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He W, Wu F, Xiong H, Zeng J, Gao Y, Cai Z, Pang J, Zheng Y. Promoting TFEB nuclear localization with curcumin analog C1 attenuates sensory hair cell injury and delays age-related hearing loss in C57BL/6 mice. Neurotoxicology 2023; 95:218-231. [PMID: 36792013 DOI: 10.1016/j.neuro.2023.02.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/16/2023] [Accepted: 02/13/2023] [Indexed: 02/16/2023]
Abstract
Sensory hair cell (HC) injuries, especially outer hair cell (OHC) loss, are well-documented to be the primary pathology of age-related hearing loss (AHL). Recent studies have demonstrated that autophagy plays an important role in HC injury in the inner ear. In our previous works, a decline in autophagy levels and HC loss were found to occur simultaneously in the inner ears of aged C57BL/6 mice, and the administration of rapamycin promoted autophagy levels, which reduced OHC loss and delayed AHL, but the underlying mechanism of autophagy in AHL has not been well elucidated. Transcription factor EB (TFEB), an autophagy regulator and the downstream target of mammalian target of rapamycin (mTOR), is involved in the pathological development of neurodegenerative disease. This study would address the link between autophagy and TFEB in aged C57BL/6 mouse cochleae and clarify the effect of the TFEB activator curcumin analog C1 (C1) in aged cochleae. Decreased TFEB nuclear localization (p = 0.0371) and autophagy dysfunction (p = 0.0273) were observed in the cochleae of aged C57BL/6 mice that exhibited AHL, HCs loss and HCs senescence. Treatment with C1 promoted TFEB nuclear localization and restored autophagy, subsequently alleviating HC injury and delaying AHL. The protective effect of C1 on HEI-OC1 cells against autophagy disorder and aging induced by D-galactose was abolished by chloroquine, which is one of the commonly used autophagy inhibitors. Overall, our results demonstrated that the capacity to perform autophagy is mediated by the nuclear localization of TFEB in aged C57BL/6 mouse cochleae. C1 promotes the nuclear localization of TFEB, subsequently alleviating HC injury and delaying AHL by restoring the impaired autophagy function. TFEB may serve as a new therapeutic target for AHL treatment.
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Affiliation(s)
- Wuhui He
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Fan Wu
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Hao Xiong
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China
| | - Junbo Zeng
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China
| | - Yiming Gao
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ziyi Cai
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jiaqi Pang
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Yiqing Zheng
- Department of Otolaryngology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Institute of Hearing and Speech-Language Science, Sun Yat-sen University, Guangzhou, China.
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El-Azab MF, Wakiel AE, Nafea YK, Youssef ME. Role of cannabinoids and the endocannabinoid system in modulation of diabetic cardiomyopathy. World J Diabetes 2022; 13:387-407. [PMID: 35664549 PMCID: PMC9134026 DOI: 10.4239/wjd.v13.i5.387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 04/28/2022] [Indexed: 02/06/2023] Open
Abstract
Diabetic complications, chiefly seen in long-term situations, are persistently deleterious to a large extent, requiring multi-factorial risk reduction strategies beyond glycemic control. Diabetic cardiomyopathy is one of the most common deleterious diabetic complications, being the leading cause of mortality among diabetic patients. The mechanisms of diabetic cardiomyopathy are multi-factorial, involving increased oxidative stress, accumulation of advanced glycation end products (AGEs), activation of various pro-inflammatory and cell death signaling pathways, and changes in the composition of extracellular matrix with enhanced cardiac fibrosis. The novel lipid signaling system, the endocannabinoid system, has been implicated in the pathogenesis of diabetes and its complications through its two main receptors: Cannabinoid receptor type 1 and cannabinoid receptor type 2, alongside other components. However, the role of the endocannabinoid system in diabetic cardiomyopathy has not been fully investigated. This review aims to elucidate the possible mechanisms through which cannabinoids and the endocannabinoid system could interact with the pathogenesis and the development of diabetic cardiomyopathy. These mechanisms include oxidative/ nitrative stress, inflammation, accumulation of AGEs, cardiac remodeling, and autophagy. A better understanding of the role of cannabinoids and the endocannabinoid system in diabetic cardiomyopathy may provide novel strategies to manipulate such a serious diabetic complication.
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Affiliation(s)
- Mona F El-Azab
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Ahmed E Wakiel
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Yossef K Nafea
- Program of Biochemistry, McMaster University, Hamilton L8S 4L8, Ontario, Canada
| | - Mahmoud E Youssef
- Department of Pharmacology and Biochemistry, Delta University for Science and Technology, Mansoura 35511, New Cairo, Egypt
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3
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Post-Translational Modifications of ATG4B in the Regulation of Autophagy. Cells 2022; 11:cells11081330. [PMID: 35456009 PMCID: PMC9025542 DOI: 10.3390/cells11081330] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 11/16/2022] Open
Abstract
Autophagy plays a key role in eliminating and recycling cellular components in response to stress, including starvation. Dysregulation of autophagy is observed in various diseases, including neurodegenerative diseases, cancer, and diabetes. Autophagy is tightly regulated by autophagy-related (ATG) proteins. Autophagy-related 4 (ATG4) is the sole cysteine protease, and four homologs (ATG4A–D) have been identified in mammals. These proteins have two domains: catalytic and short fingers. ATG4 facilitates autophagy by promoting autophagosome maturation through reversible lipidation and delipidation of seven autophagy-related 8 (ATG8) homologs, including microtubule-associated protein 1-light chain 3 (LC3) and GABA type A receptor-associated protein (GABARAP). Each ATG4 homolog shows a preference for a specific ATG8 homolog. Post-translational modifications of ATG4, including phosphorylation/dephosphorylation, O-GlcNAcylation, oxidation, S-nitrosylation, ubiquitination, and proteolytic cleavage, regulate its activity and ATG8 processing, thus modulating its autophagic activity. We reviewed recent advances in our understanding of the effect of post-translational modification on the regulation, activity, and function of ATG4, the main protease that controls autophagy.
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Zavadskiy S, Sologova S, Moldogazieva N. Oxidative distress in aging and age-related diseases: Spatiotemporal dysregulation of protein oxidation and degradation. Biochimie 2022; 195:114-134. [PMID: 34890732 DOI: 10.1016/j.biochi.2021.12.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 12/03/2021] [Accepted: 12/04/2021] [Indexed: 12/31/2022]
Abstract
The concept of oxidative distress had arisen from the assessment of cellular response to high concentrations of reactive species that result from an imbalance between oxidants and antioxidants and cause biomolecular damage. The intracellular distribution and flux of reactive species dramatically change in time and space contributing to the remodeling of the redox landscape and sensitivity of protein residues to oxidants. Here, we hypothesize that compromised spatiotemporal control of generation, conversions, and removal of reactive species underlies protein damage and dysfunction of protein degradation machineries. This leads to the accumulation of oxidatively damaged proteins resulted in an age-dependent decline in the organismal adaptability to oxidative stress. We highlight recent data obtained with the use of various cell cultures, animal models, and patients on irreversible and non-repairable oxidation of key redox-sensitive residues. Multiple reaction products include peptidyl hydroperoxides, alcohols, carbonyls, and carbamoyl moieties as well as Tyr-Tyr, Trp-Tyr, Trp-Trp, Tyr-Cys, His-Lys, His-Arg, and Tyr-Lys cross-links. These lead to protein fragmentation, misfolding, covalent cross-linking, oligomerization, aggregation, and ultimately, causing impaired protein function and turnover. 20S proteasome and autophagy-lysosome pathways are two major types of machinery for the degradation and elimination of oxidatively damaged proteins. Spatiotemporal dysregulation of these pathways under oxidative distress conditions is implicated in aging and age-related disorders such as neurodegenerative and cardiovascular diseases and diabetes. Future investigations in this field allow the discovery of new drugs to target components of dysregulated cell signaling and protein degradation machinery to combat aging and age-related chronic diseases.
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Affiliation(s)
- Sergey Zavadskiy
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University, Sechenov University, 119991, Moscow, Russia
| | - Susanna Sologova
- Department of Pharmacology, Nelyubin Institute of Pharmacy, I.M. Sechenov First Moscow State Medical University, Sechenov University, 119991, Moscow, Russia
| | - Nurbubu Moldogazieva
- Laboratory of Bioinformatics, Institute of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University, Sechenov University, 119991, Moscow, Russia.
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5
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Xia F, Fu Y, Xie H, Chen Y, Fang D, Zhang W, Liu P, Li M. Suppression of ATG4B by copper inhibits autophagy and involves in Mallory body formation. Redox Biol 2022; 52:102284. [PMID: 35349929 PMCID: PMC8965161 DOI: 10.1016/j.redox.2022.102284] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/01/2022] [Accepted: 03/10/2022] [Indexed: 12/19/2022] Open
Abstract
Autophagy is an evolutionarily conserved self-protecting mechanism implicated in cellular homeostasis. ATG4B plays a vital role in autophagy process via undertaking priming and delipidation of LC3. Chemical inhibitors and regulative modifications such as oxidation of ATG4B have been demonstrated to modulate autophagy function. Whether and how ATG4B could be regulated by metal ions is largely unknown. Copper is an essential trace metal served as static co-factors in redox reactions in physiology process. Excessive accumulation of copper in ATP7B mutant cells leads to pathology progression such as insoluble Mallory body (MB) in Wilson disease (WD). The clearance of MB via autophagy pathway was thought as a promising strategy for WD. Here, we discovered that copper ion instead of other ions could inhibit the activity of ATG4B followed by autophagy suppression. In addition, copper could induce ATG4B oligomers depending on cysteine oxidation which could be abolished in reduced condition. Copper also promotes the formation of insoluble ATG4B aggregates, as well as p62-and ubiquitin-positive aggregates, which is consistent with the components of MB caused by copper overload in WD cell model. Importantly, overexpression of ATG4B could partially reduce the formation of MB and rescue impaired autophagy. Taken together, our results uncovered for the first time a new damage mechanism mediated by copper and implied new insights of the crosstalk between the toxicity of copper and autophagy in the pathogenesis of WD.
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Affiliation(s)
- Fan Xia
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Yuanyuan Fu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Huazhong Xie
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Yuxin Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Dongmei Fang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Wei Zhang
- Laboratory Animal Center, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Peiqing Liu
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006, China
| | - Min Li
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, National and Local Joint Engineering Laboratory of Druggability and New Drugs Evaluation, Guangdong Engineering Laboratory of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510006, China.
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6
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Peña-Oyarzún D, San Martin C, Hernández-Cáceres MP, Lavandero S, Morselli E, Budini M, Burgos PV, Criollo A. Autophagy in aging-related oral diseases. Front Endocrinol (Lausanne) 2022; 13:903836. [PMID: 35992149 PMCID: PMC9390882 DOI: 10.3389/fendo.2022.903836] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Abstract
Autophagy is an intracellular degradation mechanism that allows recycling of organelles and macromolecules. Autophagic function increases metabolite availability modulating metabolic pathways, differentiation and cell survival. The oral environment is composed of several structures, including mineralized and soft tissues, which are formed by complex interactions between epithelial and mesenchymal cells. With aging, increased prevalence of oral diseases such as periodontitis, oral cancer and periapical lesions are observed in humans. These aging-related oral diseases are chronic conditions that alter the epithelial-mesenchymal homeostasis, disrupting the oral tissue architecture affecting the quality of life of the patients. Given that autophagy levels are reduced with age, the purpose of this review is to discuss the link between autophagy and age-related oral diseases.
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Affiliation(s)
- Daniel Peña-Oyarzún
- Physiology Department, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile
- Interdisciplinary Center for Research in Territorial Health of the Aconcagua Valley (CIISTe Aconcagua), School of Medicine, Faculty of Medicine, San Felipe Campus, Universidad de Valparaíso, San Felipe, Chile
- Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - Carla San Martin
- Interdisciplinary Center for Research in Territorial Health of the Aconcagua Valley (CIISTe Aconcagua), School of Medicine, Faculty of Medicine, San Felipe Campus, Universidad de Valparaíso, San Felipe, Chile
| | - María Paz Hernández-Cáceres
- Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile
| | - Sergio Lavandero
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- Cardiology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Eugenia Morselli
- Department of Basic Sciences, Faculty of Medicine and Sciences, Universidad San Sebastián, Santiago de Chile, Chile
- Autophagy Research Center, Universidad de Chile, Santiago de Chile, Chile
| | - Mauricio Budini
- Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile
- Autophagy Research Center, Universidad de Chile, Santiago de Chile, Chile
| | - Patricia V. Burgos
- Autophagy Research Center, Universidad de Chile, Santiago de Chile, Chile
- Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile
- Centro de Envejecimiento y Regeneración (CARE-UC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica, Santiago, Chile
- Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago, Chile
| | - Alfredo Criollo
- Instituto de Investigación en Ciencias Odontológicas (ICOD), Facultad de Odontología, Universidad de Chile, Santiago, Chile
- Advanced Center for Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, Chile
- Autophagy Research Center, Universidad de Chile, Santiago de Chile, Chile
- *Correspondence: Alfredo Criollo,
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Over Fifty Years of Life, Death, and Cannibalism: A Historical Recollection of Apoptosis and Autophagy. Int J Mol Sci 2021; 22:ijms222212466. [PMID: 34830349 PMCID: PMC8618802 DOI: 10.3390/ijms222212466] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/02/2021] [Accepted: 11/03/2021] [Indexed: 01/18/2023] Open
Abstract
Research in biomedical sciences has changed dramatically over the past fifty years. There is no doubt that the discovery of apoptosis and autophagy as two highly synchronized and regulated mechanisms in cellular homeostasis are among the most important discoveries in these decades. Along with the advancement in molecular biology, identifying the genetic players in apoptosis and autophagy has shed light on our understanding of their function in physiological and pathological conditions. In this review, we first describe the history of key discoveries in apoptosis with a molecular insight and continue with apoptosis pathways and their regulation. We touch upon the role of apoptosis in human health and its malfunction in several diseases. We discuss the path to the morphological and molecular discovery of autophagy. Moreover, we dive deep into the precise regulation of autophagy and recent findings from basic research to clinical applications of autophagy modulation in human health and illnesses and the available therapies for many diseases caused by impaired autophagy. We conclude with the exciting crosstalk between apoptosis and autophagy, from the early discoveries to recent findings.
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8
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Mu Q, Lv Y, Luo C, Liu X, Huang C, Xiu Y, Tang L. Research Progress on the Functions and Mechanism of circRNA in Cisplatin Resistance in Tumors. Front Pharmacol 2021; 12:709324. [PMID: 34566636 PMCID: PMC8458655 DOI: 10.3389/fphar.2021.709324] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 08/30/2021] [Indexed: 12/24/2022] Open
Abstract
Cisplatin is a common chemotherapeutic drug that has been used to treat of numerous tumors, including testicular, lung, bladder, ovarian, liver and head and neck cancers. Although clinical chemotherapy based on cisplatin has shown a remarkable therapeutic effect, the resistance to cisplatin becomes increasingly obvious as a patient uses it for a prolonged period. It not only affects the prognosis of these tumors, but also causes the recurrence of cancer and decreases the overall survival rate. The development of cisplatin resistance involves several mechanisms, including DNA damage repair, ATP-binding cassette (ABC) transporter, autophagy, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), and other related signaling pathways. Interestingly, these mechanisms have been found to be influenced by circular RNAs (circRNAs) to regulate tumor proliferation, invasion, chemosensitivity, and other biological behaviors in the tumor microenvironment (TME). In recent years, circRNAs in cisplatin resistance in tumors, especially lung cancer and gastric cancer, have gradually drawn peoples' attention. This review summarizes recent studies on the functions and mechanisms of circRNAs in cisplatin resistance. We emphasize that circRNA can be used as a promising target gene to improve drug resistance and therapeutic efficacy.
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Affiliation(s)
- Qingchun Mu
- The People’s Hospital of Gaozhou, Gaozhou, China
| | - Yue Lv
- Department of Urology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Chunmei Luo
- The People’s Hospital of Gaozhou, Gaozhou, China
| | - Xiaojing Liu
- The People’s Hospital of Gaozhou, Gaozhou, China
| | | | - Youcheng Xiu
- Department of Urology, The First Affiliated Hospital, Harbin Medical University, Harbin, China
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Prasanth MI, Malar DS, Tencomnao T, Brimson JM. The emerging role of the sigma-1 receptor in autophagy: hand-in-hand targets for the treatment of Alzheimer's. Expert Opin Ther Targets 2021; 25:401-414. [PMID: 34110944 DOI: 10.1080/14728222.2021.1939681] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 06/03/2021] [Indexed: 01/18/2023]
Abstract
INTRODUCTION Autophagy is a cellular catabolic mechanism that helps clear damaged cellular components and is essential for normal cellular and tissue function. The sigma-1 receptor (σ-1R) is a chaperone protein involved in signal transduction, neurite outgrowth, and plasticity, improving memory, and neuroprotection. Recent evidence shows that σ-1R can promote autophagy. Autophagy activation by the σ-1Rs along with other neuroprotective effects makes it an interesting target for the treatment of Alzheimer's disease. AF710B, T-817 MA, and ANAVEX2-73 are some of the σ-1R agonists which have shown promising results and have entered clinical trials. These molecules have also been found to induce autophagy and show cytoprotective effects in cellular models. AREAS COVERED This review provides insight into the current understanding of σ-1R functions related to autophagy and their role in alleviating AD. EXPERT OPINION We propose a mechanism through which the activation of σ-1R and autophagy could alter amyloid precursor protein processing to inhibit amyloid-β production by reconstituting cholesterol and gangliosides in the lipid raft to offer neuroprotection against AD. Future AD treatment could involve the combined targeting of the σ-1R and autophagy activation. We suggest that future studies investigate the link between autophagy the σ-1R and AD.
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Affiliation(s)
- Mani Iyer Prasanth
- Natural Products for Neuroprotection and Anti-ageing Research Unit, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Dicson Sheeja Malar
- Natural Products for Neuroprotection and Anti-ageing Research Unit, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - Tewin Tencomnao
- Natural Products for Neuroprotection and Anti-ageing Research Unit, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
| | - James Michael Brimson
- Natural Products for Neuroprotection and Anti-ageing Research Unit, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
- Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok, Thailand
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10
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Wang YL, Zheng CM, Lee YH, Cheng YY, Lin YF, Chiu HW. Micro- and Nanosized Substances Cause Different Autophagy-Related Responses. Int J Mol Sci 2021; 22:4787. [PMID: 33946416 PMCID: PMC8124422 DOI: 10.3390/ijms22094787] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/27/2021] [Accepted: 04/29/2021] [Indexed: 02/07/2023] Open
Abstract
With rapid industrialization, humans produce an increasing number of products. The composition of these products is usually decomposed. However, some substances are not easily broken down and gradually become environmental pollutants. In addition, these substances may cause bioaccumulation, since the substances can be fragmented into micro- and nanoparticles. These particles or their interactions with other toxic matter circulate in humans via the food chain or air. Whether these micro- and nanoparticles interfere with extracellular vesicles (EVs) due to their similar sizes is unclear. Micro- and nanoparticles (MSs and NSs) induce several cell responses and are engulfed by cells depending on their size, for example, particulate matter with a diameter ≤2.5 μm (PM2.5). Autophagy is a mechanism by which pathogens are destroyed in cells. Some artificial materials are not easily decomposed in organisms. How do these cells or tissues respond? In addition, autophagy operates through two pathways (increasing cell death or cell survival) in tumorigenesis. Many MSs and NSs have been found that induce autophagy in various cells and tissues. As a result, this review focuses on how these particles interfere with cells and tissues. Here, we review MSs, NSs, and PM2.5, which result in different autophagy-related responses in various tissues or cells.
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Affiliation(s)
- Yung-Li Wang
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-L.W.); (Y.-F.L.)
| | - Cai-Mei Zheng
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan;
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Yu-Hsuan Lee
- Department of Cosmeceutics, China Medical University, Taichung 406040, Taiwan;
| | - Ya-Yun Cheng
- Department of Environmental Health, Harvard University T.H. Chan School of Public Health, Boston, MA 02115, USA;
| | - Yuh-Feng Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-L.W.); (Y.-F.L.)
- Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan;
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
| | - Hui-Wen Chiu
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (Y.-L.W.); (Y.-F.L.)
- TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
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11
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Moss JJ, Hammond CL, Lane JD. Zebrafish as a model to study autophagy and its role in skeletal development and disease. Histochem Cell Biol 2020; 154:549-564. [PMID: 32915267 PMCID: PMC7609422 DOI: 10.1007/s00418-020-01917-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2020] [Indexed: 12/13/2022]
Abstract
In the last twenty years, research using zebrafish as a model organism has increased immensely. With the many advantages that zebrafish offer such as high fecundity, optical transparency, ex vivo development, and genetic tractability, they are well suited to studying developmental processes and the effect of genetic mutations. More recently, zebrafish models have been used to study autophagy. This important protein degradation pathway is needed for cell and tissue homeostasis in a variety of contexts. Correspondingly, its dysregulation has been implicated in multiple diseases including skeletal disorders. In this review, we explore how zebrafish are being used to study autophagy in the context of skeletal development and disease, and the ways these areas are intersecting to help identify potential therapeutic targets for skeletal disorders.
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Affiliation(s)
- Joanna J Moss
- School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol, UK.,School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol, UK
| | - Chrissy L Hammond
- School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, University of Bristol, Bristol, UK.
| | - Jon D Lane
- School of Biochemistry, Biomedical Sciences Building, University of Bristol, Bristol, UK.
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12
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Humbert M, Morán M, de la Cruz-Ojeda P, Muntané J, Wiedmer T, Apostolova N, McKenna SL, Velasco G, Balduini W, Eckhart L, Janji B, Sampaio-Marques B, Ludovico P, Žerovnik E, Langer R, Perren A, Engedal N, Tschan MP. Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot. BIOLOGY 2020; 9:E59. [PMID: 32245178 PMCID: PMC7150830 DOI: 10.3390/biology9030059] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 03/18/2020] [Accepted: 03/19/2020] [Indexed: 12/14/2022]
Abstract
Autophagy is a highly conserved degradation mechanism that is essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there is immense interest in targeting autophagy for therapeutic approaches. Accordingly, there is a need to determine autophagic activity in human tissues, an endeavor that is hampered by the fact that autophagy is characterized by the flux of substrates whereas histology informs only about amounts and localization of substrates and regulators at a single timepoint. Despite this challenging task, considerable progress in establishing markers of autophagy has been made in recent years. The importance of establishing clear-cut autophagy markers that can be used for tissue analysis cannot be underestimated. In this review, we attempt to summarize known techniques to quantify autophagy in human tissue and their drawbacks. Furthermore, we provide some recommendations that should be taken into consideration to improve the reliability and the interpretation of autophagy biomarkers in human tissue samples.
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Grants
- none Bernese Cancer League
- none Stiftung für klinisch-experimentelle Tumorforschung
- none Werner and Hedy Berger-Janser Foundation for Cancer Research
- PI14/01085 and PI17/00093 FIS and FEDER funds from the EU
- CPII16/00023 ISCIII and FSE funds
- RTI2018-096748-B-100 the Spanish Minsitry of Science, Innovation and Universities
- none University Professor Training Fellowship, Ministry of Science, Innovation and University, Government of Spain
- PI18/00442 the State Plan for R & D + I2013-2016 and funded by the Instituto de Salud Carlos III
- none European Regional Development Fund
- C18/BM/12670304/COMBATIC Luxembourg National Research Fund
- NORTE-01-0145-FEDER-000013 Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, by the European Regional Development Fund (FEDER), through the Competitiveness Factors Operational Programme (COMPETE)
- POCI-01-0145-FEDER-028159 and POCI-01-0145-FEDER-030782 FEDER, through the COMPETE
- none National funds, through the Foundation for Science and Technology (FCT
- none ARRS - the Slovenian research agency, programme P1-0140: Proteolysis and its regulation
- KFS-3360-02-2014 the Swiss Cancer Research
- KFS-3409-02-2014 the Swiss Cancer Research
- 31003A_173219 Swiss National Science Foundation
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Affiliation(s)
- Magali Humbert
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
| | - María Morán
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Mitochondrial and Neuromuscular Diseases Laboratory, Instituto de Investigación Sanitaria Hospital ‘12 de Octubre’ (‘imas12’), 28041 Madrid, Spain
- Spanish Network for Biomedical Research in Rare Diseases (CIBERER), U723, Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
| | - Patricia de la Cruz-Ojeda
- Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Seville, Spain;
- Department of Surgery, School of Medicine, University of Seville, 41009 Seville, Spain
| | - Jordi Muntané
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Institute of Biomedicine of Seville (IBiS), Hospital University “Virgen del Rocío”/CSIC/University of Seville, 41013 Seville, Spain;
- Department of Surgery, School of Medicine, University of Seville, 41009 Seville, Spain
- Spanish Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
| | - Tabea Wiedmer
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
| | - Nadezda Apostolova
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Spanish Network for Biomedical Research in Hepatic and Digestive Diseases (CIBERehd), Institute of Health Carlos III (ISCIII), 28029 Madrid, Spain
- Department of Pharmacology, University of Valencia, 46010 Valencia, Spain
| | - Sharon L. McKenna
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Cancer Research at UCC, Western Gateway Building, University College Cork, T12 XF62 Cork, Ireland
| | - Guillermo Velasco
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Biochemistry and Molecular Biology, School of Biology, Complutense University, and Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Walter Balduini
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61029 Urbino, Italy
| | - Leopold Eckhart
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Dermatology, Medical University of Vienna, Vienna 1090, Austria
| | - Bassam Janji
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Tumor Immunotherapy and Microenvironment (TIME) Group, Department of Oncology—Luxembourg Institute of Health, 1526 Luxembourg City, Luxembourg
| | - Belém Sampaio-Marques
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Paula Ludovico
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal
- ICVS/3B’s—PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Eva Žerovnik
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Biochemistry and Molecular and Structural Biology, Jožef Stefan Institute, 1000 Ljubljana, Slovenia
| | - Rupert Langer
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
| | - Aurel Perren
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
| | - Nikolai Engedal
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway
| | - Mario P. Tschan
- TRANSAUTOPHAGY: European Network for Multidisciplinary Research and Translation of Autophagy Knowledge, COST Action CA15138, 08193 Barcelona, Spain; (M.M.); (J.M.); (N.A.); (S.L.M.); (G.V.); (W.B.); (L.E.); (B.J.); (B.S.-M.); (P.L.); (E.Ž.); (N.E.)
- Institute of Pathology, University of Bern, Murtenstrasse 31, CH-3008 Bern, Switzerland; (T.W.); (R.L.); (A.P.)
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13
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Gusev EY, Zotova NV. Cellular Stress and General Pathological Processes. Curr Pharm Des 2020; 25:251-297. [PMID: 31198111 DOI: 10.2174/1381612825666190319114641] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 03/13/2019] [Indexed: 02/06/2023]
Abstract
From the viewpoint of the general pathology, most of the human diseases are associated with a limited number of pathogenic processes such as inflammation, tumor growth, thrombosis, necrosis, fibrosis, atrophy, pathological hypertrophy, dysplasia and metaplasia. The phenomenon of chronic low-grade inflammation could be attributed to non-classical forms of inflammation, which include many neurodegenerative processes, pathological variants of insulin resistance, atherosclerosis, and other manifestations of the endothelial dysfunction. Individual and universal manifestations of cellular stress could be considered as a basic element of all these pathologies, which has both physiological and pathophysiological significance. The review examines the causes, main phenomena, developmental directions and outcomes of cellular stress using a phylogenetically conservative set of genes and their activation pathways, as well as tissue stress and its role in inflammatory and para-inflammatory processes. The main ways towards the realization of cellular stress and its functional blocks were outlined. The main stages of tissue stress and the classification of its typical manifestations, as well as its participation in the development of the classical and non-classical variants of the inflammatory process, were also described. The mechanisms of cellular and tissue stress are structured into the complex systems, which include networks that enable the exchange of information with multidirectional signaling pathways which together make these systems internally contradictory, and the result of their effects is often unpredictable. However, the possible solutions require new theoretical and methodological approaches, one of which includes the transition to integral criteria, which plausibly reflect the holistic image of these processes.
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Affiliation(s)
- Eugeny Yu Gusev
- Laboratory of the Immunology of Inflammation, Institute of Immunology and Physiology, Yekaterinburg, Russian Federation
| | - Natalia V Zotova
- Laboratory of the Immunology of Inflammation, Institute of Immunology and Physiology, Yekaterinburg, Russian Federation.,Department of Medical Biochemistry and Biophysics, Ural Federal University named after B.N.Yeltsin, Yekaterinburg, Russian Federation
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14
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Hou G, Bai Y, Jia A, Ren Y, Wang Y, Lu J, Wang P, Zhang J, Lu Z. Inhibition of autophagy improves resistance and enhances sensitivity of gastric cancer cells to cisplatin. Can J Physiol Pharmacol 2020; 98:449-458. [PMID: 32058824 DOI: 10.1139/cjpp-2019-0477] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Autophagy plays critical roles in tumorigenesis, while the effects of autophagy on chemoresistance of cancer cells had great disparity. This study aims to explore the impacts of autophagy on the sensitivity and resistance of gastric cancer cells to cisplatin (DDP). We firstly demonstrated that there was stronger autophagy activity in gastric cancer SGC-7901 cells than that in DDP-resisting SGC-7901/DDP cells. Then, we discovered that inhibiting autophagy by chloroquine (CQ) significantly enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP to SGC-7901 and SGC-7901/DDP cells. Moreover, CQ could partially reverse the resistance of SGC-7901/DDP cells to DDP in a concentration-dependent manner. However, the autophagy inducer everolimus (RAD001) had no obvious effects on the sensitivity of gastric cells to DDP. Mechanistically, we demonstrated that CQ might enhance the sensitivity of SGC-7901cells and improve the resistance of SGC-7901/DDP cells to DDP through inhibiting the mTORC1 pathway, especially to SGC-7901/DDP cells. Additionally, we found interfering Beclin-1 using Beclin-1 shRNA also enhanced the proliferation-inhibiting and apoptosis-inducing effects of DDP on gastric cancer cells by inhibiting phosphorylation of Akt. Our study shows that inhibiting autophagy could improve the chemoresistance and enhanced sensitivity of gastric cancer cells to DDP and provide a rationale for the administration of cisplatin combined with CQ for treating patients with gastric cancer.
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Affiliation(s)
- Guiqin Hou
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China
| | - Yiru Bai
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China.,First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471000, People's Republic of China
| | - Ang Jia
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China
| | - Yandan Ren
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China
| | - Yang Wang
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China
| | - Jie Lu
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China
| | - Peng Wang
- College of Public Health, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China
| | - Jianying Zhang
- Henan Academy of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China
| | - Zhaoming Lu
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan 450001, People's Republic of China.,Collaborative Innovation Center of Cancer Chemoprevention, Henan Province, Zhengzhou 450001, People's Republic of China
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15
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Albanese F, Novello S, Morari M. Autophagy and LRRK2 in the Aging Brain. Front Neurosci 2019; 13:1352. [PMID: 31920513 PMCID: PMC6928047 DOI: 10.3389/fnins.2019.01352] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 12/02/2019] [Indexed: 12/20/2022] Open
Abstract
Autophagy is a highly conserved process by which long-lived macromolecules, protein aggregates and dysfunctional/damaged organelles are delivered to lysosomes for degradation. Autophagy plays a crucial role in regulating protein quality control and cell homeostasis in response to energetic needs and environmental challenges. Indeed, activation of autophagy increases the life-span of living organisms, and impairment of autophagy is associated with several human disorders, among which neurodegenerative disorders of aging, such as Parkinson’s disease. These disorders are characterized by the accumulation of aggregates of aberrant or misfolded proteins that are toxic for neurons. Since aging is associated with impaired autophagy, autophagy inducers have been viewed as a strategy to counteract the age-related physiological decline in brain functions and emergence of neurodegenerative disorders. Parkinson’s disease is a hypokinetic, multisystemic disorder characterized by age-related, progressive degeneration of central and peripheral neuronal populations, associated with intraneuronal accumulation of proteinaceous aggregates mainly composed by the presynaptic protein α-synuclein. α-synuclein is a substrate of macroautophagy and chaperone-mediated autophagy (two major forms of autophagy), thus impairment of its clearance might favor the process of α-synuclein seeding and spreading that trigger and sustain the progression of this disorder. Genetic factors causing Parkinson’s disease have been identified, among which mutations in the LRRK2 gene, which encodes for a multidomain protein encompassing central GTPase and kinase domains, surrounded by protein-protein interaction domains. Six LRRK2 mutations have been pathogenically linked to Parkinson’s disease, the most frequent being the G2019S in the kinase domain. LRRK2-associated Parkinson’s disease is clinically and neuropathologically similar to idiopathic Parkinson’s disease, also showing age-dependency and incomplete penetrance. Several mechanisms have been proposed through which LRRK2 mutations can lead to Parkinson’s disease. The present article will focus on the evidence that LRRK2 and its mutants are associated with autophagy dysregulation. Studies in cell lines and neurons in vitro and in LRRK2 knock-out, knock-in, kinase-dead and transgenic animals in vivo will be reviewed. The role of aging in LRRK2-induced synucleinopathy will be discussed. Possible mechanisms underlying the LRRK2-mediated control over autophagy will be analyzed, and the contribution of autophagy dysregulation to the neurotoxic actions of LRRK2 will be examined.
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Affiliation(s)
- Federica Albanese
- Section of Pharmacology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Salvatore Novello
- Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Michele Morari
- Section of Pharmacology, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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16
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The Emerging Roles of mTORC1 in Macromanaging Autophagy. Cancers (Basel) 2019; 11:cancers11101422. [PMID: 31554253 PMCID: PMC6826502 DOI: 10.3390/cancers11101422] [Citation(s) in RCA: 201] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 09/22/2019] [Accepted: 09/23/2019] [Indexed: 01/18/2023] Open
Abstract
Autophagy is a process of self-degradation that enables the cell to survive when faced with starvation or stressful conditions. The mechanistic target of rapamycin (mTOR), also known as the mammalian target of rapamycin, plays a critical role in maintaining a balance between cellular anabolism and catabolism. mTOR complex 1 (mTORC1) was unveiled as a master regulator of autophagy since inhibition of mTORC1 was required to initiate the autophagy process. Evidence has emerged in recent years to indicate that mTORC1 also directly regulates the subsequent steps of the autophagy process, including the nucleation, autophagosome elongation, autophagosome maturation and termination. By phosphorylating select protein targets of the autophagy core machinery and/or their regulators, mTORC1 can alter their functions, increase their proteasomal degradation or modulate their acetylation status, which is a key switch of the autophagy process. Moreover, it phosphorylates and alters the subcellular localization of transcription factors to suppress the expression of genes needed for autophagosome formation and lysosome biogenesis. The purpose of this review article is to critically analyze current literatures to provide an integrated view of how mTORC1 regulates various steps of the autophagy process.
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17
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Nilangekar K, Murmu N, Sahu G, Shravage BV. Generation and Characterization of Germline-Specific Autophagy and Mitochondrial Reactive Oxygen Species Reporters in Drosophila. Front Cell Dev Biol 2019; 7:47. [PMID: 31001531 PMCID: PMC6456670 DOI: 10.3389/fcell.2019.00047] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Accepted: 03/15/2019] [Indexed: 12/12/2022] Open
Abstract
Oogenesis is a fundamental process that forms the egg and, is crucial for the transmission of genetic information to the next generation. Drosophila oogenesis has been used extensively as a genetically tractable model to study organogenesis, niche-germline stem cell communication, and more recently reproductive aging including germline stem cell (GSC) aging. Autophagy, a lysosome-mediated degradation process, is implicated in gametogenesis and aging. However, there is a lack of genetic tools to study autophagy in the context of gametogenesis and GSC aging. Here we describe the generation of three transgenic lines mcherry-Atg8a, GFP-Ref(2)P and mito-roGFP2-Orp1 that are specifically expressed in the germline compartment including GSCs during Drosophila oogenesis. These transgenes are expressed from the nanos promoter and present a better alternative to UASp mediated overexpression of transgenes. These fluorescent reporters can be used to monitor and quantify autophagy, and the production of reactive oxygen species during oogenesis. These reporters provide a valuable tool that can be utilized in designing genetic screens to identify novel regulators of autophagy and redox homeostasis during oogenesis.
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Affiliation(s)
- Kiran Nilangekar
- Developmental Biology Group, Agharkar Research Institute, Pune, India.,Department of Biotechnology, Savitribai Phule Pune University (SPPU), Pune, India
| | - Nidhi Murmu
- Developmental Biology Group, Agharkar Research Institute, Pune, India.,Department of Biotechnology, Savitribai Phule Pune University (SPPU), Pune, India
| | - Govind Sahu
- Developmental Biology Group, Agharkar Research Institute, Pune, India
| | - Bhupendra V Shravage
- Developmental Biology Group, Agharkar Research Institute, Pune, India.,Department of Biotechnology, Savitribai Phule Pune University (SPPU), Pune, India
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18
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Nissar AU, Sharma L, Mudasir MA, Nazir LA, Umar SA, Sharma PR, Vishwakarma RA, Tasduq SA. Chemical chaperone 4-phenyl butyric acid (4-PBA) reduces hepatocellular lipid accumulation and lipotoxicity through induction of autophagy. J Lipid Res 2017; 58:1855-1868. [PMID: 28655725 PMCID: PMC5580899 DOI: 10.1194/jlr.m077537] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 06/22/2017] [Indexed: 12/11/2022] Open
Abstract
Defective autophagy has been linked to lipotoxicity in several cellular models. We aimed to investigate autophagy in lipid-stimulated hepatoma (Huh7) cells and tested whether 4-phenyl butyric acid (4-PBA), a chemical chaperone, has a beneficial role in hepatic fat accumulation and lipotoxicity. We report that long-term (24 h) exposure of hepatocytes to palmitate block autophagic flux that leads to lipid accumulation and cell death. Western blotting analysis showed increased accumulation of SQSTM1/p62, and decreased expression of Beclin1 and Atg7 in palmitate-treated cells. Autophagy inhibition by 3-methyladenine (3-MA) in palmitate-treated cells neither increased SQSTMI/p62 accumulation nor cell death, thus suggesting complete blockade of autophagy by palmitate. 4-PBA reduced lipid accumulation and cell death that were associated with restoration of autophagy. siRNA-mediated knockdown of Atg7 and presence of autophagy inhibitors, 3-MA and chloroquine, resulted in the decrease in lipid-lowering effect of 4-PBA, suggesting that 4-PBA mediates its lipid-lowering effect via autophagy. Apoptotic parameters, including altered Bcl2:Bax ratio and PARP1 cleavage induced by palmitate, were improved by 4-PBA. Our results indicate that palmitate impairs autophagy and increases lipid accumulation in Huh7 cells, whereas 4-PBA plays a protective role in lipid accumulation and lipotoxicity through activation of autophagy.
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Affiliation(s)
- Ashraf U Nissar
- Academy of Scientific and Innovative Research, Jammu Campus, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India; Pharmacokinetic-Pharmacodynamic and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India
| | - Love Sharma
- Academy of Scientific and Innovative Research, Jammu Campus, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India; Pharmacokinetic-Pharmacodynamic and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India
| | - Malik A Mudasir
- Pharmacokinetic-Pharmacodynamic and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India
| | - Lone A Nazir
- Academy of Scientific and Innovative Research, Jammu Campus, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India; Pharmacokinetic-Pharmacodynamic and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India
| | - Sheikh A Umar
- Pharmacokinetic-Pharmacodynamic and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India
| | - Parduman R Sharma
- Pharmacokinetic-Pharmacodynamic and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India
| | - Ram A Vishwakarma
- Academy of Scientific and Innovative Research, Jammu Campus, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India; Pharmacokinetic-Pharmacodynamic and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India
| | - Sheikh A Tasduq
- Academy of Scientific and Innovative Research, Jammu Campus, Council of Scientific and Industrial Research (CSIR)-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India; Pharmacokinetic-Pharmacodynamic and Toxicology Division, CSIR-Indian Institute of Integrative Medicine, Jammu Tawi, Jammu and Kashmir, India.
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19
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Li YJ, Lei YH, Yao N, Wang CR, Hu N, Ye WC, Zhang DM, Chen ZS. Autophagy and multidrug resistance in cancer. CHINESE JOURNAL OF CANCER 2017. [PMID: 28646911 PMCID: PMC5482965 DOI: 10.1186/s40880-017-0219-2] [Citation(s) in RCA: 510] [Impact Index Per Article: 63.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Multidrug resistance (MDR) occurs frequently after long-term chemotherapy, resulting in refractory cancer and tumor recurrence. Therefore, combatting MDR is an important issue. Autophagy, a self-degradative system, universally arises during the treatment of sensitive and MDR cancer. Autophagy can be a double-edged sword for MDR tumors: it participates in the development of MDR and protects cancer cells from chemotherapeutics but can also kill MDR cancer cells in which apoptosis pathways are inactive. Autophagy induced by anticancer drugs could also activate apoptosis signaling pathways in MDR cells, facilitating MDR reversal. Therefore, research on the regulation of autophagy to combat MDR is expanding and is becoming increasingly important. We summarize advanced studies of autophagy in MDR tumors, including the variable role of autophagy in MDR cancer cells.
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Affiliation(s)
- Ying-Jie Li
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
| | - Yu-He Lei
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
| | - Nan Yao
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
| | - Chen-Ran Wang
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
| | - Nan Hu
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
| | - Wen-Cai Ye
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, P. R. China
| | - Dong-Mei Zhang
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, P. R. China.
| | - Zhe-Sheng Chen
- Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University, Guangzhou, 510632, Guangdong, P. R. China. .,Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
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20
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Abstract
Proteases target many substrates, triggering changes in distinct biological processes correlated with cell migration, EMT/EndMT and fibrosis. Extracellular protease activity, demonstrated by secreted and membrane-bound protease forms, leads to ECM degradation, activation of other proteases (i.e., proteolysis of nonactive zymogens), decomposition of cell-cell junctions, release of sequestered growth factors (TGF-β and VEGF), activation of signal proteins and receptors, degradation of inflammatory inhibitors or inflammation-related proteins, and changes in cell mechanosensing and motility. Intracellular proteases, mainly caspases and cathepsins, modulate lysosome activity and signal transduction pathways. Herein, we discuss the current knowledge on the multidimensional impact of proteases on the development of fibrosis.
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21
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Gil J, Pesz KA, Sąsiadek MM. May autophagy be a novel biomarker and antitumor target in colorectal cancer? Biomark Med 2016; 10:1081-1094. [PMID: 27626110 DOI: 10.2217/bmm-2016-0083] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Autophagy is a catabolic process associated with intracellular self-digestion of damaged organelles or redundant proteins enabling maintenance of cell homeostasis. It is accepted that impaired autophagy is closely linked to cancer development and has been extensively studied in a variety of malignancies including colorectal cancer (CRC) to elucidate its influence on carcinogenesis, metastasis and antitumor therapy response. CRC remains a great epidemiological problem because of poor 5-year survival and treatment resistance. Many studies concerning autophagy in CRC gave inconsistent and contradictory results, illustrating a multifaceted nature of this process. In this review, we focus on current knowledge of autophagy in CRC development to determinate its role as a potential prognostic and predictive biomarker as well as target in antitumor therapy.
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Affiliation(s)
- Justyna Gil
- Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
| | - Karolina A Pesz
- Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
| | - Maria M Sąsiadek
- Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
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22
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Autophagy induction targeting mTORC1 enhances Mycobacterium tuberculosis replication in HIV co-infected human macrophages. Sci Rep 2016; 6:28171. [PMID: 27302320 PMCID: PMC4908603 DOI: 10.1038/srep28171] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 05/31/2016] [Indexed: 12/30/2022] Open
Abstract
To survive and replicate in macrophages Mycobacterium tuberculosis (Mtb) has developed strategies to subvert host defence mechanisms, including autophagy. Autophagy induction has the potential to clear Mtb, but little is known about its effect during controlled tuberculosis and HIV co-infection. Mammalian target of rapamycin complex1 (mTORC1) inhibitors were used to induce autophagy in human macrophages pre-infected with HIV-1BaL and infected with a low dose of Mtb (co-infected), or single Mtb infected (single infected). The controlled Mtb infection was disrupted upon mTOR inhibition resulting in increased Mtb replication in a dose-dependent manner which was more pronounced during co-infection. The increased Mtb replication could be explained by the marked reduction in phagosome acidification upon mTOR inhibition. Autophagy stimulation targeting mTORC1 clearly induced a basal autophagy with flux that was unlinked to the subcellular environment of the Mtb vacuoles, which showed a concurrent suppression in acidification and maturation/flux. Overall our findings indicate that mTOR inhibition during Mtb or HIV/Mtb co-infection interferes with phagosomal maturation, thereby supporting mycobacterial growth during low-dose and controlled infection. Therefore pharmacological induction of autophagy through targeting of the canonical mTORC1-pathway should be handled with caution during controlled tuberculosis, since this could have serious consequences for patients with HIV/Mtb co-infection.
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23
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Ondrej M, Cechakova L, Durisova K, Pejchal J, Tichy A. To live or let die: Unclear task of autophagy in the radiosensitization battle. Radiother Oncol 2016; 119:265-75. [PMID: 26993419 DOI: 10.1016/j.radonc.2016.02.028] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Revised: 01/26/2016] [Accepted: 02/18/2016] [Indexed: 02/06/2023]
Abstract
Radiation-induced autophagy is believed to represent a radioprotective mechanism of cancer cells. Thus, its inhibition should support radiation treatment and increase its efficacy. On the other hand, there is evidence that radiation alone or in combination with various chemical agents can induce autophagy that results into increased cell death, especially within transformed apoptosis-resistant cells. In this paper, besides description of autophagic process and its relation to cancer and radiotherapy, we compared two contradictory radiosensitization approaches that employ inhibition and induction of autophagy. In spite of the classical concept based on cytoprotective model, there is a plethora of recently developed inducers of autophagy, which indicates the future trend in radiosensitization via modulation of autophagy. Because contemporary literature is conflicting and inconsistent in this respect, we reviewed the recent studies focused on enhancement of sensitivity of cancer cells toward radiation in regard to autophagy, revealing some striking discrepancies. The deeper the knowledge, the more complex this situation is. To interpret results of various studies correctly one has to take into account the methodology of autophagy assessment and also the fact that radiosensitization might be mediated by other than intrinsic mechanisms related to autophagy. Notwithstanding, targeting autophagy remains an attractive anti-tumor strategy.
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Affiliation(s)
- Martin Ondrej
- Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defense in Brno, Czech Republic
| | - Lucie Cechakova
- Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defense in Brno, Czech Republic
| | - Kamila Durisova
- Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defense in Brno, Czech Republic
| | - Jaroslav Pejchal
- Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defense in Brno, Czech Republic
| | - Ales Tichy
- Department of Radiobiology, Faculty of Military Health Sciences in Hradec Kralove, University of Defense in Brno, Czech Republic; Centre of Biomedical Research, University Hospital, Hradec Kralove, Czech Republic.
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24
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Dever SM, Rodriguez M, Lapierre J, Costin BN, El-Hage N. Differing roles of autophagy in HIV-associated neurocognitive impairment and encephalitis with implications for morphine co-exposure. Front Microbiol 2015. [PMID: 26217309 PMCID: PMC4491626 DOI: 10.3389/fmicb.2015.00653] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
We investigated the role of autophagy in HIV-infected subjects with neurocognitive impairment (NCI) ± HIV encephalitis (HIVE), many of which had a history of polysubstance abuse/dependence, using post-mortem brain tissues to determine whether differences in autophagy related factors may be more associated with NCI or NCI-encephalitis. Using qRT-PCR, we detected significant differences in gene expression levels with SQSTM1, LAMP1 higher in HIV-infected subjects without NCI while ATG5, SQSTM1 were then lower in HIV infection/NCI and ATG7, SQSTM1 being higher in NCI-HIVE. Immunohistochemical labeling of these autophagy associated proteins (also including Beclin 1 and LC3B) in Iba1-positive microglial cells showed generally higher immunoreactivity in the NCI and NCI-HIVE groups with more focal vs. diffuse patterns of expression in the NCI-HIVE group. Furthermore, analysis of microarray data from these same subjects found significantly higher levels of LAMP1 in NCI-HIVE compared to uninfected subjects in the basal ganglia. Finally, we tested the effect of supernatant from HIV-1-infected microglia and HIV-1 Tat protein in combination with morphine on neurons in vitro and found opposing events with both significant inhibition of autophagic flux and reduced dendrite length for morphine and supernatant treatment while Tat and morphine exposure resulted in lower autophagic activity at an earlier time point and higher levels in the later. These results suggest autophagy genes and their corresponding proteins may be differentially regulated at the transcriptional, translational, and post-translational levels in the brain during various stages of the HIV disease and that infected individuals exposed to morphine can experience mixed signaling of autophagic activity which could lead to more severe NCI than those without opioid use.
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Affiliation(s)
- Seth M Dever
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond VA, USA ; Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami FL, USA
| | - Myosotys Rodriguez
- Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami FL, USA
| | - Jessica Lapierre
- Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami FL, USA
| | - Blair N Costin
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond VA, USA
| | - Nazira El-Hage
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond VA, USA ; Department of Immunology, Herbert Wertheim College of Medicine, Florida International University, Miami FL, USA
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25
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Molejon MI, Ropolo A, Re AL, Boggio V, Vaccaro MI. The VMP1-Beclin 1 interaction regulates autophagy induction. Sci Rep 2013; 3:1055. [PMID: 23316280 PMCID: PMC3542764 DOI: 10.1038/srep01055] [Citation(s) in RCA: 130] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 12/13/2012] [Indexed: 12/22/2022] Open
Abstract
The Vacuole Membrane Protein 1 -VMP1- is a pancreatitis-associated transmembrane protein whose expression triggers autophagy in several human diseases. In the current study, we unveil the mechanism through which this protein induces autophagosome formation in mammalian cells. We show that VMP1 autophagy-related function requires its 20-aminoacid C-terminus hydrophilic domain (VMP1-AtgD). This is achieved through its direct binding to the BH3 motif of Beclin 1 leading to the formation of a complex with the Class III phosphatidylinositol-3 kinase (PI3K) hVps34, a key positive regulator of autophagy, at the site where autophagosomes are generated. This interaction also concomitantly promotes the dissociation of Bcl-2, an autophagy inhibitor, from Beclin 1. Moreover, we show that the VMP1-Beclin 1-hVps34 complex favors the association of Atg16L1 and LC3 with the autophagosomal membranes. Collectively, these findings reveal that VMP1 expression recruits and activates the Class III PI3K complex at the site of autophagosome formation during mammalian autophagy.
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Affiliation(s)
- Maria I Molejon
- Institute for Biochemistry and Molecular Medicine, CONICET, Department of Pathophysiology, School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
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