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1.
Autophagy in Human Health and Disease: Novel Therapeutic Opportunities.
Giampieri, F, Afrin, S, Forbes-Hernandez, TY, Gasparrini, M, Cianciosi, D, Reboredo-Rodriguez, P, Varela-Lopez, A, Quiles, JL, Battino, M
Antioxidants & redox signaling. 2019;(4):577-634
Abstract
SIGNIFICANCE In eukaryotes, autophagy represents a highly evolutionary conserved process, through which macromolecules and cytoplasmic material are degraded into lysosomes and recycled for biosynthetic or energetic purposes. Dysfunction of the autophagic process has been associated with the onset and development of many human chronic pathologies, such as cardiovascular, metabolic, and neurodegenerative diseases as well as cancer. Recent Advances: Currently, comprehensive research is being carried out to discover new therapeutic agents that are able to modulate the autophagic process in vivo. Recent evidence has shown that a large number of natural bioactive compounds are involved in the regulation of autophagy by modulating several transcriptional factors and signaling pathways. CRITICAL ISSUES Critical issues that deserve particular attention are the inadequate understanding of the complex role of autophagy in disease pathogenesis, the limited availability of therapeutic drugs, and the lack of clinical trials. In this context, the effects that natural bioactive compounds exert on autophagic modulation should be clearly highlighted, since they depend on the type and stage of the pathological conditions of diseases. FUTURE DIRECTIONS Research efforts should now focus on understanding the survival-supporting and death-promoting roles of autophagy, how natural compounds interact exactly with the autophagic targets so as to induce or inhibit autophagy and on the evaluation of their pharmacological effects in a more in-depth and mechanistic way. In addition, clinical studies on autophagy-inducing natural products are strongly encouraged, also to highlight some fundamental aspects, such as the dose, the duration, and the possible synergistic action of these compounds with conventional therapy.
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The Relationship between Ferroptosis and Tumors: A Novel Landscape for Therapeutic Approach.
Xia, X, Fan, X, Zhao, M, Zhu, P
Current gene therapy. 2019;(2):117-124
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Abstract
BACKGROUND Ferroptosis is a newly discovered form of iron-dependent oxidative cell death characterized by lethal accumulation of lipid-based reactive oxygen species (ROS). It is distinct from other forms of cell death including apoptosis, necrosis, and autophagy in terms of morphology, biochemistry and genetics. DISCUSSION Ferroptosis can be induced by system xc- inhibitors or glutathione peroxidase 4 (GPx4) inhibitors, as well as drugs such as sorafenib, sulfasalazine (SAS), and artesunate (ART). Ferroptosis has been recently shown to be critical in regulating growth of tumors, such as hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic carcinoma, and diffuse large B cell lymphoma (DLBCL). Ferroptosis is also associated with resistance to chemotherapeutic drugs and the anti-tumor efficacy of immunotherapy. CONCLUSION This review summarizes the mechanism of ferroptosis and its relationship with different types of tumors, to advance our understanding of cell death and to find a novel approach for clinical cancer management.
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Autophagic dysfunction in Alzheimer's disease: Cellular and molecular mechanistic approaches to halt Alzheimer's pathogenesis.
Uddin, MS, Mamun, AA, Labu, ZK, Hidalgo-Lanussa, O, Barreto, GE, Ashraf, GM
Journal of cellular physiology. 2019;(6):8094-8112
Abstract
Autophagy is a preserved cytoplasmic self-degradation process and endorses recycling of intracellular constituents into bioenergetics for the controlling of cellular homeostasis. Functional autophagy process is essential in eliminating cytoplasmic waste components and helps in the recycling of some of its constituents. Studies have revealed that neurodegenerative disorders may be caused by mutations in autophagy-related genes and alterations of autophagic flux. Alzheimer's disease (AD) is an irrevocable deleterious neurodegenerative disorder characterized by the formation of senile plaques and neurofibrillary tangles (NFTs) in the hippocampus and cortex. In the central nervous system of healthy people, there is no accretion of amyloid β (Aβ) peptides due to the balance between generation and degradation of Aβ. However, for AD patients, the generation of Aβ peptides is higher than lysis that causes accretion of Aβ. Likewise, the maturation of autophagolysosomes and inhibition of their retrograde transport creates favorable conditions for Aβ accumulation. Furthermore, increasing mammalian target of rapamycin (mTOR) signaling raises tau levels as well as phosphorylation. Alteration of mTOR activity occurs in the early stage of AD. In addition, copious evidence links autophagic/lysosomal dysfunction in AD. Compromised mitophagy is also accountable for dysfunctional mitochondria that raises Alzheimer's pathology. Therefore, autophagic dysfunction might lead to the deposit of atypical proteins in the AD brain and manipulation of autophagy could be considered as an emerging therapeutic target. This review highlights the critical linkage of autophagy in the pathogenesis of AD, and avows a new insight to search for therapeutic target for blocking Alzheimer's pathogenesis.
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Autophagy in Skin Diseases.
Guo, Y, Zhang, X, Wu, T, Hu, X, Su, J, Chen, X
Dermatology (Basel, Switzerland). 2019;(5):380-389
Abstract
Autophagy, or self-eating, is an evolutionarily conserved process in which cytosol and organelles are sequestered within double-membrane vesicles that deliver the contents to the lysosome/vacuole for the degradation and recycling of cytoplasmic components in eukaryotes. It is well recognized that autophagy plays an important role in maintaining cellular homeostasis under physiological and pathophysiological con-ditions and the upregulation of autophagy may serve as an adaptive process to provide nutrients and energy when under stresses. Recently, studies have illustrated that autophagy is intricately related to skin diseases. This review provides a brief synopsis of the process of autophagy and aims to elucidate the roles of autophagy in different skin diseases and to highlight the need for increased research in the field.
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Signaling alterations caused by drugs and autophagy.
Dent, P, Booth, L, Poklepovic, A, Hancock, JF
Cellular signalling. 2019;:109416
Abstract
Autophagy is an evolutionary conserved process that recycles cellular materials in times of nutrient restriction to maintain viability. In cancer therapeutics, the role of autophagy in response to multi-kinase inhibitors, alone or when combined with histone deacetylase (HDAC) inhibitors acts, generally, to facilitate the killing of tumor cells. Furthermore, the formation of autophagosomes and subsequent degradation of their contents can reduce the expression of HDAC proteins themselves as well as of other signaling regulatory molecules such as protein chaperones and mutated RAS proteins. Reduced levels of HDAC6 causes the acetylation and inactivation of heat shock protein 90, and, together with reduced expression of the chaperones HSP70 and GRP78, generates a strong endoplasmic reticulum (ER) stress response. Prolonged intense ER stress signaling causes tumor cell death. Reduced expression of HDACs 1, 2 and 3 causes the levels of programed death ligand 1 (PD-L1) to decline and the expression of Class I MHCA to increase which correlates with elevated immunogenicity of the tumor cells in vivo. This review will specifically focus on the downstream implications that result from autophagic-degradation of HDACs, RAS and protein chaperones.
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The Role and Regulation of Autophagy and the Proteasome During Aging and Senescence in Plants.
Wang, H, Schippers, JHM
Genes. 2019;(4)
Abstract
Aging and senescence in plants has a major impact on agriculture, such as in crop yield, the value of ornamental crops, and the shelf life of vegetables and fruits. Senescence represents the final developmental phase of the leaf and inevitably results in the death of the organ. Still, the process is completely under the control of the plant. Plants use their protein degradation systems to maintain proteostasis and transport or salvage nutrients from senescing organs to develop reproductive parts. Herein, we present an overview of current knowledge about the main protein degradation pathways in plants during senescence: The proteasome and autophagy. Although both pathways degrade proteins, autophagy appears to prevent aging, while the proteasome functions as a positive regulator of senescence.
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MicroRNAs play an essential role in autophagy regulation in various disease phenotypes.
Zhao, Y, Wang, Z, Zhang, W, Zhang, L
BioFactors (Oxford, England). 2019;(6):844-856
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Abstract
Autophagy is a highly conserved catabolic process and fundamental biological process in eukaryotic cells. It recycles intracellular components to provide nutrients during starvation and maintains quality control of organelles and proteins. In addition, autophagy is a well-organized homeostatic cellular process that is responsible for the removal of damaged organelles and intracellular pathogens. Moreover, it also modulates the innate and adaptive immune systems. Micro ribonucleic acids (microRNAs) are a mature class of post-transcriptional modulators that are widely expressed in tissues and organs. And, it can suppress gene expression by targeting messenger RNAs for translational repression or, at a lesser extent, degradation. Research indicates that microRNAs regulate autophagy through different pathways, playing an essential role in the treatment of various diseases. It is an important regulator of fundamental cellular processes such as proliferation, autophagy, and cell apoptosis. In this review article, we first review the current knowledge of autophagy and the function of microRNAs. Then, we summarize the mechanism of autophagy and the signaling pathways related to autophagy by citing at least the main proteins involved in the different phases of the process. Second, we introduce other members of RNA and report some examples in various pathologies. Finally, we review the current literature regarding microRNA-based therapies for cancer, atherosclerosis, cardiac disease, tuberculosis, and viral diseases. MicroRNAs can cause autophagy upregulation or downregulation by targeting genes or affecting autophagy-related signaling pathways. Therefore, the microRNAs have a huge potential in autophagy regulation, and it is the function as diagnostic and prognostic markers.
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The Role of Autophagy in Chondrocyte Metabolism and Osteoarthritis: A Comprehensive Research Review.
Luo, P, Gao, F, Niu, D, Sun, X, Song, Q, Guo, C, Liang, Y, Sun, W
BioMed research international. 2019;:5171602
Abstract
Chondrocytes are the sole cellular constituents of normal cartilage. The degeneration and apoptosis of these cells are considered the main cause of osteoarthritis (OA). Previous studies have suggested that the enhancement of autophagy in chondrocytes can delay the progression of osteoarthritis by affecting intracellular metabolic activity, i.e., by regulating the metabolism of nutrients, which can delay cell aging and death. In this review, we explored the relationship between autophagy and chondrocyte metabolism and provided new ideas for the prevention and treatment of OA.
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Autophagy in Alzheimer's disease and promising modulatory effects of herbal medicine.
Zeng, Q, Siu, W, Li, L, Jin, Y, Liang, S, Cao, M, Ma, M, Wu, Z
Experimental gerontology. 2019;:100-110
Abstract
Alzheimer's disease (AD) is a progressive and unremitting neurodegenerative disorder characterized by memory loss and cognitive impairment. It affects the quality of life of victims severely. The prevalence of AD has been increasing in recent years. Therefore, it is of great importance to elucidate the pathogenesis of AD and find out effective therapeutic approaches. Autophagy, a primary intracellular way of degrading aggregated proteins and damaged organelles, has been discovered to be involved in the pathological changes of AD. In the last few years, much progress has been made in finding autophagy regulators from natural products, providing new insights to develop treatment strategy for AD by targeting autophagy. In the present review, we provided an overview of the recent research progress regarding the function role of autophagy in AD, the regulation mechanisms of autophagy-lysosomal pathway as well as therapeutic potential of herbal medicine on AD by targeting autophagy.
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Remove, Recycle, Degrade: Regulating Plasma Membrane Protein Accumulation.
Rodriguez-Furlan, C, Minina, EA, Hicks, GR
The Plant cell. 2019;(12):2833-2854
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Abstract
Interactions between plant cells and the environment rely on modulation of protein receptors, transporters, channels, and lipids at the plasma membrane (PM) to facilitate intercellular communication, nutrient uptake, environmental sensing, and directional growth. These functions are fine-tuned by cellular pathways maintaining or reducing particular proteins at the PM. Proteins are endocytosed, and their fate is decided between recycling and degradation to modulate localization, abundance, and activity. Selective autophagy is another pathway regulating PM protein accumulation in response to specific conditions or developmental signals. The mechanisms regulating recycling, degradation, and autophagy have been studied extensively, yet we are just now addressing their regulation and coordination. Here, we (1) provide context concerning regulation of protein accumulation, recycling, or degradation by overviewing endomembrane trafficking; (2) discuss pathways regulating recycling and degradation in terms of cellular roles and cargoes; (3) review plant selective autophagy and its physiological significance; (4) focus on two decision-making mechanisms: regulation of recycling versus degradation of PM proteins and coordination between autophagy and vacuolar degradation; and (5) identify future challenges.