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Autophagy in Health, Aging and Disease 3.0

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 25280

Special Issue Editors


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1. Department of Neuroscience, Imaging and Clinical Sciences, “G. d’Annunzio” University of Chieti, 66100 Chieti, Italy
2. Center for Research on Aging and Translational Medicine (CeSI-MeT), “G. d’Annunzio” University of Chieti, 66100 Chieti, Italy
Interests: oxidative/nitrosative stress; neurodegenerative diseases
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Special Issue Information

Dear Colleagues,

Autophagy is an evolutionarily conserved intracellular catabolic process. It has an essential role in cellular homeostasis, facilitating lysosomal degradation and the recycling of harmful and damaged cytoplasmic components. Autophagy was first discovered as a survival mechanism in yeasts subjected to nutrient deprivation, and since then, studies in several different organisms have established its critical roles in a variety of biological processes ranging from development to aging. Interestingly, autophagy is often found perturbed in age-related disorders such as cancer, diabetes, neurodegenerative diseases, and sarcopenia. Accordingly, autophagy is important for the maintenance of organismal health, which prominently declines with aging.

This Special Issue of the International Journal of Molecular Sciences, “Autophagy in Health, Ageing, and Disease”, will include a selection of original articles and reviews aimed at expanding our understanding of this multifaceted process and providing support for further investigations on the role of autophagy in cellular homeostasis, aging, and disease. In particular, it will contribute to better explaining the complex machinery of autophagy and lead to further investigations on physiological and pathological fields in which the study of this process is still in its infancy. Moreover, studies on the role of autophagy in age-related processes to open new avenues for the development of novel potential anti-aging therapeutic approaches are also welcome.

Prof. Dr. Patrizia Ballerini
Prof. Dr. Antonia Patruno
Dr. Mirko Pesce
Guest Editors

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Keywords

  • Autophagy
  • Aging
  • Aging diseases
  • Cell survival
  • Inflammation
  • Oxidative stress
  • Signaling pathway
  • Target identification

Published Papers (9 papers)

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Research

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12 pages, 3785 KiB  
Article
CurQ+, a Next-Generation Formulation of Curcumin, Ameliorates Growth Plate Chondrocyte Stress and Increases Limb Growth in a Mouse Model of Pseudoachondroplasia
by Jacqueline T. Hecht, Alka C. Veerisetty, Mohammad G. Hossain, Frankie Chiu and Karen L. Posey
Int. J. Mol. Sci. 2023, 24(4), 3845; https://doi.org/10.3390/ijms24043845 - 14 Feb 2023
Cited by 1 | Viewed by 1403
Abstract
Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage [...] Read more.
Mutations in cartilage oligomeric matrix protein (COMP) causes protein misfolding and accumulation in chondrocytes that compromises skeletal growth and joint health in pseudoachondroplasia (PSACH), a severe dwarfing condition. Using the MT-COMP mice, a murine model of PSACH, we showed that pathological autophagy blockage was key to the intracellular accumulation of mutant-COMP. Autophagy is blocked by elevated mTORC1 signaling, preventing ER clearance and ensuring chondrocyte death. We demonstrated that resveratrol reduces the growth plate pathology by relieving the autophagy blockage allowing the ER clearance of mutant-COMP, which partially rescues limb length. To expand potential PSACH treatment options, CurQ+, a uniquely absorbable formulation of curcumin, was tested in MT-COMP mice at doses of 82.3 (1X) and 164.6 mg/kg (2X). CurQ+ treatment of MT-COMP mice from 1 to 4 weeks postnatally decreased mutant COMP intracellular retention, inflammation, restoring both autophagy and chondrocyte proliferation. CurQ+ reduction of cellular stress in growth plate chondrocytes dramatically reduced chondrocyte death, normalized femur length at 2X 164.6 mg/kg and recovered 60% of lost limb growth at 1X 82.3 mg/kg. These results indicate that CurQ+ is a potential therapy for COMPopathy-associated lost limb growth, joint degeneration, and other conditions involving persistent inflammation, oxidative stress, and a block of autophagy. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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14 pages, 3721 KiB  
Article
The Greatwall–Endosulfine Switch Accelerates Autophagic Flux during the Cell Divisions Leading to G1 Arrest and Entry into Quiescence in Fission Yeast
by Alicia Vázquez-Bolado, Rafael López-San Segundo, Natalia García-Blanco, Ana Elisa Rozalén, Daniel González-Álvarez, M. Belén Suárez, Livia Pérez-Hidalgo and Sergio Moreno
Int. J. Mol. Sci. 2023, 24(1), 148; https://doi.org/10.3390/ijms24010148 - 21 Dec 2022
Cited by 1 | Viewed by 1254
Abstract
Entry into quiescence in the fission yeast Schizosaccharomyces pombe is induced by nitrogen starvation. In the absence of nitrogen, proliferating fission yeast cells divide twice without cell growth and undergo cell cycle arrest in G1 before becoming G0 quiescent cells. Under these conditions, [...] Read more.
Entry into quiescence in the fission yeast Schizosaccharomyces pombe is induced by nitrogen starvation. In the absence of nitrogen, proliferating fission yeast cells divide twice without cell growth and undergo cell cycle arrest in G1 before becoming G0 quiescent cells. Under these conditions, autophagy is induced to produce enough nitrogen for the two successive cell divisions that take place before the G1 arrest. In parallel to the induction of autophagy, the Greatwall–Endosulfine switch is activated upon nitrogen starvation to down-regulate protein phosphatase PP2A/B55 activity, which is essential for cell cycle arrest in G1 and implementation of the quiescent program. Here we show that, although inactivation of PP2A/B55 by the Greatwall–Endosulfine switch is not required to promote autophagy initiation, it increases autophagic flux at least in part by upregulating the expression of a number of autophagy-related genes. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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19 pages, 4554 KiB  
Article
Apoptosis, Proliferation, and Autophagy Are Involved in Local Anesthetic-Induced Cytotoxicity of Human Breast Cancer Cells
by Jia-Lin Chen, Shu-Ting Liu, Shih-Ming Huang and Zhi-Fu Wu
Int. J. Mol. Sci. 2022, 23(24), 15455; https://doi.org/10.3390/ijms232415455 - 07 Dec 2022
Cited by 4 | Viewed by 1522
Abstract
Breast cancer accounts for almost one quarter of all female cancers worldwide, and more than 90% of those who are diagnosed with breast cancer undergo mastectomy or breast conservation surgery. Local anesthetics effectively inhibit the invasion of cancer cells at concentrations that are [...] Read more.
Breast cancer accounts for almost one quarter of all female cancers worldwide, and more than 90% of those who are diagnosed with breast cancer undergo mastectomy or breast conservation surgery. Local anesthetics effectively inhibit the invasion of cancer cells at concentrations that are used in surgical procedures. The limited treatment options for triple-negative breast cancer (TNBC) demonstrate unmet clinical needs. In this study, four local anesthetics, lidocaine, levobupivacaine, bupivacaine, and ropivacaine, were applied to two breast tumor cell types, TNBC MDA-MB-231 cells and triple-positive breast cancer BT-474 cells. In addition to the induction of apoptosis and the suppression of the cellular proliferation rate, the four local anesthetics decreased the levels of reactive oxygen species and increased the autophagy elongation indicator in both cell types. Our combination index analysis with doxorubicin showed that ropivacaine had a synergistic effect on the two cell types, and lidocaine had a synergistic effect only in MDA-MB-231 cells; the others had no synergistic effects on doxorubicin. Lidocaine contributed significantly to the formation of autophagolysosomes in a dose-dependent manner in MDA-MB-231 cells but not in BT-474 cells. Our study demonstrated that the four local anesthetics can reduce tumor growth and proliferation and promote apoptosis and autophagy. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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16 pages, 3410 KiB  
Article
New Insights into Dose-Dependent Effects of Curcumin on ARPE-19 Cells
by Giulia Carozza, Annamaria Tisi, Annamaria Capozzo, Benedetta Cinque, Aldo Giovannelli, Marco Feligioni, Vincenzo Flati and Rita Maccarone
Int. J. Mol. Sci. 2022, 23(23), 14771; https://doi.org/10.3390/ijms232314771 - 25 Nov 2022
Cited by 1 | Viewed by 1286
Abstract
Opposing dose-dependent effects of curcumin (Cur) have been documented in Retinal Pigment Epithelium (RPE); therefore, to shed the light on the mechanisms of action is crucial for ophthalmic applications. On this basis we explored new insights about the dose-dependent mechanisms triggered by Cur [...] Read more.
Opposing dose-dependent effects of curcumin (Cur) have been documented in Retinal Pigment Epithelium (RPE); therefore, to shed the light on the mechanisms of action is crucial for ophthalmic applications. On this basis we explored new insights about the dose-dependent mechanisms triggered by Cur in human retinal pigment epithelial cells (ARPE-19). Three concentrations (0.01 mM; 0.05 mM; 0.1 mM) of Cur were tested, followed by morphological, molecular, and functional analysis of the cells. Cur 0.01 mM promotes a significant increase in cell proliferation, not affecting cell cycle progression and apoptosis; by contrast, Cur 0.05 mM and 0.1 mM block cellular proliferation and trigger S-phase cell cycle arrest without inducing apoptosis. The observation of neuronal-like morphological changes in Cur 0.05 mM and 0.1 mM were not associated with neuronal differentiation, as observed by the quantification of Neurofilament-200 and by the analysis of voltage-dependent currents by patch clamp. Evaluation of autophagic markers LC3BII and p62 revealed significant modulations, suggesting an important activation of autophagy in ARPE-19 cells treated with Cur 0.05 mM and Cur 0.1 mM; conversely, Cur 0.01 mM did not affect autophagy. Altogether, our findings show new dose-dependent mechanisms of action of Cur that suggest a wide therapeutic application in ocular diseases with different pathogenesis (i.e., proliferative vitreoretinopathy or Age-Related Macular Degeneration). Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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17 pages, 3051 KiB  
Article
Quantitative Metabolomic Analysis of Changes in the Rat Blood Serum during Autophagy Modulation: A Focus on Accelerated Senescence
by Olga Snytnikova, Yuri Tsentalovich, Renad Sagdeev, Nataliya Kolosova and Oyuna Kozhevnikova
Int. J. Mol. Sci. 2022, 23(21), 12720; https://doi.org/10.3390/ijms232112720 - 22 Oct 2022
Cited by 2 | Viewed by 1930
Abstract
Autophagy is involved in the maintenance of cellular homeostasis and the removal of damaged proteins and organelles and is necessary to maintain cell metabolism in conditions of energy and nutrient deficiency. A decrease in autophagic activity plays an important role in age-related diseases. [...] Read more.
Autophagy is involved in the maintenance of cellular homeostasis and the removal of damaged proteins and organelles and is necessary to maintain cell metabolism in conditions of energy and nutrient deficiency. A decrease in autophagic activity plays an important role in age-related diseases. However, the metabolic response to autophagy modulation remains poorly understood. Here, we for the first time explored the effects of (1) autophagy activation by 48 h fasting, (2) inhibition by chloroquine (CQ) treatment, and (3) combined effects of fasting and CQ on the quantitative composition of metabolites in the blood serum of senescent-accelerated OXYS and control Wistar rats at the age of 4 months. By means of high-resolution 1H NMR spectroscopy, we identified the quantitative content of 55 serum metabolites, including amino acids, organic acids, antioxidants, osmolytes, glycosides, purine, and pyrimidine derivatives. Groups of 48 h fasting (induction of autophagy), CQ treatment (inhibition of autophagy), and combined effects (CQ + fasting) are clearly separated from control groups by principal component analysis. Fasting for 48 h led to significant changes in the serum metabolomic profile, primarily affecting metabolic pathways related to fatty acid metabolism, and led to metabolism of several amino acids. Under CQ treatment, the most affected metabolites were citrate, betaine, cytidine, proline, tryptophan, glutamate, and mannose. As shown by two-way ANOVA, for many metabolites the effects of autophagy modulation depend on the animal genotype, indicating a dysregulation of metabolome reactivity in OXYS rats. Thus, the metabolic responses to modulation of autophagy in OXYS rats and Wistar rats are different. Altered metabolites in OXYS rats may serve as potential biomarkers of the manifestation of the signs of accelerated aging. Metabolic signatures characteristic to fasting and CQ treatment revealed in this work might provide a better understanding of the connections between metabolism and autophagy. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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15 pages, 15174 KiB  
Article
Exercise and Training Regulation of Autophagy Markers in Human and Rat Skeletal Muscle
by Javier Botella, Nicholas A. Jamnick, Cesare Granata, Amanda J. Genders, Enrico Perri, Tamim Jabar, Andrew Garnham, Michael Lazarou and David J. Bishop
Int. J. Mol. Sci. 2022, 23(5), 2619; https://doi.org/10.3390/ijms23052619 - 27 Feb 2022
Cited by 5 | Viewed by 3253
Abstract
Autophagy is a key intracellular mechanism by which cells degrade old or dysfunctional proteins and organelles. In skeletal muscle, evidence suggests that exercise increases autophagosome content and autophagy flux. However, the exercise-induced response seems to differ between rodents and humans, and little is [...] Read more.
Autophagy is a key intracellular mechanism by which cells degrade old or dysfunctional proteins and organelles. In skeletal muscle, evidence suggests that exercise increases autophagosome content and autophagy flux. However, the exercise-induced response seems to differ between rodents and humans, and little is known about how different exercise prescription parameters may affect these results. The present study utilised skeletal muscle samples obtained from four different experimental studies using rats and humans. Here, we show that, following exercise, in the soleus muscle of Wistar rats, there is an increase in LC3B-I protein levels immediately after exercise (+109%), and a subsequent increase in LC3B-II protein levels 3 h into the recovery (+97%), despite no change in Map1lc3b mRNA levels. Conversely, in human skeletal muscle, there is an immediate exercise-induced decrease in LC3B-II protein levels (−24%), independent of whether exercise is performed below or above the maximal lactate steady state, which returns to baseline 3.5 h following recovery, while no change in LC3B-I protein levels or MAP1LC3B mRNA levels is observed. SQSTM1/p62 protein and mRNA levels did not change in either rats or humans following exercise. By employing an ex vivo autophagy flux assay previously used in rodents we demonstrate that the exercise-induced decrease in LC3B-II protein levels in humans does not reflect a decreased autophagy flux. Instead, effect size analyses suggest a modest-to-large increase in autophagy flux following exercise that lasts up to 24 h. Our findings suggest that exercise-induced changes in autophagosome content markers differ between rodents and humans, and that exercise-induced decreases in LC3B-II protein levels do not reflect autophagy flux level. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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15 pages, 4004 KiB  
Article
Ellagic Acid Prevents α-Synuclein Aggregation and Protects SH-SY5Y Cells from Aggregated α-Synuclein-Induced Toxicity via Suppression of Apoptosis and Activation of Autophagy
by Mustafa T Ardah, Nabil Eid, Tohru Kitada and M. Emdadul Haque
Int. J. Mol. Sci. 2021, 22(24), 13398; https://doi.org/10.3390/ijms222413398 - 13 Dec 2021
Cited by 7 | Viewed by 2702
Abstract
Parkinson’s disease (PD) is a neurodegenerative disease characterized by the loss of dopamine neurons and the deposition of misfolded proteins known as Lewy bodies (LBs), which contain α-synuclein (α-syn). The causes and molecular mechanisms of PD are not clearly understood to date. However, [...] Read more.
Parkinson’s disease (PD) is a neurodegenerative disease characterized by the loss of dopamine neurons and the deposition of misfolded proteins known as Lewy bodies (LBs), which contain α-synuclein (α-syn). The causes and molecular mechanisms of PD are not clearly understood to date. However, misfolded proteins, oxidative stress, and impaired autophagy are believed to play important roles in the pathogenesis of PD. Importantly, α-syn is considered a key player in the development of PD. The present study aimed to assess the role of Ellagic acid (EA), a polyphenol found in many fruits, on α-syn aggregation and toxicity. Using thioflavin and seeding polymerization assays, in addition to electron microscopy, we found that EA could dramatically reduce α-syn aggregation. Moreover, EA significantly mitigated the aggregated α-syn-induced toxicity in SH-SY5Y cells and thus enhanced their viability. Mechanistically, these cytoprotective effects of EA are mediated by the suppression of apoptotic proteins BAX and p53 and a concomitant increase in the anti-apoptotic protein, BCL-2. Interestingly, EA was able to activate autophagy in SH-SY5Y cells, as evidenced by normalized/enhanced expression of LC3-II, p62, and pAKT. Together, our findings suggest that EA may attenuate α-syn toxicity by preventing aggregation and improving viability by restoring autophagy and suppressing apoptosis. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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21 pages, 4654 KiB  
Article
Curcumin Alleviates the Senescence of Canine Bone Marrow Mesenchymal Stem Cells during In Vitro Expansion by Activating the Autophagy Pathway
by Jiaqiang Deng, Ping Ouyang, Weiyao Li, Lijun Zhong, Congwei Gu, Liuhong Shen, Suizhong Cao, Lizi Yin, Zhihua Ren, Zhicai Zuo, Junliang Deng, Qigui Yan and Shumin Yu
Int. J. Mol. Sci. 2021, 22(21), 11356; https://doi.org/10.3390/ijms222111356 - 21 Oct 2021
Cited by 13 | Viewed by 3673
Abstract
Senescence in mesenchymal stem cells (MSCs) not only hinders the application of MSCs in regenerative medicine but is also closely correlated with biological aging and the development of degenerative diseases. In this study, we investigated the anti-aging effects of curcumin (Cur) on canine [...] Read more.
Senescence in mesenchymal stem cells (MSCs) not only hinders the application of MSCs in regenerative medicine but is also closely correlated with biological aging and the development of degenerative diseases. In this study, we investigated the anti-aging effects of curcumin (Cur) on canine bone marrow-derived MSCs (cBMSCs), and further elucidated the potential mechanism of action based on the modulation of autophagy. cBMSCs were expanded in vitro with standard procedures to construct a cell model of premature senescence. Our evidence indicates that compared with the third passage of cBMSCs, many typical senescence-associated phenotypes were observed in the sixth passage of cBMSCs. Cur treatment can improve cBMSC survival and retard cBMSC senescence according to observations that Cur (1 μM) treatment can improve the colony-forming unit-fibroblasts (CFU-Fs) efficiency and upregulated the mRNA expression of pluripotent transcription factors (SOX-2 and Nanog), as well as inhibiting the senescence-associated beta-galactosidase (SA-β-gal) activities and mRNA expression of the senescence-related markers (p16 and p21) and pro-inflammatory molecules (tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)). Furthermore, Cur (0.1 μM~10 μM) was observed to increase autophagic activity, as identified by upregulation of microtubule-associated protein 1 light chain 3 (LC3), unc51-like autophagy-activating kinase-1 (ULK1), autophagy-related gene (Atg) 7 and Atg12, and the generation of type II of light chain 3 (LC3-II), thereby increasing autophagic vacuoles and acidic vesicular organelles, as well as causing a significant decrease in the p62 protein level. Moreover, the autophagy activator rapamycin (RAP) and Cur were found to partially ameliorate the senescent features of cBMSCs, while the autophagy inhibitor 3-methyladenine (3-MA) was shown to aggravate cBMSCs senescence and Cur treatment was able to restore the suppressed autophagy and counteract 3-MA-induced cBMSC senescence. Hence, our study highlights the important role of Cur-induced autophagy and its effects for ameliorating cBMSC senescence and provides new insight for delaying senescence and improving the therapeutic potential of MSCs. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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Review

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66 pages, 11179 KiB  
Review
Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer
by Md. Abdul Alim Al-Bari, Yuko Ito, Samrein Ahmed, Nada Radwan, Hend S. Ahmed and Nabil Eid
Int. J. Mol. Sci. 2021, 22(18), 9807; https://doi.org/10.3390/ijms22189807 - 10 Sep 2021
Cited by 19 | Viewed by 6373
Abstract
Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to [...] Read more.
Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to cancer and aging. It is well known that regulating autophagy by targeting specific regulatory molecules in its machinery can modulate multiple disease processes. Therefore, autophagy represents a significant pharmacological target for drug development and therapeutic interventions in various diseases, including cancers. According to the framework of autophagy, the suppression or induction of autophagy can exert therapeutic properties through the promotion of cell death or cell survival, which are the two main events targeted by cancer therapies. Remarkably, natural products have attracted attention in the anticancer drug discovery field, because they are biologically friendly and have potential therapeutic effects. In this review, we summarize the up-to-date knowledge regarding natural products that can modulate autophagy in various cancers. These findings will provide a new position to exploit more natural compounds as potential novel anticancer drugs and will lead to a better understanding of molecular pathways by targeting the various autophagy stages of upcoming cancer therapeutics. Full article
(This article belongs to the Special Issue Autophagy in Health, Aging and Disease 3.0)
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