Health And Disease

Mitochondria are an iconic distinguishing feature of eukaryotic cells. Mitochondria encompass an active organellar network that fuses, divides, and directs a myriad of vital biological functions, including energy metabolism, cell death regulation, and innate immune signaling in different tissues. Another crucial and often underappreciated function of these dynamic organelles is their central role in the metabolism of the most abundant and biologically versatile transition metals in mammalian cells, iron. In recent years, cellular and animal models of mitochondrial iron dysfunction have provided vital information in identifying new proteins that have elucidated the pathways involved in mitochondrial homeostasis and iron metabolism. Specific signatures of mitochondrial iron dysregulation that are associated with disease pathogenesis and/or progression are becoming increasingly important. Understanding the molecular mechanisms regulating mitochondrial iron pathways will help better define the role of this important metal in mitochondrial function and in human health and disease.

scholarly journals A Protocol for Extraction of Infective Viromes Suitable for Metagenomics Sequencing from Low Volume Fecal Samples

Viruses ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 667 ◽  
Author(s):  
Ling Deng ◽  
Ronalds Silins ◽  
Josué L. Castro-Mejía ◽  
Witold Kot ◽  
Leon Jessen ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Large Scale ◽  
Metagenomic Sequencing ◽  
High Input ◽  
Human Gut ◽  
Specific Host ◽  
Substantial Progress ◽  
Low Volume ◽  
Made In

The human gut microbiome (GM) plays an important role in human health and diseases. However, while substantial progress has been made in understanding the role of bacterial inhabitants of the gut, much less is known regarding the viral component of the GM. Bacteriophages (phages) are viruses attacking specific host bacteria and likely play important roles in shaping the GM. Although metagenomic approaches have led to the discoveries of many new viruses, they remain largely uncultured as their hosts have not been identified, which hampers our understanding of their biological roles. Existing protocols for isolation of viromes generally require relatively high input volumes and are generally more focused on extracting nucleic acids of good quality and purity for down-stream analysis, and less on purifying viruses with infective capacity. In this study, we report the development of an efficient protocol requiring low sample input yielding purified viromes containing phages that are still infective, which also are of sufficient purity for genome sequencing. We validated the method through spiking known phages followed by plaque assays, qPCR, and metagenomic sequencing. The protocol should facilitate the process of culturing novel viruses from the gut as well as large scale studies on gut viromes.

TLR4 signalling in the intestine in health and disease

2007 ◽  
Vol 35 (6) ◽  
pp. 1473-1478 ◽  
Author(s):  
M. Fukata ◽  
M.T. Abreu
Keyword(s):  
Mammalian Cells ◽  
Metabolic Energy ◽  
Short Term ◽  
Receptor Signalling ◽  
Health And Disease ◽  
Inflammatory Bowel ◽  
Term Benefit ◽  
Tlr Signalling

The colonic epithelium is lined along its apical membrane with ∼1014 bacteria/g of tissue. Commensal bacteria outnumber mammalian cells in the gut severalfold. The reason for this degree of commensalism probably resides in the recent recognition of the microbiome as an important source of metabolic energy in the setting of poorly digestible nutrients. As in many themes in biology, the host may have sacrificed short-term benefit, i.e. nutritional advantages, for long-term consequences, such as chronic inflammation or colon cancer. In the present review, we examine the role of TLR (Toll-like receptor) signalling in the healthy host and the diseased host. We pay particular attention to the role of TLR signalling in idiopathic IBD (inflammatory bowel disease) and colitis-associated carcinogenesis. In general, TLR signalling in health contributes to homoeostatic functions. These include induction of antimicrobial peptides, proliferation and wound healing in the intestine. The pathogenesis of IBD, ulcerative colitis and Crohn's disease may be due to increased TLR or decreased TLR signalling respectively. Finally, we discuss the possible role of TLR signalling in colitis-associated neoplasia.

scholarly journals Structural plasticity of actin-spectrin membrane skeleton and functional role of actin and spectrin in axon degeneration

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Guiping Wang ◽  
David J Simon ◽  
Zhuhao Wu ◽  
Deanna M Belsky ◽  
Evan Heller ◽  
...  
Keyword(s):  
Potential Role ◽  
Structural Plasticity ◽  
Membrane Skeleton ◽  
Retrograde Signaling ◽  
Axon Degeneration ◽  
Protein Loss ◽  
Connectivity Patterns ◽  
Substantial Progress ◽  
Made In

Axon degeneration sculpts neuronal connectivity patterns during development and is an early hallmark of several adult-onset neurodegenerative disorders. Substantial progress has been made in identifying effector mechanisms driving axon fragmentation, but less is known about the upstream signaling pathways that initiate this process. Here, we investigate the behavior of the actin-spectrin-based Membrane-associated Periodic Skeleton (MPS), and effects of actin and spectrin manipulations in sensory axon degeneration. We show that trophic deprivation (TD) of mouse sensory neurons causes a rapid disassembly of the axonal MPS, which occurs prior to protein loss and independently of caspase activation. Actin destabilization initiates TD-related retrograde signaling needed for degeneration; actin stabilization prevents MPS disassembly and retrograde signaling during TD. Depletion of βII-spectrin, a key component of the MPS, suppresses retrograde signaling and protects axons against degeneration. These data demonstrate structural plasticity of the MPS and suggest its potential role in early steps of axon degeneration.

scholarly journals Gut Microbiota Manipulation in Foals—Naturopathic Diarrhea Management, or Unsubstantiated Folly?

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1137
Author(s):  
Rachel Goodman-Davis ◽  
Marianna Figurska ◽  
Anna Cywinska
Keyword(s):  
Quality Control ◽  
Clinical Trials ◽  
Fecal Microbiota Transplantation ◽  
Fecal Microbiota ◽  
Evidence Based ◽  
Economic Consequence ◽  
Bacterial Strains ◽  
Antimicrobial Resistance Genes ◽  
Health And Disease ◽  
Pros And Cons

Diarrhea in foals is a problem of significant clinical and economic consequence, and there are good reasons to believe microbiota manipulation can play an important role in its management. However, given the dynamic development of the foal microbiota and its importance in health and disease, any prophylactic or therapeutic efforts to alter its composition should be evidence based. The few clinical trials of probiotic preparations conducted in foals to date show underwhelming evidence of efficacy and a demonstrated potential to aggravate rather than mitigate diarrhea. Furthermore, recent studies have affirmed that variable but universally inadequate quality control of probiotics enables inadvertent administration of toxin-producing or otherwise pathogenic bacterial strains, as well as strains bearing transferrable antimicrobial resistance genes. Consequently, it seems advisable to approach probiotic therapy in particular with caution for the time being. While prebiotics show initial promise, an even greater scarcity of clinical trials makes it impossible to weigh the pros and cons of their use. Advancing technology will surely continue to enable more detailed and accurate mapping of the equine adult and juvenile microbiota and potentially elucidate the complexities of causation in dysbiosis and disease. In the meantime, fecal microbiota transplantation may be an attractive therapeutic shortcut, allowing practitioners to reconstruct a healthy microbiota even without fully understanding its constitution.

scholarly journals PrPC as a Transducer of Physiological and Pathological Signals

2021 ◽  
Vol 14 ◽  
Author(s):  
Jessica D. Panes ◽  
Paulina Saavedra ◽  
Benjamin Pineda ◽  
Kathleen Escobar ◽  
Magdalena E. Cuevas ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Physiological Role ◽  
Cellular Prion Protein ◽  
Amyloid Peptide ◽  
Metabotropic Receptors ◽  
Cellular Analysis ◽  
The Central Nervous System ◽  
Health And Disease ◽  
Β Amyloid Peptide

After the discovery of prion phenomenon, the physiological role of the cellular prion protein (PrPC) remained elusive. In the past decades, molecular and cellular analysis has shed some light regarding interactions and functions of PrPC in health and disease. PrPC, which is located mainly at the plasma membrane of neuronal cells attached by a glycosylphosphatidylinositol (GPI) anchor, can act as a receptor or transducer from external signaling. Although the precise role of PrPC remains elusive, a variety of functions have been proposed for this protein, namely, neuronal excitability and viability. Although many issues must be solved to clearly define the role of PrPC, its connection to the central nervous system (CNS) and to several misfolding-associated diseases makes PrPC an interesting pharmacological target. In a physiological context, several reports have proposed that PrPC modulates synaptic transmission, interacting with various proteins, namely, ion pumps, channels, and metabotropic receptors. PrPC has also been implicated in the pathophysiological cell signaling induced by β-amyloid peptide that leads to synaptic dysfunction in the context of Alzheimer’s disease (AD), as a mediator of Aβ-induced cell toxicity. Additionally, it has been implicated in other proteinopathies as well. In this review, we aimed to analyze the role of PrPC as a transducer of physiological and pathological signaling.

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