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16 pages, 28290 KiB

Open AccessArticle

IL-36α and Lipopolysaccharide Cooperatively Induce Autophagy by Triggering Pro-Autophagic Biased Signaling

by Zaid I. I. Al-Luhaibi, Áron Dernovics, György Seprényi, Ferhan Ayaydin, Zsolt Boldogkői, Zoltán Veréb and Klára Megyeri

Biomedicines 2021, 9(11), 1541; https://doi.org/10.3390/biomedicines9111541 - 26 Oct 2021

Cited by 1 | Viewed by 1995

Abstract

Autophagy is an intracellular catabolic process that controls infections both directly and indirectly via its multifaceted effects on the innate and adaptive immune responses. It has been reported that LPS stimulates this cellular process, whereas the effect of IL-36α on autophagy remains largely [...] Read more.

Autophagy is an intracellular catabolic process that controls infections both directly and indirectly via its multifaceted effects on the innate and adaptive immune responses. It has been reported that LPS stimulates this cellular process, whereas the effect of IL-36α on autophagy remains largely unknown. We therefore investigated how IL-36α modulates the endogenous and LPS-induced autophagy in THP-1 cells. The levels of LC3B-II and autophagic flux were determined by Western blotting. The intracellular localization of LC3B was measured by immunofluorescence assay. The activation levels of signaling pathways implicated in autophagy regulation were evaluated by using a phosphokinase array. Our results showed that combined IL-36α and LPS treatment cooperatively increased the levels of LC3B-II and Beclin-1, stimulated the autophagic flux, facilitated intracellular redistribution of LC3B, and increased the average number of autophagosomes per cell. The IL36α/LPS combined treatment increased phosphorylation of STAT5a/b, had minimal effect on the Akt/PRAS40/mTOR pathway, and reduced the levels of phospho-Yes, phospho-FAK, and phospho-WNK1. Thus, this cytokine/PAMP combination triggers pro-autophagic biased signaling by several mechanisms and thus cooperatively stimulates the autophagic cascade. An increased autophagic activity of innate immune cells simultaneously exposed to IL-36α and LPS may play an important role in the pathogenesis of Gram-negative bacterial infections. Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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22 pages, 5976 KiB

Open AccessArticle

GRP78 Overexpression Triggers PINK1-IP₃R-Mediated Neuroprotective Mitophagy

by Tatiana Leiva-Rodríguez, David Romeo-Guitart, Mireia Herrando-Grabulosa, Pau Muñoz-Guardiola, Miriam Polo, Celia Bañuls, Valerie Petegnief, Assumpció Bosch, Jose Miguel Lizcano, Nadezda Apostolova, Joaquim Forés and Caty Casas

Biomedicines 2021, 9(8), 1039; https://doi.org/10.3390/biomedicines9081039 - 18 Aug 2021

Cited by 5 | Viewed by 2722

Abstract

An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy [...] Read more.

An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection. Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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14 pages, 3752 KiB

Open AccessArticle

Therapeutic Effect of Endothelin-Converting Enzyme Inhibitor on Chronic Kidney Disease through the Inhibition of Endoplasmic Reticulum Stress and the NLRP3 Inflammasome

by Yung-Ho Hsu, Cai-Mei Zheng, Chu-Lin Chou, Yi-Jie Chen, Yu-Hsuan Lee, Yuh-Feng Lin and Hui-Wen Chiu

Biomedicines 2021, 9(4), 398; https://doi.org/10.3390/biomedicines9040398 - 07 Apr 2021

Cited by 8 | Viewed by 2505

Abstract

Chronic inflammation and oxidative stress significantly contribute to the development and progression of chronic kidney disease (CKD). The NOD-like receptor family pyrin containing domain-3 (NLRP3) inflammasome plays a key role in the inflammatory response. The renal endothelin (ET) system is activated in all [...] Read more.

Chronic inflammation and oxidative stress significantly contribute to the development and progression of chronic kidney disease (CKD). The NOD-like receptor family pyrin containing domain-3 (NLRP3) inflammasome plays a key role in the inflammatory response. The renal endothelin (ET) system is activated in all cases of CKD. Furthermore, ET-1 promotes renal cellular injury, inflammation, fibrosis and proteinuria. Endothelin-converting enzymes (ECEs) facilitate the final processing step of ET synthesis. However, the roles of ECEs in CKD are not clear. In this study, we investigated the effects of ETs and ECEs on kidney cells. We found that ET-1 and ET-2 expression was significantly upregulated in the renal tissues of CKD patients. ET-1 and ET-2 showed no cytotoxicity on human kidney tubular epithelial cells. However, ET-1 and ET-2 caused endoplasmic reticulum (ER) stress and NLRP3 inflammasome activation in tubular epithelial cells. The ECE inhibitor phosphoramidon induced autophagy. Furthermore, phosphoramidon inhibited ER stress and the NLRP3 inflammasome in tubular epithelial cells. In an adenine diet-induced CKD mouse model, phosphoramidon attenuated the progression of CKD by regulating autophagy, the NLRP3 inflammasome and ER stress. In summary, these findings showed a new strategy to delay CKD progression by inhibiting ECEs through autophagy activation and restraining ER stress and the NLRP3 inflammasome. Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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13 pages, 3083 KiB

Open AccessArticle

Effects of Nicorandil on Inflammation, Apoptosis and Atherosclerotic Plaque Progression

by Max Lenz, Christoph Kaun, Konstantin A. Krychtiuk, Patrick Haider, Mira Brekalo, Nadine Maier, Laura Goederle, Christoph J. Binder, Kurt Huber, Christian Hengstenberg, Johann Wojta, Philipp J. Hohensinner and Walter S. Speidl

Biomedicines 2021, 9(2), 120; https://doi.org/10.3390/biomedicines9020120 - 27 Jan 2021

Cited by 15 | Viewed by 3094

Abstract

Nicorandil, a balanced vasodilator, is used in the second-line therapy of angina pectoris. In this study, we aimed to illuminate the effects of nicorandil on inflammation, apoptosis, and atherosclerotic plaque progression. Twenty-five LDL-R -/- mice were fed a high-fat diet for 14 weeks. [...] Read more.

Nicorandil, a balanced vasodilator, is used in the second-line therapy of angina pectoris. In this study, we aimed to illuminate the effects of nicorandil on inflammation, apoptosis, and atherosclerotic plaque progression. Twenty-five LDL-R -/- mice were fed a high-fat diet for 14 weeks. After 6 weeks mice were randomly allocated to treatment with nicorandil (10 mg/kg/day) or tap water. Nicorandil treatment led to a more stable plaque phenotype, displaying an increased thickness of the fibrous cap (p = 0.014), a significant reduction in cholesterol clefts (p = 0.045), and enhanced smooth muscle cell content (p = 0.009). In endothelial cells nicorandil did not reduce the induction of adhesion molecules or proinflammatory cytokines. In H₂O₂ challenged endothelial cells, pretreatment with nicorandil significantly reduced the percentage of late apoptotic/necrotic cells (p = 0.016) and the ratio of apoptotic to living cells (p = 0.036). Atherosclerotic lesions of animals treated with nicorandil exhibited a significantly decreased content of cleaved caspase-3 (p = 0.034), lower numbers of apoptotic nuclei (p = 0.040), and reduced 8-oxogunanine staining (p = 0.039), demonstrating a stabilizing effect of nicorandil in established atherosclerotic lesions. We suggest that nicorandil has a positive effect on atherosclerotic plaque stabilization by reducing apoptosis. Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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Review

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30 pages, 2153 KiB

Open AccessReview

The Multifaceted Roles of Autophagy in Infectious, Obstructive, and Malignant Airway Diseases

by Marianna Carinci, Laura Palumbo, Giulia Pellielo, Esther Densu Agyapong, Giampaolo Morciano, Simone Patergnani, Carlotta Giorgi, Paolo Pinton and Alessandro Rimessi

Biomedicines 2022, 10(8), 1944; https://doi.org/10.3390/biomedicines10081944 - 11 Aug 2022

Cited by 3 | Viewed by 3304

Abstract

Autophagy is a highly conserved dynamic process by which cells deliver their contents to lysosomes for degradation, thus ensuring cell homeostasis. In response to environmental stress, the induction of autophagy is crucial for cell survival. The dysregulation of this degradative process has been [...] Read more.

Autophagy is a highly conserved dynamic process by which cells deliver their contents to lysosomes for degradation, thus ensuring cell homeostasis. In response to environmental stress, the induction of autophagy is crucial for cell survival. The dysregulation of this degradative process has been implicated in a wide range of pathologies, including lung diseases, representing a relevant potential target with significant clinical outcomes. During lung disease progression and infections, autophagy may exert both protective and harmful effects on cells. In this review, we will explore the implications of autophagy and its selective forms in several lung infections, such as SARS-CoV-2, Respiratory Syncytial Virus (RSV) and Mycobacterium tuberculosis (Mtb) infections, and different lung diseases such as Cystic Fibrosis (CF), Chronic Obstructive Pulmonary Disease (COPD), and Malignant Mesothelioma (MM). Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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30 pages, 1288 KiB

Open AccessReview

Molecular Mechanisms of Autophagy in Cancer Development, Progression, and Therapy

by Veronica Angela Maria Vitto, Silvia Bianchin, Alicia Ann Zolondick, Giulia Pellielo, Alessandro Rimessi, Diego Chianese, Haining Yang, Michele Carbone, Paolo Pinton, Carlotta Giorgi and Simone Patergnani

Biomedicines 2022, 10(7), 1596; https://doi.org/10.3390/biomedicines10071596 - 05 Jul 2022

Cited by 16 | Viewed by 3886

Abstract

Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many [...] Read more.

Autophagy is an evolutionarily conserved and tightly regulated process that plays an important role in maintaining cellular homeostasis. It involves regulation of various genes that function to degrade unnecessary or dysfunctional cellular components, and to recycle metabolic substrates. Autophagy is modulated by many factors, such as nutritional status, energy level, hypoxic conditions, endoplasmic reticulum stress, hormonal stimulation and drugs, and these factors can regulate autophagy both upstream and downstream of the pathway. In cancer, autophagy acts as a double-edged sword depending on the tissue type and stage of tumorigenesis. On the one hand, autophagy promotes tumor progression in advanced stages by stimulating tumor growth. On the other hand, autophagy inhibits tumor development in the early stages by enhancing its tumor suppressor activity. Moreover, autophagy drives resistance to anticancer therapy, even though in some tumor types, its activation induces lethal effects on cancer cells. In this review, we summarize the biological mechanisms of autophagy and its dual role in cancer. In addition, we report the current understanding of autophagy in some cancer types with markedly high incidence and/or lethality, and the existing therapeutic strategies targeting autophagy for the treatment of cancer. Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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20 pages, 4946 KiB

Open AccessReview

Autophagy in Extracellular Matrix and Wound Healing Modulation in the Cornea

by Duraisamy Kempuraj and Rajiv R. Mohan

Biomedicines 2022, 10(2), 339; https://doi.org/10.3390/biomedicines10020339 - 01 Feb 2022

Cited by 15 | Viewed by 5360

Abstract

Autophagy is a robust cellular mechanism for disposing of harmful molecules or recycling them to cells, which also regulates physiopathological processes in cornea. Dysregulated autophagy causes inefficient clearance of unwanted proteins and cellular debris, mitochondrial disorganization, defective inflammation, organ dysfunctions, cell death, and [...] Read more.

Autophagy is a robust cellular mechanism for disposing of harmful molecules or recycling them to cells, which also regulates physiopathological processes in cornea. Dysregulated autophagy causes inefficient clearance of unwanted proteins and cellular debris, mitochondrial disorganization, defective inflammation, organ dysfunctions, cell death, and diseases. The cornea accounts for two-thirds of the refraction of light that occurs in the eyes, but is prone to trauma/injury and infection. The extracellular matrix (ECM) is a noncellular dynamic macromolecular network in corneal tissues comprised of collagens, proteoglycans, elastin, fibronectin, laminins, hyaluronan, and glycoproteins. The ECM undergoes remodeling by matrix-degrading enzymes and maintains corneal transparency. Autophagy plays an important role in the ECM and wound healing maintenance. Delayed/dysregulated autophagy impacts the ECM and wound healing, and can lead to corneal dysfunction. Stromal wound healing involves responses from the corneal epithelium, basement membrane, keratocytes, the ECM, and many cytokines and chemokines, including transforming growth factor beta-1 and platelet-derived growth factor. Mild corneal injuries self-repair, but greater injuries lead to corneal haze/scars/fibrosis and vision loss due to disruptions in the ECM, autophagy, and normal wound healing processes. Presently, the precise role of autophagy and ECM remodeling in corneal wound healing is elusive. This review discusses recent trends in autophagy and ECM modulation in the context of corneal wound healing and homeostasis. Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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43 pages, 17527 KiB

Open AccessReview

The Emerging Roles of Autophagy in Human Diseases

by Yuchen Lei and Daniel J. Klionsky

Biomedicines 2021, 9(11), 1651; https://doi.org/10.3390/biomedicines9111651 - 09 Nov 2021

Cited by 23 | Viewed by 6370

Abstract

Autophagy, a process of cellular self-digestion, delivers intracellular components including superfluous and dysfunctional proteins and organelles to the lysosome for degradation and recycling and is important to maintain cellular homeostasis. In recent decades, autophagy has been found to help fight against a variety [...] Read more.

Autophagy, a process of cellular self-digestion, delivers intracellular components including superfluous and dysfunctional proteins and organelles to the lysosome for degradation and recycling and is important to maintain cellular homeostasis. In recent decades, autophagy has been found to help fight against a variety of human diseases, but, at the same time, autophagy can also promote the procession of certain pathologies, which makes the connection between autophagy and diseases complex but interesting. In this review, we summarize the advances in understanding the roles of autophagy in human diseases and the therapeutic methods targeting autophagy and discuss some of the remaining questions in this field, focusing on cancer, neurodegenerative diseases, infectious diseases and metabolic disorders. Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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46 pages, 2844 KiB

Open AccessReview

Macroautophagy and Mitophagy in Neurodegenerative Disorders: Focus on Therapeutic Interventions

by João Duarte Magalhães, Lígia Fão, Rita Vilaça, Sandra Morais Cardoso and Ana Cristina Rego

Biomedicines 2021, 9(11), 1625; https://doi.org/10.3390/biomedicines9111625 - 05 Nov 2021

Cited by 9 | Viewed by 4765

Abstract

Macroautophagy, a quality control mechanism, is an evolutionarily conserved pathway of lysosomal degradation of protein aggregates, pathogens, and damaged organelles. As part of its vital homeostatic role, macroautophagy deregulation is associated with various human disorders, including neurodegenerative diseases. There are several lines of [...] Read more.

Macroautophagy, a quality control mechanism, is an evolutionarily conserved pathway of lysosomal degradation of protein aggregates, pathogens, and damaged organelles. As part of its vital homeostatic role, macroautophagy deregulation is associated with various human disorders, including neurodegenerative diseases. There are several lines of evidence that associate protein misfolding and mitochondrial dysfunction in the etiology of Alzheimer’s, Parkinson’s, and Huntington’s diseases. Macroautophagy has been implicated in the degradation of different protein aggregates such as Aβ, tau, alpha-synuclein (α-syn), and mutant huntingtin (mHtt) and in the clearance of dysfunctional mitochondria. Taking these into consideration, targeting autophagy might represent an effective therapeutic strategy to eliminate protein aggregates and to improve mitochondrial function in these disorders. The present review describes our current understanding on the role of macroautophagy in neurodegenerative disorders and focuses on possible strategies for its therapeutic modulation. Full article

(This article belongs to the Special Issue The Various Faces of Autophagy in Human Disease)

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