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Jiang S, Hu L, Zhou H, Wu J, Zhou J, Yu X, Chen G. Novel Therapeutic Mechanisms and Strategies for Intracerebral Hemorrhage: Focusing on Exosomes. Int J Nanomedicine 2024; 19:8987-9007. [PMID: 39246427 PMCID: PMC11378801 DOI: 10.2147/ijn.s473611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 08/20/2024] [Indexed: 09/10/2024] Open
Abstract
Intracerebral hemorrhage (ICH) is a primary, non-traumatic cerebral event associated with substantial mortality and disability. Despite advancements in understanding its etiology and refining diagnostic techniques, a validated treatment to significantly improve ICH prognosis remains elusive. Exosomes, a subtype of extracellular vesicles, encapsulate bioactive components, predominantly microRNAs (miRNAs), facilitating and regulating intercellular communication. Currently, exosomes have garnered considerable interests in clinical transformation for their nanostructure, minimal immunogenicity, low toxicity, inherent stability, and the ability to traverse the blood-brain barrier. A wealth of studies has demonstrated that exosomes can improve the prognosis of ICH through anti-apoptosis, neurogenesis, angiogenesis, anti-inflammation, immunomodulation, and autophagy, primarily via the transportation or overexpression of selected miRNAs. More importantly, exosomes can be easily customized with specific miRNAs or bioactive compounds to establish delivery systems, broadening their potential applications. This review focuses on the therapeutic potential of exosomes in ICH, reviewing the mechanisms of molecular biology mediated by certain miRNAs, discussing the benefits, challenges, and future prospects in ICH treatment. We hope comprehensive understanding of exosomes based on miRNAs will provide new insights into the treatment of ICH and guide the translation of exosome's research from laboratory to clinical practice.
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Affiliation(s)
- Shandong Jiang
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Libin Hu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Hang Zhou
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Jianan Wu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Jiayin Zhou
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Xian Yu
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
| | - Gao Chen
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, People's Republic of China
- Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, 310016, People's Republic of China
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Jin N, Zhang M, Zhou L, Jin S, Cheng H, Li X, Shi Y, Xiang T, Zhang Z, Liu Z, Zhao H, Xie J. Mitochondria transplantation alleviates cardiomyocytes apoptosis through inhibiting AMPKα-mTOR mediated excessive autophagy. FASEB J 2024; 38:e23655. [PMID: 38767449 DOI: 10.1096/fj.202400375r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 04/16/2024] [Accepted: 04/23/2024] [Indexed: 05/22/2024]
Abstract
The disruption of mitochondria homeostasis can impair the contractile function of cardiomyocytes, leading to cardiac dysfunction and an increased risk of heart failure. This study introduces a pioneering therapeutic strategy employing mitochondria derived from human umbilical cord mesenchymal stem cells (hu-MSC) (MSC-Mito) for heart failure treatment. Initially, we isolated MSC-Mito, confirming their functionality. Subsequently, we monitored the process of single mitochondria transplantation into recipient cells and observed a time-dependent uptake of mitochondria in vivo. Evidence of human-specific mitochondrial DNA (mtDNA) in murine cardiomyocytes was observed after MSC-Mito transplantation. Employing a doxorubicin (DOX)-induced heart failure model, we demonstrated that MSC-Mito transplantation could safeguard cardiac function and avert cardiomyocyte apoptosis, indicating metabolic compatibility between hu-MSC-derived mitochondria and recipient mitochondria. Finally, through RNA sequencing and validation experiments, we discovered that MSC-Mito transplantation potentially exerted cardioprotection by reinstating ATP production and curtailing AMPKα-mTOR-mediated excessive autophagy.
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Affiliation(s)
- Ning Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
- Department of Histology and Embryology, Shanxi Medical University, Taiyuan, China
| | - Mengyao Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Li Zhou
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Shanshan Jin
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Haiqin Cheng
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Xuewei Li
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Yaqian Shi
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Tong Xiang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Zongxiao Zhang
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Zhizhen Liu
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Hong Zhao
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
| | - Jun Xie
- Department of Biochemistry and Molecular Biology, Shanxi Key Laboratory of Birth Defect and Cell Regeneration, Key Laboratory of Coal Environmental Pathogenicity and Prevention, Ministry of Education, Shanxi Medical University, Taiyuan, China
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3
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Florance I, Cordani M, Pashootan P, Moosavi MA, Zarrabi A, Chandrasekaran N. The impact of nanomaterials on autophagy across health and disease conditions. Cell Mol Life Sci 2024; 81:184. [PMID: 38630152 PMCID: PMC11024050 DOI: 10.1007/s00018-024-05199-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 03/01/2024] [Accepted: 03/03/2024] [Indexed: 04/19/2024]
Abstract
Autophagy, a catabolic process integral to cellular homeostasis, is constitutively active under physiological and stress conditions. The role of autophagy as a cellular defense response becomes particularly evident upon exposure to nanomaterials (NMs), especially environmental nanoparticles (NPs) and nanoplastics (nPs). This has positioned autophagy modulation at the forefront of nanotechnology-based therapeutic interventions. While NMs can exploit autophagy to enhance therapeutic outcomes, they can also trigger it as a pro-survival response against NP-induced toxicity. Conversely, a heightened autophagy response may also lead to regulated cell death (RCD), in particular autophagic cell death, upon NP exposure. Thus, the relationship between NMs and autophagy exhibits a dual nature with therapeutic and environmental interventions. Recognizing and decoding these intricate patterns are essential for pioneering next-generation autophagy-regulating NMs. This review delves into the present-day therapeutic potential of autophagy-modulating NMs, shedding light on their status in clinical trials, intervention of autophagy in the therapeutic applications of NMs, discusses the potency of autophagy for application as early indicator of NM toxicity.
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Affiliation(s)
- Ida Florance
- Centre for Nanobiotechnology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, 28040, Madrid, Spain.
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040, Madrid, Spain.
| | - Parya Pashootan
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran
| | - Mohammad Amin Moosavi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, P.O Box 14965/161, Tehran, Iran
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600 077, India
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan, Taiwan
| | - Natarajan Chandrasekaran
- Centre for Nanobiotechnology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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4
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Öz-Arslan D, Durer ZA, Kan B. G protein-coupled receptor-mediated autophagy in health and disease. Br J Pharmacol 2024. [PMID: 38501194 DOI: 10.1111/bph.16345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 01/05/2024] [Accepted: 01/27/2024] [Indexed: 03/20/2024] Open
Abstract
G protein-coupled receptors (GPCRs) constitute the largest and most diverse superfamily of mammalian transmembrane proteins. These receptors are involved in a wide range of physiological functions and are targets for more than a third of available drugs in the market. Autophagy is a cellular process involved in degrading damaged proteins and organelles and in recycling cellular components. Deficiencies in autophagy are involved in a variety of pathological conditions. Both GPCRs and autophagy are essential in preserving homeostasis and cell survival. There is emerging evidence suggesting that GPCRs are direct regulators of autophagy. Additionally, autophagic machinery is involved in the regulation of GPCR signalling. The interplay between GPCR and autophagic signalling mechanisms significantly impacts on health and disease; however, there is still an incomplete understanding of the underlying mechanisms and therapeutic implications in different tissues and disease contexts. This review aims to discuss the interactions between GPCR and autophagy signalling. Studies on muscarinic receptors, beta-adrenoceptors, taste receptors, purinergic receptors and adhesion GPCRs are summarized, in relation to autophagy.
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Affiliation(s)
- Devrim Öz-Arslan
- Department of Biophysics, Acibadem MAA University, School of Medicine, Istanbul, Turkey
| | - Zeynep Aslıhan Durer
- Department of Biophysics, Acibadem MAA University, School of Medicine, Istanbul, Turkey
- Department of Biochemistry, Acibadem MAA University, School of Pharmacy, Istanbul, Turkey
| | - Beki Kan
- Department of Biophysics, Acibadem MAA University, School of Medicine, Istanbul, Turkey
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Li X, Xu Y, Wei Z, Kuang J, She M, Wang Y, Jin Q. NnSnRK1-NnATG1-mediated autophagic cell death governs flower bud abortion in shaded lotus. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2024; 117:979-998. [PMID: 38102881 DOI: 10.1111/tpj.16590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 12/17/2023]
Abstract
Many plants can terminate their flowering process in response to unfavourable environments, but the mechanisms underlying this response are poorly understood. In this study, we observed that the lotus flower buds were susceptible to abortion under shaded conditions. The primary cause of abortion was excessive autophagic cell death (ACD) in flower buds. Blockade of autophagic flux in lotus flower buds consistently resulted in low levels of ACD and improved flowering ability under shaded conditions. Further evidence highlights the importance of the NnSnRK1-NnATG1 signalling axis in inducing ACD in lotus flower buds and culminating in their timely abortion. Under shaded conditions, elevated levels of NnSnRK1 activated NnATG1, which subsequently led to the formation of numerous autophagosome structures in lotus flower bud cells. Excessive autophagy levels led to the bulk degradation of cellular material, which triggered ACD and the abortion of flower buds. NnSnRK1 does not act directly on NnATG1. Other components, including TOR (target of rapamycin), PI3K (phosphatidylinositol 3-kinase) and three previously unidentified genes, appeared to be pivotal for the interaction between NnSnRK1 and NnATG1. This study reveals the role of autophagy in regulating the abortion of lotus flower buds, which could improve reproductive success and act as an energy-efficient measure in plants.
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Affiliation(s)
- Xiehongsheng Li
- Key Laboratory of Landscaping, Ministry of Agriculture and Rural Affairs, Key Laboratory of State Forestry and Grassland Administration on Biology of Ornamental Plants in East China, College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yingchun Xu
- Key Laboratory of Landscaping, Ministry of Agriculture and Rural Affairs, Key Laboratory of State Forestry and Grassland Administration on Biology of Ornamental Plants in East China, College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China
| | - Zongyao Wei
- Key Laboratory of Landscaping, Ministry of Agriculture and Rural Affairs, Key Laboratory of State Forestry and Grassland Administration on Biology of Ornamental Plants in East China, College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China
| | - Jiaying Kuang
- Key Laboratory of Landscaping, Ministry of Agriculture and Rural Affairs, Key Laboratory of State Forestry and Grassland Administration on Biology of Ornamental Plants in East China, College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China
| | - Mingzhao She
- Key Laboratory of Landscaping, Ministry of Agriculture and Rural Affairs, Key Laboratory of State Forestry and Grassland Administration on Biology of Ornamental Plants in East China, College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China
| | - Yanjie Wang
- Key Laboratory of Landscaping, Ministry of Agriculture and Rural Affairs, Key Laboratory of State Forestry and Grassland Administration on Biology of Ornamental Plants in East China, College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China
| | - Qijiang Jin
- Key Laboratory of Landscaping, Ministry of Agriculture and Rural Affairs, Key Laboratory of State Forestry and Grassland Administration on Biology of Ornamental Plants in East China, College of Horticulture, Nanjing Agricultural University, Nanjing, 210095, China
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6
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Guo P, Wang Y, Xu J, Yang Z, Zhang Z, Qian J, Hu J, Yin Z, Yang L, Liu M, Liu X, Li G, Zhang H, Rumsey R, Wang P, Zhang Z. Autophagy and cell wall integrity pathways coordinately regulate the development and pathogenicity through MoAtg4 phosphorylation in Magnaporthe oryzae. PLoS Pathog 2024; 20:e1011988. [PMID: 38289966 PMCID: PMC10857709 DOI: 10.1371/journal.ppat.1011988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 02/09/2024] [Accepted: 01/20/2024] [Indexed: 02/01/2024] Open
Abstract
Autophagy and Cell wall integrity (CWI) signaling are critical stress-responsive processes during fungal infection of host plants. In the rice blast fungus Magnaporthe oryzae, autophagy-related (ATG) proteins phosphorylate CWI kinases to regulate virulence; however, how autophagy interplays with CWI signaling to coordinate such regulation remains unknown. Here, we have identified the phosphorylation of ATG protein MoAtg4 as an important process in the coordination between autophagy and CWI in M. oryzae. The ATG kinase MoAtg1 phosphorylates MoAtg4 to inhibit the deconjugation and recycling of the key ATG protein MoAtg8. At the same time, MoMkk1, a core kinase of CWI, also phosphorylates MoAtg4 to attenuate the C-terminal cleavage of MoAtg8. Significantly, these two phosphorylation events maintain proper autophagy levels to coordinate the development and pathogenicity of the rice blast fungus.
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Affiliation(s)
- Pusheng Guo
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Yurong Wang
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Jiayun Xu
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Zhixiang Yang
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Ziqi Zhang
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Jinyi Qian
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Jiexiong Hu
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Ziyi Yin
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Leiyun Yang
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Muxing Liu
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Xinyu Liu
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Gang Li
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Haifeng Zhang
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
| | - Ryan Rumsey
- Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Ping Wang
- Department of Microbiology, Immunology, and Parasitology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, United States of America
| | - Zhengguang Zhang
- Department of Plant Pathology, College of Plant Protection, Nanjing Agricultural University, and Key Laboratory of Integrated Management of Crop Diseases and Pests, Ministry of Education, Nanjing, China
- The Key Laboratory of Plant Immunity, Nanjing Agricultural University, Nanjing, China
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Mende H, Khatri A, Lange C, Poveda-Cuevas SA, Tascher G, Covarrubias-Pinto A, Löhr F, Koschade SE, Dikic I, Münch C, Bremm A, Brunetti L, Brandts CH, Uckelmann H, Dötsch V, Rogov VV, Bhaskara RM, Müller S. An atypical GABARAP binding module drives the pro-autophagic potential of the AML-associated NPM1c variant. Cell Rep 2023; 42:113484. [PMID: 37999976 DOI: 10.1016/j.celrep.2023.113484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 09/22/2023] [Accepted: 11/08/2023] [Indexed: 11/26/2023] Open
Abstract
The nucleolar scaffold protein NPM1 is a multifunctional regulator of cellular homeostasis, genome integrity, and stress response. NPM1 mutations, known as NPM1c variants promoting its aberrant cytoplasmic localization, are the most frequent genetic alterations in acute myeloid leukemia (AML). A hallmark of AML cells is their dependency on elevated autophagic flux. Here, we show that NPM1 and NPM1c induce the autophagy-lysosome pathway by activating the master transcription factor TFEB, thereby coordinating the expression of lysosomal proteins and autophagy regulators. Importantly, both NPM1 and NPM1c bind to autophagy modifiers of the GABARAP subfamily through an atypical binding module preserved within its N terminus. The propensity of NPM1c to induce autophagy depends on this module, likely indicating that NPM1c exerts its pro-autophagic activity by direct engagement with GABARAPL1. Our data report a non-canonical binding mode of GABARAP family members that drives the pro-autophagic potential of NPM1c, potentially enabling therapeutic options.
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Affiliation(s)
- Hannah Mende
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Anshu Khatri
- Goethe University Frankfurt, Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Max-von-Laue Street 9, 60438 Frankfurt, Germany
| | - Carolin Lange
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue Street 15, 60438 Frankfurt, Germany
| | - Sergio Alejandro Poveda-Cuevas
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue Street 15, 60438 Frankfurt, Germany
| | - Georg Tascher
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Adriana Covarrubias-Pinto
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Frank Löhr
- Goethe University Frankfurt, Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Max-von-Laue Street 9, 60438 Frankfurt, Germany
| | - Sebastian E Koschade
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Goethe University Frankfurt, University Hospital, Department of Medicine, Hematology/Oncology, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Ivan Dikic
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Christian Münch
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Anja Bremm
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Lorenzo Brunetti
- Marche Polytechnic University, Department of Clinical and Molecular Sciences, Via Tronto 10, 60020 Ancona, Italy
| | - Christian H Brandts
- Goethe University Frankfurt, University Hospital, Department of Medicine, Hematology/Oncology, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Hannah Uckelmann
- Goethe University Frankfurt, University Hospital, Department of Pediatrics, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
| | - Volker Dötsch
- Goethe University Frankfurt, Institute of Biophysical Chemistry and Center for Biomolecular Magnetic Resonance, Max-von-Laue Street 9, 60438 Frankfurt, Germany
| | - Vladimir V Rogov
- Goethe University Frankfurt, Institute of Pharmaceutical Chemistry, Max-von-Laue Street 15, 60438 Frankfurt, Germany; Goethe University Frankfurt, Structural Genomics Consortium, Buchmann Institute for Molecular Life Sciences, Max-von-Laue Street 15, 60438 Frankfurt, Germany
| | - Ramachandra M Bhaskara
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany; Goethe University Frankfurt, Buchmann Institute for Molecular Life Sciences, Max-von-Laue Street 15, 60438 Frankfurt, Germany.
| | - Stefan Müller
- Goethe University Frankfurt, Institute of Biochemistry II, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
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8
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Ma H, Cui J, Liu Z, Fang W, Lu S, Cao S, Zhang Y, Chen JA, Lu L, Xie Q, Wang Y, Huang Y, Li K, Tong H, Huang J, Lu W. Blockade of de novo pyrimidine biosynthesis triggers autophagic degradation of oncoprotein FLT3-ITD in acute myeloid leukemia. Oncogene 2023; 42:3331-3343. [PMID: 37752234 DOI: 10.1038/s41388-023-02848-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 09/16/2023] [Accepted: 09/18/2023] [Indexed: 09/28/2023]
Abstract
The internal tandem duplication of the FMS-like tyrosine kinase 3 (FLT3-ITD) is one of the most frequent genetic alterations in acute myeloid leukemia (AML). Limited and transient clinical benefit of FLT3 kinase inhibitors (FLT3i) emphasizes the need for alternative therapeutic options for this subset of myeloid malignancies. Herein, we showed that FLT3-ITD mutant (FLT3-ITD+) AML cells were susceptible toward inhibitors of DHODH, a rate-limiting enzyme of de novo pyrimidine biosynthesis. Genetic and pharmacological blockade of DHODH triggered downregulation of FLT3-ITD protein, subsequently suppressed activation of downstream ERK and STAT5, and promoted cell death of FLT3-ITD+ AML cells. Mechanistically, DHODH blockade triggered autophagy-mediated FLT3-ITD degradation via inactivating mTOR, a potent autophagy repressor. Notably, blockade of DHODH synergized with an FDA-approved FLT3i quizartinib in significantly impairing the growth of FLT3-ITD+ AML cells and improving tumor-bearing mice survival. We further demonstrated that DHODH blockade exhibited profound anti-proliferation effect on quizartinib-resistant cells in vitro and in vivo. In summary, this study demonstrates that the induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.
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Affiliation(s)
- Hui Ma
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
| | - Jiayan Cui
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
| | - Zehui Liu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
| | - Wenqing Fang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
| | - Sisi Lu
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
| | - Shuying Cao
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
| | - Yuanyuan Zhang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China
| | - Ji-An Chen
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 201203, Shanghai, China
| | - Lixue Lu
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 201203, Shanghai, China
| | - Qiong Xie
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 201203, Shanghai, China
| | - Yonghui Wang
- Department of Medicinal Chemistry, School of Pharmacy, Fudan University, 201203, Shanghai, China
| | - Ying Huang
- NMPA Key Laboratory of Rapid Drug Inspection Technology, Guangdong Institute for Drug Control, 510663, Guangzhou, China
| | - Kongfei Li
- Department of Hematology, People's Hospital Affiliated to Ningbo University, 315000, Ningbo, China
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China
- Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, 310003, Hangzhou, China
| | - Hongyan Tong
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China
- Zhejiang Provincial Key Lab of Hematopoietic Malignancy, Zhejiang University, 310003, Hangzhou, China
| | - Jin Huang
- Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 200237, Shanghai, China.
| | - Weiqiang Lu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 200241, Shanghai, China.
- Shanghai Key Laboratory of Multidimensional Information Processing, East China Normal University, 200241, Shanghai, China.
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Shan XQ, Luo YY, Chang J, Song JJ, Hao N, Zhao L. Immunomodulation: The next target of mesenchymal stem cell-derived exosomes in the context of ischemic stroke. World J Stem Cells 2023; 15:52-70. [PMID: 37007453 PMCID: PMC10052343 DOI: 10.4252/wjsc.v15.i3.52] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 01/19/2023] [Accepted: 02/28/2023] [Indexed: 03/23/2023] Open
Abstract
Ischemic stroke (IS) is the most prevalent form of brain disease, characterized by high morbidity, disability, and mortality. However, there is still a lack of ideal prevention and treatment measures in clinical practice. Notably, the transplantation therapy of mesenchymal stem cells (MSCs) has been a hot research topic in stroke. Nevertheless, there are risks associated with this cell therapy, including tumor formation, coagulation dysfunction, and vascular occlusion. Also, a growing number of studies suggest that the therapeutic effect after transplantation of MSCs is mainly attributed to MSC-derived exosomes (MSC-Exos). And this cell-free mediated therapy appears to circumvent many risks and difficulties when compared to cell therapy, and it may be the most promising new strategy for treating stroke as stem cell replacement therapy. Studies suggest that suppressing inflammation via modulation of the immune response is an additional treatment option for IS. Intriguingly, MSC-Exos mediates the inflammatory immune response following IS by modulating the central nervous system, the peripheral immune system, and immunomodulatory molecules, thereby promoting neurofunctional recovery after stroke. Thus, this paper reviews the role, potential mechanisms, and therapeutic potential of MSC-Exos in post-IS inflammation in order to identify new research targets.
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Affiliation(s)
- Xiao-Qian Shan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Yong-Yin Luo
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Jun Chang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Jing-Jing Song
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Nan Hao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
| | - Lan Zhao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300381, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China
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10
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Effects and Mechanisms of Exosomes from Different Sources in Cerebral Ischemia. Cells 2022; 11:cells11223623. [PMID: 36429051 PMCID: PMC9688936 DOI: 10.3390/cells11223623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/11/2022] [Accepted: 11/11/2022] [Indexed: 11/18/2022] Open
Abstract
Cerebral ischemia refers to the symptom of insufficient blood supply to the brain. Cells of many different origins participate in the process of repairing damage after cerebral ischemia occurs, in which exosomes secreted by the cells play important roles. For their characteristics, such as small molecular weight, low immunogenicity, and the easy penetration of the blood-brain barrier (BBB), exosomes can mediate cell-to-cell communication under pathophysiological conditions. In cerebral ischemia, exosomes can reduce neuronal damage and improve the brain microenvironment by regulating inflammation, mediating pyroptosis, promoting axonal growth, and stimulating vascular remodeling. Therefore, exosomes have an excellent application prospect for the treatment of cerebral ischemia. This article reviews the roles and mechanisms of exosomes from different sources in cerebral ischemia and provides new ideas for the prevention and treatment of cerebral ischemia.
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11
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Xiong H, Hua F, Dong Y, Lin Y, Ying J, Liu J, Wang X, Zhang L, Zhang J. DNA damage response and GATA4 signaling in cellular senescence and aging-related pathology. Front Aging Neurosci 2022; 14:933015. [PMID: 36177479 PMCID: PMC9513149 DOI: 10.3389/fnagi.2022.933015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Aging is the continuous degradation of biological function and structure with time, and cellular senescence lies at its core. DNA damage response (DDR) can activate Ataxia telangiectasia-mutated serine/threonine kinase (ATM) and Rad3-related serine/threonine kinase (ATR), after which p53 activates p21, stopping the cell cycle and inducing cell senescence. GATA4 is a transcription factor that plays an important role in the development of many organs, such as the heart, testis, ovary, foregut, liver, and ventral pancreas. Studies have shown that GATA4 can also contribute to the DDR, leading to aging. Consistently, there is also evidence that the GATA4 signaling pathway is associated with aging-related diseases, including atherosclerosis and heart failure. This paper reviews the relationship between GATA4, DDR, and cellular senescence, as well as its effect on aging-related diseases.
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Affiliation(s)
- Hao Xiong
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, China
| | - Fuzhou Hua
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, China
| | - Yao Dong
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yue Lin
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, China
| | - Jun Ying
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, China
| | - Jie Liu
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, China
| | - Xifeng Wang
- Department of Anesthesiology, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Xifeng Wang
| | - Lieliang Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Key Laboratory of Anesthesiology of Jiangxi Province, Nanchang, China
- *Correspondence: Lieliang Zhang
| | - Jing Zhang
- Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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12
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HU K, GAO Y, CHU S, CHEN N. Review of the effects and Mechanisms of microglial autophagy in ischemic stroke. Int Immunopharmacol 2022; 108:108761. [DOI: 10.1016/j.intimp.2022.108761] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/28/2022] [Accepted: 04/03/2022] [Indexed: 12/30/2022]
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13
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Novel Therapeutic Strategies for Ischemic Stroke: Recent Insights into Autophagy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3450207. [PMID: 35720192 PMCID: PMC9200548 DOI: 10.1155/2022/3450207] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 04/24/2022] [Accepted: 05/11/2022] [Indexed: 11/18/2022]
Abstract
Stroke is one of the leading causes of death and disability worldwide. Autophagy is a conserved cellular catabolic pathway that maintains cellular homeostasis by removal of damaged proteins and organelles, which is critical for the maintenance of energy and function homeostasis of cells. Accumulating evidence demonstrates that autophagy plays important roles in pathophysiological mechanisms under ischemic stroke. Previous investigations show that autophagy serves as a “double-edged sword” in ischemic stroke as it can either promote the survival of neuronal cells or induce cell death in special conditions. Following ischemic stroke, autophagy is activated or inhibited in several cell types in brain, including neurons, astrocytes, and microglia, as well as microvascular endothelial cells, which involves in inflammatory activation, modulation of microglial phenotypes, and blood-brain barrier permeability. However, the exact mechanisms of underlying the role of autophagy in ischemic stroke are not fully understood. This review focuses on the recent advances regarding potential molecular mechanisms of autophagy in different cell types. The focus is also on discussing the “double-edged sword” effect of autophagy in ischemic stroke and its possible underlying mechanisms. In addition, potential therapeutic strategies for ischemic stroke targeting autophagy are also reviewed.
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14
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Zhao P, Qiu H, Wei Q, Li Y, Gao L, Zhao P. Anti-tumor effect of novel amino acid Schiff base nickel (II) complexes on oral squamous cell carcinoma cells (CAL-27) in vitro. Mol Cell Toxicol 2022. [DOI: 10.1007/s13273-022-00255-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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15
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Pan T, Qian Y, Li T, Zhang Z, He Y, Wang J, Li L, Hu Y, Lin M. Acetyl l-carnitine protects adipose-derived stem cells against serum-starvation: regulation on the network composed of reactive oxygen species, autophagy, apoptosis and senescence. Cytotechnology 2022; 74:105-121. [PMID: 35185289 PMCID: PMC8816993 DOI: 10.1007/s10616-021-00514-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 12/05/2021] [Indexed: 02/03/2023] Open
Abstract
Adipose-derived stem cells (ADSCs) play an important role in cell therapy and regenerative medicine. However, local nutritional deficiency often limits therapeutical effect of the transplanted cells. Acetyl l-carnitine (ALC) is a common energy metabolism regulator and free radical scavenger. This study investigated the effect of ALC on ADSCs exposed to severe serum-deprivation and explored the relative machanisms. Treating with 1 mM ALC improved proliferation and alleviated senescence of starved cells, accompanied with reduced reactive oxygen species (ROS) and increased protein expression of SOD1 and catalase. In addition, ALC inhibited apoptosis but increased starvation-induced autophagy, which might be related to the regulation of phases of dissociation of Bcl-2-Beclin1 and Bcl-2-Bax complexes. Evidence obtained by replacing ALC with N-acetylcysteine (N-AC) suggested that ROS might be the central inducer of autophagy, apoptosis and senescence. There was a difference between ALC and N-AC in the protection mechanism, that was, compared with N-AC, ALC maintained autophagy well at the same time as anti-oxidation. Inhibition of autophagy by 3-methyladenine (3-MA) partially offset the protective effect of ALC. However, despite low-level ROS and enhanced autophagy, ALC with high concentration (10 mM) markedly aggravated cell apoptosis and senescence, thus losing cytoprotection and even causing damage.
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Affiliation(s)
- Tianyun Pan
- Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, 315 South Street, Wuxing Direct, Huzhou City, 313000 Zhejiang Province China
| | - Yao Qian
- The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Lucheng Direct, Wenzhou City, China
| | - Tian Li
- The First Affiliated Hospital of Wenzhou Medical University, Ouhai Direct, Wenzhou City, China
| | - Zikai Zhang
- The First Affiliated Hospital of Wenzhou Medical University, Ouhai Direct, Wenzhou City, China
| | - Yucang He
- The First Affiliated Hospital of Wenzhou Medical University, Ouhai Direct, Wenzhou City, China
| | - Jingping Wang
- The First Affiliated Hospital of Wenzhou Medical University, Ouhai Direct, Wenzhou City, China
| | - Liqun Li
- The First Affiliated Hospital of Wenzhou Medical University, Ouhai Direct, Wenzhou City, China
| | - Yun Hu
- Huzhou Traditional Chinese Medicine Hospital Affiliated to Zhejiang Chinese Medical University, 315 South Street, Wuxing Direct, Huzhou City, 313000 Zhejiang Province China
| | - Ming Lin
- The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Lucheng Direct, Wenzhou City, China
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16
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Kang C, Avery L. The FMRFamide Neuropeptide FLP-20 Acts as a Systemic Signal for Starvation Responses in Caenorhabditis elegans. Mol Cells 2021; 44:529-537. [PMID: 34140426 PMCID: PMC8334353 DOI: 10.14348/molcells.2021.0051] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/26/2021] [Accepted: 04/08/2021] [Indexed: 02/07/2023] Open
Abstract
Most animals face frequent periods of starvation throughout their entire life and thus need to appropriately adjust their behavior and metabolism during starvation for their survival. Such adaptive responses are regulated by a complex set of systemic signals, including hormones and neuropeptides. While much progress has been made in identifying pathways that regulate nutrient-excessive states, it is still incompletely understood how animals systemically signal their nutrient-deficient states. Here, we showed that the FMRFamide neuropeptide FLP-20 modulates a systemic starvation response in Caenorhabditis elegans. We found that mutation of flp-20 rescued the starvation hypersensitivity of the G protein β-subunit gpb-2 mutants by suppressing excessive autophagy. FLP-20 acted in AIB neurons, where the metabotropic glutamate receptor MGL-2 also functions to modulate a systemic starvation response. Furthermore, FLP-20 modulated starvation-induced fat degradation in a manner dependent on the receptor-type guanylate cyclase GCY-28. Collectively, our results reveal a circuit that senses and signals nutrient-deficient states to modulate a systemic starvation response in multicellular organisms.
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Affiliation(s)
- Chanhee Kang
- School of Biological Sciences, Seoul National University, Seoul 08826, Korea
| | - Leon Avery
- Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
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17
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Yip HK, Dubey NK, Lin KC, Sung PH, Chiang JY, Chu YC, Huang CR, Chen YL, Deng YH, Cheng HC, Deng WP. Melatonin rescues cerebral ischemic events through upregulated tunneling nanotube-mediated mitochondrial transfer and downregulated mitochondrial oxidative stress in rat brain. Biomed Pharmacother 2021; 139:111593. [PMID: 33865018 DOI: 10.1016/j.biopha.2021.111593] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/31/2021] [Accepted: 04/02/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Cerebral ischemic events, comprising of excitotoxicity, reactive oxygen production, and inflammation, adversely impact the metabolic-redox circuit in highly active neuronal metabolic profile which maintains energy-dependent brain activities. Therefore, we investigated neuro-regenerative potential of melatonin (Mel), a natural biomaterial secreted by pineal gland. METHODS We specifically determined whether Mel could influence tunneling nanotubes (TNTs)-mediated transfer of functional mitochondria (Mito) which in turn may alter membrane potential, oxidative stress and apoptotic factors. In vitro studies assessed the effects of Mito on levels of cytochrome C, mitochondrial transfer, reactive oxygen species, membrane potential and mass, which were all further enhanced by Mel pre-treatment, whereas in vivo studies examined brain infarct area (BIA), neurological function, inflammation, brain edema and integrity of neurons and myelin sheath in control, ischemia stroke (IS), IS + Mito and IS + Mel-Mito group rats. RESULTS Results showed that Mel pre-treatment significantly increased mitochondrial transfer and antioxidants, and inhibited apoptosis. Mel-pretreated Mito also significantly reduced BIA with improved neurological function. Apoptotic, oxidative-stress, autophagic, mitochondrial/DNA-damaged biomarkers indices were also improved. CONCLUSION Conclusively, Mel is a potent biomaterial which could potentially impart neurogenesis through repairing impaired metabolic-redox circuit via enhanced TNT-mediated mitochondrial transfer, anti-oxidation, and anti-apoptotic activities in ischemia.
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Affiliation(s)
- Hon-Kan Yip
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan; Department of Nursing, Asia University, Taichung 41354, Taiwan; Division of Cardiology, Department of Internal Medicine, Xiamen Chang Gung Hospital, Xiamen, Fujian 361000, China
| | - Navneet Kumar Dubey
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan; Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Kun-Chen Lin
- Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan
| | - Pei-Hsun Sung
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - John Y Chiang
- Department of Computer Science and Engineering, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Healthcare Administration and Medical Informatics, Kaohsiung Medical University, Kaohsiung 807, Taiwan
| | - Yi-Ching Chu
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Chi-Ruei Huang
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Yi-Ling Chen
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan; Center for Shockwave Medicine and Tissue Engineering, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan
| | - Yue-Hua Deng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan; Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Hsin-Chung Cheng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan; Department of Dentistry, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Win-Ping Deng
- School of Dentistry, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan; Stem Cell Research Center, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan; Graduate Institute of Basic Medicine, Fu Jen Catholic University, Taipei, Taiwan; Department of Life Science, Tunghai University, Taichung, Taiwan.
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Dysfunction of the Neurovascular Unit in Ischemic Stroke: Highlights on microRNAs and Exosomes as Potential Biomarkers and Therapy. Int J Mol Sci 2021; 22:ijms22115621. [PMID: 34070696 PMCID: PMC8198979 DOI: 10.3390/ijms22115621] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/21/2021] [Accepted: 05/23/2021] [Indexed: 12/12/2022] Open
Abstract
Ischemic stroke is a damaging cerebral vascular disease associated with high disability and mortality rates worldwide. In spite of the continuous development of new diagnostic and prognostic methods, early detection and outcome prediction are often very difficult. The neurovascular unit (NVU) is a complex multicellular entity linking the interactions between neurons, glial cells, and brain vessels. Novel research has revealed that exosome-mediated transfer of microRNAs plays an important role in cell-to-cell communication and, thus, is integral in the multicellular crosstalk within the NVU. After a stroke, NVU homeostasis is altered, which induces the release of several potential biomarkers into the blood vessels. The addition of biological data representing all constituents of the NVU to clinical and neuroradiological findings can significantly advance stroke evaluation and prognosis. In this review, we present the current literature regarding the possible beneficial roles of exosomes derived from the components of the NVU and multipotent mesenchymal stem cells in preclinical studies of ischemic stroke. We also discuss the most relevant clinical trials on the diagnostic and prognostic roles of exosomes in stroke patients.
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Paving the Road Toward Exploiting the Therapeutic Effects of Ginsenosides: An Emphasis on Autophagy and Endoplasmic Reticulum Stress. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1308:137-160. [PMID: 33861443 DOI: 10.1007/978-3-030-64872-5_12] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Programmed cell death processes such as apoptosis and autophagy strongly contribute to the onset and progression of cancer. Along with these lines, modulation of cell death mechanisms to combat cancer cells and elimination of resistance to apoptosis is of great interest. It appears that modulation of autophagy and endoplasmic reticulum (ER) stress with specific agents would be beneficial in the treatment of several disorders. Interestingly, it has been suggested that herbal natural products may be suitable candidates for the modulation of these processes due to few side effects and significant therapeutic potential. Ginsenosides are derivatives of ginseng and exert modulatory effects on the molecular mechanisms associated with autophagy and ER stress. Ginsenosides act as smart phytochemicals that confer their effects by up-regulating ATG proteins and converting LC3-I to -II, which results in maturation of autophagosomes. Not only do ginsenosides promote autophagy but they also possess protective and therapeutic properties due to their capacity to modulate ER stress and up- and down-regulate and/or dephosphorylate UPR transducers such as IRE1, PERK, and ATF6. Thus, it would appear that ginsenosides are promising agents to potentially restore tissue malfunction and possibly eliminate cancer.
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Synthetic Cannabinoids Induce Autophagy and Mitochondrial Apoptotic Pathways in Human Glioblastoma Cells Independently of Deficiency in TP53 or PTEN Tumor Suppressors. Cancers (Basel) 2021; 13:cancers13030419. [PMID: 33499365 PMCID: PMC7865605 DOI: 10.3390/cancers13030419] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/07/2021] [Accepted: 01/20/2021] [Indexed: 01/24/2023] Open
Abstract
Simple Summary Glioblastomas (GBMs) are aggressive brain tumors with frequent genetic defects in TP53 and PTEN tumor suppressor genes, which render tumors refractory to standard chemotherapeutics. Natural and synthetic cannabinoids showed antitumor activity in glioma cells and animal glioma models. Due to differences in the expression of cannabinoid type 2 receptors (CB2), which are abundant in GBMs but absent from a healthy brain, we tested synthetic cannabinoids for their ability to kill numerous glioma cells. We performed multiple biochemical analyses to determine which cell death pathways are activated in human glioma cells. We demonstrate high susceptibility of human glioblastoma cells to synthetic cannabinoids, despite genetic defects contributing to apoptosis resistance, which makes cannabinoids promising anti-glioma therapeutics. Abstract Glioblastomas (GBMs) are aggressive brain tumors with frequent genetic alterations in TP53 and PTEN tumor suppressor genes rendering resistance to standard chemotherapeutics. Cannabinoid type 1 and 2 (CB1/CB2) receptor expression in GBMs and antitumor activity of cannabinoids in glioma cells and animal models, raised promises for a targeted treatment of these tumors. The susceptibility of human glioma cells to CB2-agonists and their mechanism of action are not fully elucidated. We determined CB1 and CB2 expression in 14 low-grade and 21 high-grade tumor biopsies, GBM-derived primary cultures and established cell lines. The non-selective CB receptor agonist WIN55,212-2 (but not its inactive enantiomer) or the CB2-selective agonist JWH133 induced apoptosis in patient-derived glioma cultures and five established glioma cell lines despite p53 and/or PTEN deficiency. Growth inhibitory efficacy of cannabinoids correlated with CB1/CB2 expression (EC50 WIN55,212-2: 7.36–15.70 µM, JWH133: 12.15–143.20 µM). Treatment with WIN55,212-2 or JWH133 led to activation of the apoptotic mitochondrial pathway and DNA fragmentation. Synthetic cannabinoid action was associated with the induction of autophagy and knockdown of autophagy genes augmented cannabinoid-induced apoptotic cell death. The high susceptibility of human glioblastoma cells to synthetic cannabinoids, despite genetic defects contributing to apoptosis resistance, makes cannabinoids promising anti-glioma therapeutics.
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Umar SA, Tasduq SA. Integrating DNA damage response and autophagy signalling axis in ultraviolet-B induced skin photo-damage: a positive association in protecting cells against genotoxic stress. RSC Adv 2020; 10:36317-36336. [PMID: 35517978 PMCID: PMC9057019 DOI: 10.1039/d0ra05819j] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 09/13/2020] [Indexed: 01/27/2023] Open
Abstract
The skin acts as both physical as well as an immunological barrier against hazardous agents from the outside environment and protects the internal organs against damage. Skin ageing is a dynamic process caused by the influence of various external factors, including damage from ultraviolet (UV-B) radiation, which is known as photo-ageing, and due to internal chronological mechanisms. A normal ageing process requires several orchestrated defense mechanisms to diverse types of stress responses, the concomitant renewal of cellular characteristics, and the homeostasis of different cell types that directly or indirectly protect the integrity of skin. Cumulative oxidative and endoplasmic reticulum (ER) stress responses and their adverse impact on biological systems in the skin are a common mechanism of the ageing process, negatively impacting DNA by causing mutations that lead to many physiological, functional, and aesthetic changes in the skin, culminating in the development of many diseases, including photo-damage and photo-carcinogenesis. Exposure of the skin to ultraviolet-(B) elicits the activation of signal transduction pathways, including DNA damage response, autophagy, and checkpoint signal adaptations associated with clearing radiation-induced DNA damage. Recent experimental reports suggest that autophagy is involved in maintaining skin homeostasis upon encountering different stresses, notably genotoxic stress. It has also been revealed that autophagy positively regulates the recognition of DNA damage by nucleotide excision repair and that skin ageing is associated with defects in the autophagy process. Moreover, autophagy is constitutively active in the skin epithelium, imparting protection to skin cells against a diverse range of outside insults, thus increasing resistance to environmental stressors. It has also been found that the stress-induced suppression of the autophagy response in experimental settings leads to enhanced apoptosis during photo-ageing upon UV-B exposure and that the maintenance of homeostasis depends on cellular autophagy levels. More recent reports in this domain claim that relieving the oxidative-stress-mediated induction of the ER stress response upon UV-B irradiation protects skin cells from photo-damage effects. The integration of autophagy and the DNA damage response under genotoxic stress is being considered as a meaningful partnership for finding novel molecular targets and devising suitable therapeutic strategies against photo-ageing disorders. Here, we summarize and review the current understanding of the mechanisms governing the intricate interplay between autophagy and the DNA damage response and its regulation by UV-B, the roles of autophagy in regulating the cellular response to UV-B-induced photodamage, and the implications of the modulation of autophagy as a meaningful partnership in the treatment and prevention of photoaging disorders.
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Affiliation(s)
- Sheikh Ahmad Umar
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad 201002 India
- Pharmacokinetics-Pharmacodynamics and Toxicology Division, CSIR-Indian Institute of Integrative Medicine Jammu Tawi Jammu and Kashmir India +91-1912569000-10 ext.332
| | - Sheikh Abdullah Tasduq
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad 201002 India
- Pharmacokinetics-Pharmacodynamics and Toxicology Division, CSIR-Indian Institute of Integrative Medicine Jammu Tawi Jammu and Kashmir India +91-1912569000-10 ext.332
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22
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Li Y, Dong J, Zhao P, Hu P, Yang D, Gao L, Li L. Synthesis of Amino Acid Schiff Base Nickel (II) Complexes as Potential Anticancer Drugs In Vitro. Bioinorg Chem Appl 2020; 2020:8834859. [PMID: 33061947 PMCID: PMC7542481 DOI: 10.1155/2020/8834859] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/18/2020] [Indexed: 11/22/2022] Open
Abstract
Three hexacoordinated octahedral nickel (II) complexes, [Ni (Trp-sal) (phen) (CH3OH)] (1), [Ni (Trp-o-van) (phen) (CH3OH)]•2CH3OH (2), and [Ni (Trp-naph) (phen) (CH3OH)] (3) (where Trp-sal = Schiff base derived from tryptophan and salicylaldehyde, Trp-o-van = Schiff base derived from tryptophan and o-vanillin, Trp-naph = Schiff base derived from tryptophan and 2-hydroxy-1-naphthaldehyde, phen = 1, 10-phenanthroline), have been synthesized and characterized as potential anticancer agents. Details of structural study of these complexes using single-crystal X-ray crystallography showed that distorted octahedral environment around nickel (II) ion has been satisfied by three nitrogen atoms and three oxygen atoms. All these complexes displayed moderate cytotoxicity toward esophageal cancer cell line Eca-109 with the IC50 values of 23.95 ± 2.54 μM for 1, 18.14 ± 2.39 μM for 2, and 21.89 ± 3.19 μM for 3. Antitumor mechanism studies showed that complex 2 can increase the autophagy, reactive oxygen species (ROS) levels, and decrease the mitochondrial membrane potential remarkably in a dose-dependent manner in the Eca-109 cells. Complex 2 can cause cell cycle arrest in the G2/M phase. Additionally, complex 2 can regulate the Bcl-2 family and autophagy-related proteins.
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Affiliation(s)
- Yang Li
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng 252000, China
| | - Jianfang Dong
- Department of Material Science, Shandong Polytechnic Technician College, Liaocheng 252000, China
| | - Peiran Zhao
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng 252000, China
| | - Ping Hu
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng 252000, China
| | - Dawei Yang
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng 252000, China
| | - Lei Gao
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng 252000, China
| | - Lianzhi Li
- School of Chemistry and Chemical Engineering, Liaocheng University, Liaocheng 252000, China
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23
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Guizzardi S, Picotto G, Rodriguez V, Welsh J, Narvaez C, Bohl L, Tolosa de Talamoni N. Combined treatment of menadione and calcitriol increases the antiproliferative effect by promoting oxidative/nitrosative stress, mitochondrial dysfunction, and autophagy in breast cancer MCF-7 cells. Can J Physiol Pharmacol 2020; 98:548-556. [PMID: 32762631 DOI: 10.1139/cjpp-2019-0585] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The aim of this study was to determine new insights into the molecular mechanisms involved in the antiproliferative action of menadione + calcitriol (MEN+D) on MCF-7 cells. After 24 h, MEN+D inhibited the cell growth but was not observed with each single treatment. The combined drugs reduced the mitochondrial respiration at that time, as judged by an increase in the proton leak and a decrease in the ATP generation and coupling efficiency. At longer times, 48 or 96 h, either D or MEN reduced the proliferation, but the effect was higher when both drugs were used together. The combined treatment increased the superoxide anion ([Formula: see text]) and nitric oxide (NO•) contents as well as acidic vesicular organelles (AVOs) formation. The percentage of cells showing the lower mitochondrial membrane potential (ΔΨm) was highly increased by the combined therapy. LC3-II protein expression was enhanced by any treatment. In conclusion, the antiproliferative action of MEN+D involves oxidative/nitrosative stress, mitochondrial alteration, and autophagy. This combined therapy could be useful to treat breast cancer cells because it inhibits multiple oncogenic pathways more effectively than each single agent.
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Affiliation(s)
- Solange Guizzardi
- Laboratorio "Dr. Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-UNC), Córdoba, Argentina
| | - Gabriela Picotto
- Laboratorio "Dr. Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-UNC), Córdoba, Argentina
| | - Valeria Rodriguez
- Laboratorio "Dr. Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-UNC), Córdoba, Argentina
| | - JoEllen Welsh
- University at Albany Cancer Research Center, Rensselaer, NY, USA
| | - Carmen Narvaez
- University at Albany Cancer Research Center, Rensselaer, NY, USA
| | - Luciana Bohl
- Centro de Investigaciones y Transferencia Villa María (CITVM-CONICET), Universidad Nacional Villa María, Villa María, Argentina
| | - Nori Tolosa de Talamoni
- Laboratorio "Dr. Cañas", Cátedra de Bioquímica y Biología Molecular, Facultad de Ciencias Médicas, INICSA (CONICET-UNC), Córdoba, Argentina
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24
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Zhang ZL, Liu ML, Huang YS, Liang WY, Zhang MM, Fan YD, Ma MF. Ginsenoside Re enhances the survival of H9c2 cardiac muscle cells through regulation of autophagy. JOURNAL OF ASIAN NATURAL PRODUCTS RESEARCH 2020; 22:774-787. [PMID: 31232107 DOI: 10.1080/10286020.2019.1632834] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 06/08/2019] [Accepted: 06/09/2019] [Indexed: 06/09/2023]
Abstract
We examined the effect of ginsenoside Re (G-Re) on autophagy in H9c2 cardiomyocytes cultured in glucose deprivation (GD). Levels of the membrane-bound autophagy-related microtubule-associated protein 1A/1B-light chain 3 (LC3) B-2 were measured via immunoblotting and immunofluorescence was conducted to assess autophagosome formation. GD H9c2 cells were treated with 100 μmol/l G-Re. Cell viability was determined in culture medium. Phosphorylated 5' AMP-activated protein kinase (AMPK)-α and mammalian target of rapamycin (mTOR) levels were measured to explore the mechanisms underlying the effects of G-Re on autophagy in GD cells. G-Re treatment inhibited autophagosome formation and may be beneficial to GD cardiomyocytes.
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Affiliation(s)
- Zi-Long Zhang
- Department of Cardiology, Emergency General Hospital, Beijing 100028, China
| | - Mei-Lin Liu
- Department of Geriatric, Peking University First Hospital, Beijing 100034, China
| | - Ying-Shuo Huang
- Department of Research Ward, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Wen-Yi Liang
- Department of Geriatric, Peking University First Hospital, Beijing 100034, China
| | - Miao-Miao Zhang
- Department of Cardiology, Emergency General Hospital, Beijing 100028, China
| | - Yu-Dong Fan
- Department of Cardiology, Emergency General Hospital, Beijing 100028, China
| | - Ming-Feng Ma
- Department of Cardiology, Fenyang Hospital of Shanxi Province, Fenyang 032200, China
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25
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Yang JJ, Zhang XH, Ma XH, Duan WJ, Xu NG, Chen YJ, Liang L. Astragaloside IV enhances GATA-4 mediated myocardial protection effect in hypoxia/reoxygenation injured H9c2 cells. Nutr Metab Cardiovasc Dis 2020; 30:829-842. [PMID: 32278611 DOI: 10.1016/j.numecd.2020.01.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2019] [Revised: 01/15/2020] [Accepted: 01/16/2020] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND AIM The transcription factor GATA-4 plays an important role in myocardial protection. Astragaloside IV (Ast-IV) was reported with the effects on improving cardiac function after ischemia. In this study, we explored how Ast-IV interacts with GATA-4 to protect myocardial cells H9c2 against Hypoxia/Reoxygenation (H/R) stress. METHODS AND RESULTS H9c2 cells were cultured under the H/R condition. Various cell activity and morphology assays were used to assess the rates of apoptosis and autophagy. In these H/R injured H9c2 cells, increased apoptosis (P < 0.01) and autophagosome number (P < 0.01) were observed, and the addition of Ast-IV ameliorated this tendency. Mechanistically, we used the RT-qPCR and Western blot to evaluate the expressions of various molecules. The results showed that Ast-IV treatment upregulated gene expression of GATA-4 (P < 0.01) and the survival factors (Bcl-2, P < 0.05; p62, P < 0.01), but suppressed apoptosis and autophagy related genes (PARP, Caspase-3, Beclin-1, and LC3-II; All P < 0.01). Furthermore, overexpressing of GATA-4 by its agonist phenylephrine can also protect H/R injured H9c2 cells, and the addition of Ast-IV further enhanced this protection of GATA-4. In contrast, silencing GATA-4 expression abolished the H/R protection of Ast-IV, which demonstrated that the myocardial protection of Ast-IV is mediated by GATA-4. Lastly, along with GATA overexpression, enhanced interactions between Bcl-2 and Beclin-1 were detected by Chromatin immunoprecipitation (P < 0.01). CONCLUSION Ast-IV rescued the H/R injury induced apoptosis and autophagy in H9c2 cells. Ast-IV treatment can stimulate the overexpression of GATA-4, and further enhanced the myocardial protection effect of GATA-4.
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Affiliation(s)
- Jing-Jing Yang
- School of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, China; Pharmacy Department, Huizhou Traditional Chinese Medical Hospital, Huizhou, 516000, China
| | - Xu-Hui Zhang
- Second Department of Oncology, Guangdong Second Provincial General Hospital, 466 Xingangzhong Road, Guangzhou, 510317, China
| | - Xiao-Hui Ma
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Wen-Jun Duan
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China
| | - Neng-Gui Xu
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China
| | - Yong-Jun Chen
- South China Research Center for Acupuncture and Moxibustion, Medical College of Acu-Moxi and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.
| | - Lei Liang
- Guangdong Engineering Research Center of Chinese Medicine & Disease Susceptibility, Jinan University, Guangzhou, 510632, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), College of Pharmacy, Jinan University, Guangzhou, 510632, China; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou, 510632, China.
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26
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Rastaldo R, Vitale E, Giachino C. Dual Role of Autophagy in Regulation of Mesenchymal Stem Cell Senescence. Front Cell Dev Biol 2020; 8:276. [PMID: 32391362 PMCID: PMC7193103 DOI: 10.3389/fcell.2020.00276] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Accepted: 03/31/2020] [Indexed: 12/20/2022] Open
Abstract
During their development and overall life, mesenchymal stem cells (MSCs) encounter a plethora of internal and external stress signals and therefore, they need to put in action homeostatic changes in order to face these stresses. To this aim, similar to other mammalian cells, MSCs are endowed with two crucial biological responses, autophagy and senescence. Sharing of a number of stimuli like shrinkage of telomeres, oncogenic and oxidative stress, and DNA damage, suggest an intriguingly close relationship between autophagy and senescence. Autophagy is at first reported to suppress MSC senescence by clearing injured cytoplasmic organelles and impaired macromolecules, yet recent investigations also showed that autophagy can promote MSC senescence by inducing the production of senescence-associated secretory proteins (SASP). These apparently contrary contributions of autophagy may mirror an intricate image of autophagic regulation on MSC senescence. We here tackle the pro-senescence and anti-senescence roles of autophagy in MSCs while concentrating on some possible mechanistic explanations of such an intricate liaison. Clarifying the autophagy/senescence relationship in MSCs will help the development of more effective and safer therapeutic strategies.
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Affiliation(s)
- Raffaella Rastaldo
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Emanuela Vitale
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
| | - Claudia Giachino
- Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
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27
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Wong SQ, Kumar AV, Mills J, Lapierre LR. C. elegans to model autophagy-related human disorders. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2020; 172:325-373. [PMID: 32620247 DOI: 10.1016/bs.pmbts.2020.01.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Autophagy is a highly conserved degradation process that clears damaged intracellular macromolecules and organelles in order to maintain cellular health. Dysfunctional autophagy is fundamentally linked to the development of various human disorders and pathologies. The use of the nematode Caenorhabditis elegans as a model system to study autophagy has improved our understanding of its regulation and function in organismal physiology. Here, we review the genetic, functional, and regulatory conservation of the autophagy pathway in C. elegans and we describe tools to quantify and study the autophagy process in this incredibly useful model organism. We further discuss how these nematodes have been modified to model autophagy-related human diseases and underscore the important insights obtained from such models. Altogether, we highlight the strengths of C. elegans as an exceptional tool to understand the genetic and molecular foundations underlying autophagy-related human diseases.
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Affiliation(s)
- Shi Quan Wong
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States
| | - Anita V Kumar
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States
| | - Joslyn Mills
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States
| | - Louis R Lapierre
- Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI, United States.
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28
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Quan M, Hong MW, Ko MS, Kim YY. Relationships Between Disc Degeneration and Autophagy Expression in Human Nucleus Pulposus. Orthop Surg 2019; 12:312-320. [PMID: 31802633 PMCID: PMC7031585 DOI: 10.1111/os.12573] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 08/22/2019] [Accepted: 10/14/2019] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVES To elaborate on the relationship between degeneration grade and autophagy expression in human nucleus pulposus obtained from surgical procedures. METHODS For the 16 patients included in the present study, we determined the Pfirrmann classifications of degenerative lesions by MRI. Western blot analysis, LC3, LAMP2, and p62 protein expressions were quantified in different degeneration grades of disc nucleus pulposus. Double immunofluorescence staining was used to show co-localization of LC3 and LAMP2, and immunohistochemistry to show LC3 and p62 in the nucleus pulposus. RESULTS In the western blot analysis, LC3-II was highly expressed in grade III and decreased progressively from grade IV to V. In addition, LC3-II expression in grade III was significantly higher than in grade II, IV, and V (P < 0.05). LAMP2 expression in grade V was significantly higher than that in grade II, III, and IV (P < 0.05). P62 increased with decreasing autophagy expression up through grade V. In the double staining, the LC3 level was highly expressed in grade III and decreased progressively from grades IV to V, as in the western blot analysis. LAMP2 rose with increasing disc degeneration grade through grade V. In the quantitative analysis of colocalization, grade III is significantly higher than grade II and V (P < 0.05). Immunohistochemical staining showed that LC3 was highly expressed in grade III but weakly expressed in other grades, with few positive areas around the nucleus pulposus. However, p62 increased progressively with increasing disc degeneration grade. CONCLUSION Pfirrmann grade III disc degeneration showed that autophagosomes were formed, which led to the reversible decomposition of degenerative substances. Thus, by analyzing the effect of autophagy on degenerative discs, we showed the possibility of reversing degenerative changes, but only in grades III and lower.
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Affiliation(s)
- Meiling Quan
- Department of Orthopedics, Daejeon St. Mary's Hospital, College of Medicine, Daejeon, Korea.,Department of Orthopedics, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Myoung-Wha Hong
- Department of Orthopedics, Daejeon St. Mary's Hospital, College of Medicine, Daejeon, Korea
| | - Myung-Sup Ko
- Department of Orthopedics, Daejeon St. Mary's Hospital, College of Medicine, Daejeon, Korea
| | - Young-Yul Kim
- Department of Orthopedics, Daejeon St. Mary's Hospital, College of Medicine, Daejeon, Korea
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29
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Chen K, Sun Z. Autophagy plays a critical role in Klotho gene deficiency-induced arterial stiffening and hypertension. J Mol Med (Berl) 2019; 97:1615-1625. [PMID: 31630227 DOI: 10.1007/s00109-019-01841-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Revised: 09/03/2019] [Accepted: 10/09/2019] [Indexed: 01/09/2023]
Abstract
Klotho is an anti-aging gene that shortens the life span when disrupted and extends the lifespan when overexpressed. This study investigated whether autophagy plays a role in Klotho gene deficiency-induced arterial stiffening and hypertension. Klotho mutant heterozygous (KL+/-) mice and age- and sex-matched wild-type (WT) mice were used. Arteries were examined for autophagy using Western blot assays. Pulse wave velocity (PWV), a direct measure of arterial stiffness, and blood pressure (BP) increased significantly in KL (+/-) mice. The autophagy level, as measured by LC3-II expression and autophagy flux, increased in aortas of KL (+/-) mice, indicating that Klotho gene deficiency upregulated autophagy. Chloroquine diminished Klotho gene deficiency-induced increases in PWV and BP and eliminated the upregulation of autophagic flux in KL (+/-) mice. Klotho gene deficiency-induced arterial stiffness was accompanied by upregulation of MMP9, TGFβ-1, TGFβ-3, RUNX2, and ALP, but these changes were effectively mitigated by chloroquine. Chloroquine also halted an increase in scleraxis expression in aortas of Klotho (+/-) mice. In cultured mouse aortic smooth muscle cells, Klotho gene deficiency increased autophagy, leading to upregulation of scleraxis, a key transcription factor of collagen synthesis. Klotho gene deficiency failed to upregulate scleraxis expression when autophagy was inhibited, suggesting that autophagy is a critical mediator of Klotho gene deficiency-induced upregulation of scleraxis. Suppression of enhanced autophagy by chloroquine lessens Klotho gene deficiency-induced arterial stiffening and hypertension by stopping upregulation of MMP9 and scleraxis. The enhanced autophagic activity plays a crucial role in Klotho gene deficiency-induced arterial stiffening and hypertension. KEY MESSAGES: Klotho gene deficiency upregulates autophagy. Upregulation of autophagy plays a role in the pathogenesis of arterial stiffening. Autophagy regulates MMP9 activity and scleraxis expression.
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Affiliation(s)
- Kai Chen
- Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.,Department of Physiology, College of Medicine, The University of Tennessee Health Science Center, C302B Coleman Bldg., 956 Court Ave, Memphis, TN, 38163-2116, USA
| | - Zhongjie Sun
- Department of Physiology, College of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA. .,Department of Physiology, College of Medicine, The University of Tennessee Health Science Center, C302B Coleman Bldg., 956 Court Ave, Memphis, TN, 38163-2116, USA.
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30
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Wu C, Yan X, Liao Y, Liao L, Huang S, Zuo Q, Zhou L, Gao L, Wang Y, Lin J, Li S, Wang K, Ge X, Song H, Yang R, Lu F. Increased perihematomal neuron autophagy and plasma thrombin-antithrombin levels in patients with intracerebral hemorrhage: An observational study. Medicine (Baltimore) 2019; 98:e17130. [PMID: 31574813 PMCID: PMC6775380 DOI: 10.1097/md.0000000000017130] [Citation(s) in RCA: 12] [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] [Indexed: 11/26/2022] Open
Abstract
Animal studies have demonstrated that autophagy was involved in neuronal damage after intracerebral hemorrhage (ICH). Several studies showed thrombin-antithrombin (TAT) plasma levels were elevated in patients with ICH. In this study, we aimed to evaluate if autophagy occurred in patients with ICH; and the relationship between the severity of brain injury and plasma TAT levels.A novel tissue harvesting device was used during hematoma removal surgery to collect loose fragments of tissue surrounding the affected brain area in 27 ICH patients with hematoma volumes of >30 mL in the basal ganglia. Control tissues were obtained from patients who underwent surgery for arteriovenous malformation (n = 25). Transmission electron microscopy (TEM) and immunohistochemistry for autophagy-related proteins were used to evaluate the ultrastructural and morphologic cellular characteristics; and the extent of autophagy in the recovered tissue specimens. Stroke severity was assessed by using the Glasgow Coma Scale (GCS) and the National Institutes of Health Stroke Scale (NIHSS). An enzyme-linked immunosorbent assay (ELISA) was used to measure plasma TAT levels.Transmission electron microscopy showed autophagosomes and autolysosomes exist in neurons surrounding the hematoma, but not in the control tissues. The number of cells containing autophagic vacuoles correlated with the severity of brain injury. Immunohistochemistry showed strong LC3, beclin 1, and cathepsin D staining in ICH tissue specimens. Plasma TAT levels correlated positively with autophagic cells and ICH severity (P < .01).Autophagy was induced in perihematomal neurons after ICH. Autophagy and plasma TAT levels correlated positively with severity of brain injury. These results suggest that autophagy and increased plasma TAT levels may contribute to the secondary damage in ICH patients.
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Affiliation(s)
- Chenghan Wu
- Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine
| | - Xiaohua Yan
- Department of Neurosurgery and TCM, Fujian Provincial Hospital
| | - Yuansheng Liao
- Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine
| | - Lianming Liao
- Central Laboratory, Union Hospital of Fujian Medical University
| | - Shengyue Huang
- Department of Neurosurgery and TCM, Fujian Provincial Hospital
| | - Quanting Zuo
- Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine
| | - Linying Zhou
- Laboratory of Electron Microscopy, Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
| | - Lili Gao
- Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine
| | - Yinzhou Wang
- Department of Neurosurgery and TCM, Fujian Provincial Hospital
| | - Jushan Lin
- Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine
| | - Shiju Li
- Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine
| | - Kaiyu Wang
- Department of Neurosurgery and TCM, Fujian Provincial Hospital
| | - Xiuming Ge
- Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine
| | - Hailong Song
- Department of Pathology and Anatomical Sciences, University of Missouri, Columbia, MO
| | - Ruiling Yang
- Department of Neurology, Second Affiliated Clinical College of Fujian University of Traditional Chinese Medicine
| | - Feng Lu
- Fujian University of Traditional Chinese Medicine, Fuzhou, China
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Duan Y, Dong Y, Hu H, Wang Q, Guo S, Fu D, Song X, Kalvakolanu DV, Tian Z. IL-33 contributes to disease severity in Psoriasis-like models of mouse. Cytokine 2019; 119:159-167. [PMID: 30913451 DOI: 10.1016/j.cyto.2019.02.019] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2018] [Revised: 02/15/2019] [Accepted: 02/22/2019] [Indexed: 12/16/2022]
Abstract
Immune cells infiltrating the psoriatic skin secrete high amounts of pro-inflammatory cytokines IL-17, TNF-α, IL-21 and IL-36 resulting in chronic inflammation. However, the exact cellular and molecular mechanisms have not been fully understood. We report here elevation of IL-33 expression in psoriatic lesions. Studies in imiquimod (IMQ)-induced mice with psoriatic inflammation confirmed a critical role for IL-33 in driving the disease. IL-33 reduces the CD4+ and CD8+ cells, inhibits autophagy in IMQ-treated mouse skin, and promoted tyrosyl phosphorylation of STAT3. Thus, IL-33 appears to be a major risk factor for severity of psoriasis-like skin inflammation. Our findings may open new perspectives for understanding the mechanisms and developing a therapeutic strategy for psoriasis.
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Affiliation(s)
- Yaju Duan
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Henan, Xinxiang 453000, China
| | - Yonghua Dong
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Henan, Xinxiang 453000, China
| | - Hua Hu
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Henan, Xinxiang 453000, China
| | - Qiumei Wang
- Department of Dermatology, The Central Hospital of Xinxiang, Henan, Xinxiang 453000, China
| | - Sheng Guo
- Institute of Precision Medicine, Xinxiang Medical University, School of Basic Medical Sciences, Xinxiang Medical University, Henan, Xinxiang 453000, China; Department of Immunology, Xinxiang Medical University, Henan, Xinxiang 453000, China
| | - Dandan Fu
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Henan, Xinxiang 453000, China
| | - Xiangfeng Song
- Institute of Precision Medicine, Xinxiang Medical University, School of Basic Medical Sciences, Xinxiang Medical University, Henan, Xinxiang 453000, China; Department of Immunology, Xinxiang Medical University, Henan, Xinxiang 453000, China
| | - Dhan V Kalvakolanu
- Department of Microbiology & Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
| | - Zhongwei Tian
- Department of Dermatology, The First Affiliated Hospital of Xinxiang Medical University, Henan, Xinxiang 453000, China.
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He H, Zeng Q, Huang G, Lin Y, Lin H, Liu W, Lu P. Bone marrow mesenchymal stem cell transplantation exerts neuroprotective effects following cerebral ischemia/reperfusion injury by inhibiting autophagy via the PI3K/Akt pathway. Brain Res 2018; 1707:124-132. [PMID: 30448444 DOI: 10.1016/j.brainres.2018.11.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 11/11/2018] [Accepted: 11/12/2018] [Indexed: 12/11/2022]
Abstract
Although cerebral ischemia itself is associated with a high rate of disability, secondary cerebral ischemia/reperfusion (I/R) injury following recanalization is associated with much more severe outcomes. The mechanisms underlying cerebral I/R injury are complex, involving neuronal death caused by apoptosis and autophagy. Autophagy is critical for cell survival and plays an important role in the pathogenesis of cerebral I/R injury. Research has indicated that transplantation of bone marrow mesenchymal stem cells (BMSCs) is effective in repairing and reconstructing brain tissue, and that this effect may be associated with the regulation of autophagy. To explore this hypothesis, we intravenously transplanted BMSCs into a rat model of cerebral I/R injury (middle cerebral artery occlusion [MCAO]). Our results indicated that BMSCs transplantation promoted behavioral recovery, reduced cerebral infarction volume, and decreased the number of apoptotic cells in rats exposed to cerebral I/R injury. Moreover, this effect was associated with reduced expression of the autophagy-associated proteins microtubule-associated protein 1 light chain 3 (LC3) and Beclin-1. Furthermore, BMSCs remarkably increased the expression of p-Akt and p-mTOR following cerebral I/R injury. Expression of LC3 also increased when the PI3K pathway was blocked using LY294002. In summary, our results indicated that the protective effects of BMSCs in cerebral I/R injury may be associated with the inhibition of autophagy via the activation of the PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- He He
- Rehabilitation Medicine Department, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, China
| | - Qing Zeng
- Rehabilitation Medicine Department, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, China
| | - Guozhi Huang
- Rehabilitation Medicine Department, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, China.
| | - Yiqiu Lin
- Rehabilitation Medicine Department, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, China
| | - Hongxin Lin
- Rehabilitation Medicine Department, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, China
| | - Wei Liu
- Rehabilitation Medicine Department, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, China
| | - Pengcheng Lu
- Rehabilitation Medicine Department, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou, Guangdong, China
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C. elegans Eats Its Own Intestine to Make Yolk Leading to Multiple Senescent Pathologies. Curr Biol 2018; 28:2544-2556.e5. [PMID: 30100339 PMCID: PMC6108400 DOI: 10.1016/j.cub.2018.06.035] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 05/08/2018] [Accepted: 06/18/2018] [Indexed: 11/30/2022]
Abstract
Aging (senescence) is characterized by the development of numerous pathologies, some of which limit lifespan. Key to understanding aging is discovery of the mechanisms (etiologies) that cause senescent pathology. In C. elegans, a major senescent pathology of unknown etiology is atrophy of its principal metabolic organ, the intestine. Here we identify a cause of not only this pathology but also of yolky lipid accumulation and redistribution (a form of senescent obesity): autophagy-mediated conversion of intestinal biomass into yolk. Inhibiting intestinal autophagy or vitellogenesis rescues both visceral pathologies and can also extend lifespan. This defines a disease syndrome leading to multimorbidity and contributing to late-life mortality. Activation of gut-to-yolk biomass conversion by insulin/IGF-1 signaling (IIS) promotes reproduction and senescence. This illustrates how major, IIS-promoted senescent pathologies in C. elegans can originate not from damage accumulation but from direct effects of futile, continued action of a wild-type biological program (vitellogenesis).
C. elegans consume their own intestine to synthesize yolk and promote reproduction This causes diseases of aging, including atrophy of the intestine and yolk steatosis Intestinal senescence in C. elegans is promoted by autophagy Here destructive run-on of wild-type biological programs causes senescent pathologies
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PU.1/microRNA-142-3p targets ATG5/ATG16L1 to inactivate autophagy and sensitize hepatocellular carcinoma cells to sorafenib. Cell Death Dis 2018; 9:312. [PMID: 29472524 PMCID: PMC5833744 DOI: 10.1038/s41419-018-0344-0] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 01/14/2018] [Accepted: 01/23/2018] [Indexed: 12/12/2022]
Abstract
Sorafenib is currently the only systemic agent approved for treatment of advanced hepatocellular carcinoma (HCC). However, intrinsic and acquired resistance to sorafenib remains a great challenge with respect to improving the prognoses of patients with HCC. The cyto-protective functions of autophagy have been suggested as a potential mechanism by which chemoresistance or targeted drug resistance occurs in tumour cells. In the present study, miR-142-3p was identified as a novel autophagy-regulating microRNA (miRNA) that plays a vital role in sorafenib resistance in HCC cells. Gain- and loss-of-function assays revealed that ectopic miR-142-3p upregulation sensitized HCC cells to sorafenib by reducing sorafenib-induced autophagy, enhancing sorafenib-induced apoptosis and inhibiting cell growth, whereas miR-142-3p inhibition exerted contrasting effects. Bioinformatics analysis and luciferase reporter and rescue assays showed that autophagy-related 5 (ATG5) and autophagy-related 16-like 1 (ATG16L1) are potential targets through which miR-142-3p regulates autophagy inhibition. Furthermore, we verified that PU.1 regulated the expression of miR-142-3p in conjunction with our cellular experiments and the related results in the literature. Our findings show that targeting the PU.1-miR-142-3p-ATG5/ATG16L1 axis may be a useful therapeutic strategy for preventing cyto-protective autophagy to overcome sorafenib resistance.
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Duris K, Splichal Z, Jurajda M. The Role of Inflammatory Response in Stroke Associated Programmed Cell Death. Curr Neuropharmacol 2018; 16:1365-1374. [PMID: 29473512 PMCID: PMC6251044 DOI: 10.2174/1570159x16666180222155833] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 07/17/2017] [Accepted: 02/22/2018] [Indexed: 01/13/2023] Open
Abstract
Stroke represents devastating pathology which is associated with a high morbidity and mortality. Initial damage caused directly by the onset of stroke, primary injury, may be eclipsed by secondary injury which may have a much more devastating effect on the brain. Primary injury is predominantly associated with necrotic cell death due to fatal insufficiency of oxygen and glucose. Secondary injury may on the contrary, lead apoptotic cell death due to structural damage which is not compatible with cellular functions or which may even represent the danger of malign transformation. The immune system is responsible for surveillance, defense and healing processes and the immune system plays a major role in triggering programmed cell death. Severe pathologies, such as stroke, are often associated with deregulation of the immune system, resulting in aggravation of secondary brain injury. The goal of this article is to overview the current knowledge about the role of immune system in the pathophysiology of stroke with respect to programmed neuronal cell death as well as to discuss current therapeutic strategies targeting inflammation after stroke.
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Affiliation(s)
| | | | - M. Jurajda
- Address correspondence to this author at the Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic; E-mail:
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High LC3/Beclin Expression Correlates with Poor Survival in Glioma: a Definitive Role for Autophagy as Evidenced by In Vitro Autophagic Flux. Pathol Oncol Res 2017; 25:137-148. [PMID: 29022195 DOI: 10.1007/s12253-017-0310-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 09/13/2017] [Indexed: 12/26/2022]
Abstract
Recent studies suggest the role of autophagy, an evolutionarily conserved catabolic process, in determining the response of gliomas to treatment either positively or negatively. The study attempts to characterize autophagy in low and high-grade glioma by investigating the autophagic flux and clinical significance of autophagy proteins (LC3 and beclin 1) in a group of glioma patients. We evaluated the expression of autophagic markers in resected specimens of low-grade glioma (LGG) and high-grade glioma (HGG) tissues, by immunohistochemistry and Western blotting. Our results show that expression of autophagy proteins were more prominent in HGG than in LGG. Increased level of autophagic proteins in HGG can be due to an increased rate of autophagy or can be because of blockage in the final degradation step of autophagy (defective autophagy). To distinguish these possibilities, the autophagic flux assay which helps to determine the rate of degradation/synthesis of autophagic proteins (LC3-II and p62) over a period of time by blocking the final degradation step of autophagy using bafilomycin A1 was used . The assessment of autophagic flux in ex vivo culture of primary glioma cells revealed for the first time increased turnover of autophagy in high grade compared to low grade-glioma. Though autophagic markers were reduced in LGG, functionally autophagy was non defective in both grades of glioma. We then investigated whether autophagy in gliomas is regulated by nutrient sensing pathways including mTOR and promote cell survival by providing an alternate energy source in response to metabolic stress. The results depicted that the role of autophagy during stress varies with tissue and has a negative correlation with mTOR substrate phosphorylation. We also evaluated the expression of LC3 and beclin 1 with progression free survival (PFS) using Kaplan-Meier survival analysis and have found that patients with low LC3/beclin 1 expression had better PFS than those with high expression of LC3/beclin 1 in their tumors. Together, we provide evidence that autophagy is non-defective in glioma and also show that high LC3/beclin 1 expression correlates with poor PFS in both LGG and HGG.
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Kwon Y, Kim JW, Jeoung JA, Kim MS, Kang C. Autophagy Is Pro-Senescence When Seen in Close-Up, but Anti-Senescence in Long-Shot. Mol Cells 2017; 40:607-612. [PMID: 28927262 PMCID: PMC5638768 DOI: 10.14348/molcells.2017.0151] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Accepted: 08/15/2017] [Indexed: 12/12/2022] Open
Abstract
When mammalian cells and animals face a variety of internal or external stresses, they need to make homeostatic changes so as to cope with various stresses. To this end, mammalian cells are equipped with two critical stress responses, autophagy and cellular senescence. Autophagy and cellular senescence share a number of stimuli including telomere shortening, DNA damage, oncogenic stress and oxidative stress, suggesting their intimate relationship. Autophagy is originally thought to suppress cellular senescence by removing damaged macromolecules or organelles, yet recent studies also indicated that autophagy promotes cellular senescence by facilitating the synthesis of senescence-associated secretory proteins. These seemingly opposite roles of autophagy may reflect a complex picture of autophagic regulation on cellular senescence, including different types of autophagy or a unique spatiotemporal activation of autophagy. Thus, a better understanding of autophagy process will lead us to not only elucidate the conundrum how autophagy plays dual roles in the regulation of cellular senescence but also helps the development of new therapeutic strategies for many human diseases associated with cellular senescence. We address the pro-senescence and anti-senescence roles of autophagy while focusing on the potential mechanistic aspects of this complex relationship between autophagy and cellular senescence.
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Affiliation(s)
- Yoojin Kwon
- School of Biological Sciences, Seoul National University, Seoul 08826,
Korea
| | - Ji Wook Kim
- School of Biological Sciences, Seoul National University, Seoul 08826,
Korea
| | - Jo Ae Jeoung
- School of Biological Sciences, Seoul National University, Seoul 08826,
Korea
| | - Mi-Sung Kim
- School of Biological Sciences, Seoul National University, Seoul 08826,
Korea
| | - Chanhee Kang
- School of Biological Sciences, Seoul National University, Seoul 08826,
Korea
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38
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Dou Y, Shen H, Feng D, Li H, Tian X, Zhang J, Wang Z, Chen G. Tumor necrosis factor receptor-associated factor 6 participates in early brain injury after subarachnoid hemorrhage in rats through inhibiting autophagy and promoting oxidative stress. J Neurochem 2017; 142:478-492. [PMID: 28543180 DOI: 10.1111/jnc.14075] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 04/24/2017] [Accepted: 05/17/2017] [Indexed: 12/21/2022]
Abstract
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is a member of the TRAF family and an important multifunctional intracellular adaptin of the tumor necrosis factor superfamily and toll/IL-1 receptor (TIR) superfamily. TRAF6 has been studied in several central nervous system diseases, including ischemic stroke, traumatic brain injury, and neurodegenerative diseases, but its role in subarachnoid hemorrhage (SAH) has not been fully illustrated. This study was designed to explore changes of expression level and potential roles and mechanisms of TRAF6 in early brain injury (EBI) after SAH using a Sprague-Dawley rat model of SAH induced in 0.3 mL non-heparinized autologous arterial blood injected into the pre-chiasmatic cistern. First, compared with the sham group, we found that the expression levels of TRAF6 increased gradually and peaked at 24 h after SAH. Second, the results showed that application of TRAF6 over-expression plasmid and genetic silencing siRNA could increase or decrease expression of TRAF6, respectively, and severely exacerbate or relieve EBI after SAH, including neuronal death, brain edema, and blood-brain barrier injury. Meanwhile, the levels of autophagy and oxidative stress were reduced and increased separately. Finally, GFP-TRAF6-C70A, which is a TRAF6 mutant that lacks E3 ubiquitin ligase activity, was used to explore the mechanism of TRAF6 in SAH, and the results showed that EBI and oxidative stress were reduced, but the levels of autophagy were increased under this condition. Collectively, these results indicated that TRAF6 affected the degree of EBI after SAH by inhibiting autophagy and promoting oxidative stress.
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Affiliation(s)
- Yang Dou
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | | | - Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiaodi Tian
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Jian Zhang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhong Wang
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Zhu Z, Huang Y, Lv L, Tao Y, Shao M, Zhao C, Xue M, Sun J, Niu C, Wang Y, Kim S, Cong W, Mao W, Jin L. Acute ethanol exposure-induced autophagy-mediated cardiac injury via activation of the ROS-JNK-Bcl-2 pathway. J Cell Physiol 2017; 233:924-935. [PMID: 28369910 DOI: 10.1002/jcp.25934] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Accepted: 03/24/2017] [Indexed: 12/27/2022]
Abstract
Binge drinking is associated with increased cardiac autophagy, and often triggers heart injury. Given the essential role of autophagy in various cardiac diseases, this study was designed to investigate the role of autophagy in ethanol-induced cardiac injury and the underlying mechanism. Our study showed that ethanol exposure enhanced the levels of LC3-II and LC3-II positive puncta and promoted cardiomyocyte apoptosis in vivo and in vitro. In addition, we found that ethanol induced autophagy and cardiac injury largely via the sequential triggering of reactive oxygen species (ROS) accumulation, activation of c-Jun NH2-terminal kinase (JNK), phosphorylation of Bcl-2, and dissociation of the Beclin 1/Bcl-2 complex. By contrast, inhibition of ethanol-induced autophagic flux with pharmacologic agents in the hearts of mice and cultured cells significantly alleviated ethanol-induced cardiomyocyte apoptosis and heart injury. Elimination of ROS with the antioxidant N-acetyl cysteine (NAC) or inhibition of JNK with the JNK inhibitor SP600125 reduced ethanol-induced autophagy and subsequent autophagy-mediated apoptosis. Moreover, metallothionein (MT), which can scavenge reactive oxygen and nitrogen species, also attenuated ethanol-induced autophagy and cell apoptosis in MT-TG mice. In conclusion, our findings suggest that acute ethanol exposure induced autophagy-mediated heart toxicity and injury mainly through the ROS-JNK-Bcl-2 signaling pathway.
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Affiliation(s)
- Zhongxin Zhu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Yewei Huang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Lingchun Lv
- The First Affiliated Hospital of Zhejiang Chinese Medical University, First Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, P. R. China.,Department of Cardiology, Lishui Central Hospital and the Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, P. R. China
| | - Youli Tao
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Minglong Shao
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Congcong Zhao
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Mei Xue
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Jia Sun
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Chao Niu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Yang Wang
- Department of Histology and Embryology, Institute of neuroscience, Wenzhou Medical University, Wenzhou, P. R. China
| | - Sunam Kim
- Natural Products Research Institute, Korea Institute of Science and Technology, Gangneung, Korea
| | - Weitao Cong
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
| | - Wei Mao
- The First Affiliated Hospital of Zhejiang Chinese Medical University, First Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, P. R. China
| | - Litai Jin
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, P. R. China
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Li H, Wu J, Shen H, Yao X, Liu C, Pianta S, Han J, Borlongan CV, Chen G. Autophagy in hemorrhagic stroke: Mechanisms and clinical implications. Prog Neurobiol 2017; 163-164:79-97. [PMID: 28414101 DOI: 10.1016/j.pneurobio.2017.04.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Revised: 02/13/2017] [Accepted: 04/08/2017] [Indexed: 02/07/2023]
Abstract
Accumulating evidence advances the critical role of autophagy in brain pathology after stroke. Investigations employing autophagy induction or inhibition using pharmacological tools or autophagy-related gene knockout mice have recently revealed the biological significance of intact and functional autophagy in stroke. Most of the reported cases attest to a pro-survival role for autophagy in stroke, by facilitating removal of damaged proteins and organelles, which can be recycled for energy generation and cellular defenses. However, these observations are difficult to reconcile with equally compelling evidence demonstrating stroke-induced upregulation of brain cell death index that parallels enhanced autophagy. This begs the question of whether drug-induced autophagy during stroke culminates in improved or worsened pathological outcomes. A corollary fascinating hypothesis, but presents as a tricky conundrum, involves the effects of autophagy on cell death and inflammation, which are two main culprits in the disease progression of stroke-induced brain injury. Evidence has extended the roles of autophagy in inflammation via cytokine regulation in an unconventional secretion manner or by targeting inflammasomes for degradation. Moreover, in the recently concluded Vancouver Autophagy Symposium (VAS) held in 2014, the potential of selective autophagy for clinical treatment has been recognized. The role of autophagy in ischemic stroke has been reviewed previously in detail. Here, we evaluate the strength of laboratory and clinical evidence by providing a comprehensive summary of the literature on autophagy, and thereafter we offer our perspectives on exploiting autophagy as a drug target for cerebral ischemia, especially in hemorrhagic stroke.
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Affiliation(s)
- Haiying Li
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - Jiang Wu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - Haitao Shen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - Xiyang Yao
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - Chenglin Liu
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China
| | - S Pianta
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine,12901 Bruce B Downs Blvd Tampa, FL 33612 USA
| | - J Han
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine,12901 Bruce B Downs Blvd Tampa, FL 33612 USA
| | - C V Borlongan
- Center of Excellence for Aging and Brain Repair, Department of Neurosurgery & Brain Repair, University of South Florida Morsani College of Medicine,12901 Bruce B Downs Blvd Tampa, FL 33612 USA
| | - Gang Chen
- Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University,188 Shizi Street, Suzhou 215006, China.
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Shi Y, Zhao Y, Shao N, Ye R, Lin Y, Zhang N, Li W, Zhang Y, Wang S. Overexpression of microRNA-96-5p inhibits autophagy and apoptosis and enhances the proliferation, migration and invasiveness of human breast cancer cells. Oncol Lett 2017; 13:4402-4412. [PMID: 28588711 DOI: 10.3892/ol.2017.6025] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 02/03/2017] [Indexed: 12/11/2022] Open
Abstract
MicroRNAs (miRNA/miR) are short non-coding RNAs that function in the endogenous regulation of genes. miRNAs serve important roles in cellular events such as apoptosis, cell proliferation, migration, invasion, autophagy and the cell cycle. They also control the genesis and progression of tumors. Autophagy is a self-digestive process that occurs as a response to stress, and serves two opposite roles in tumor promotion or inhibition that may result in resistance to therapy. A number of studies have revealed that miRNAs control autophagic activity by targeting autophagy-associated genes, particularly in cancer. These previous studies demonstrated that miR-96-5p is upregulated in several types of malignant tumors. However, other functions of miR-96-5p in breast cancer, particularly those that are associated with autophagy, remain unknown. miR-96-5p expression was demonstrated to be upregulated in breast cancer cells compared with in normal breast epithelial cells. The overexpression of miR-96-5p inhibited autophagy, particularly starvation-induced autophagy, in MCF-7 and MDA-MB-231 cells. In addition, this inhibitory effect may have resulted in the suppression of Forkhead box O1. Additionally, the overexpression of miR-96-5p may promote cell proliferation, migration and invasion and inhibit apoptosis in MCF-7 and MDA-MB-231 cells. These data indicate that miR-96-5p is involved in the progression of breast cancer cells and may represent a potential therapeutic target for the treatment of breast cancer.
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Affiliation(s)
- Yawei Shi
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yang Zhao
- Department of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Nan Shao
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Runyi Ye
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Yin Lin
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Ning Zhang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Wen Li
- Laboratory of General Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.,Guangdong Engineering Laboratory for Diagnosis and Treatment of Vascular Disease, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510275, P.R. China
| | - Yunjian Zhang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Shenming Wang
- Department of Thyroid and Breast Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China.,Department of Vascular Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong 510080, P.R. China
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Catalpol protects glucose-deprived rat embryonic cardiac cells by inducing mitophagy and modulating estrogen receptor. Biomed Pharmacother 2017; 89:973-982. [PMID: 28292026 DOI: 10.1016/j.biopha.2017.02.069] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 02/14/2017] [Accepted: 02/20/2017] [Indexed: 02/07/2023] Open
Abstract
Catalpol, a bioactive component from Rehmannia glutinosa (Di Huang), has been widely used to protect cardiomyocytes against myocardial ischemia. The aim of the present study was to investigate the anti-apoptotic and anti-oxidative effects of Catalpol on glucose-starved H9c2 cells for cardio-protection and to elucidate the underlying mechanisms. Here, we showed that Catalpol protected the glucose-starved H9c2 cells through reducing apoptosis and attenuating oxidative damage. Moreover, the increases of autophagic lysosomes, LC3, autophagic flux and autophagic vacuole were observed in Catalpol-treated cells using flow cytometer and fluorescence microscope. Western blotting analyses showed that the autophagy-related proteins (LC3, Beclin1 and ULK) were markedly increased in Catalpol-treated cells, suggesting that Catalpol up-regulated autophagy in glucose starved H9c2 cells. Mechanistic investigations revealed that the autophagy inhibitor 3-MA markedly abrogated Catalpol's anti-apoptotic and anti-oxidative effects and prevented Catalpol-induced mitophagy. Furthermore, the estrogen receptor inhibitor tamoxifen significantly abolished Catalpol up-regulation of mitophagic related proteins (LC3, Beclin 1, p62, ATG5). Collectively, these data revealed that Catalpol inhibited apoptosis and oxidative stress in glucose-deprived H9c2 cell through promoting cell mitophagy and modulating estrogen receptor, supporting the notion that Catalpol could be a novel drug candidate against myocardial ischemia for the treatment of cardiovascular diseases.
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Interferon regulatory factor-1 activates autophagy to aggravate hepatic ischemia-reperfusion injury via the P38/P62 pathway in mice. Sci Rep 2017; 7:43684. [PMID: 28266555 PMCID: PMC5339805 DOI: 10.1038/srep43684] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 01/30/2017] [Indexed: 01/07/2023] Open
Abstract
Increasing evidence has linked autophagy to a detrimental role in hepatic ischemia- reperfusion (IR) injury (IRI). Here we focus on the role of interferon regulatory factor-1 (IRF-1) in regulating autophagy to aggravate hepatic IRI. We found that IRF-1 was up-regulated during hepatic IRI and was associated with an activation of the autophagic signaling. This increased IRF-1 expression, which was allied with high autophagic activity, amplified liver damage to IR, an effect which was abrogated by IRF-1 depletion. Moreover, IRF-1 contributed to P38 induced autophagic and apoptotic cell death, that can play a key role in liver dysfunction. The levels of P62 mRNA and protein were increased when P38 was activated and decreased when P38 was inhibited by SB203580. We conclude that IRF-1 functioned as a trigger to activate autophagy via P38 activation and that P62 was required for this P38-mediated autophagy. IRF-1 appears to exert a pivotal role in hepatic IRI, by predisposing hepatocytes to activate an autophagic pathway. Such an effect promotes autophagic cell death through the P38/P62 pathway. The identification of this novel pathway, that links expression levels of IRF-1 with autophagy, may provide new insights for the generation of novel protective therapies directed against hepatic IRI.
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Brusentsev EY, Tikhonova MA, Herbeck YE, Ragaeva DS, Rozhkova IN, Amstislavsky SY. Developmental aspects of senescence. Russ J Dev Biol 2017; 48:93-105. [DOI: 10.1134/s1062360417020035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/04/2023]
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Feng J, Chen X, Shen J. Reactive nitrogen species as therapeutic targets for autophagy: implication for ischemic stroke. Expert Opin Ther Targets 2017; 21:305-317. [DOI: 10.1080/14728222.2017.1281250] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- Jinghan Feng
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China
| | - Xingmiao Chen
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China
| | - Jiangang Shen
- School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
- The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Shenzhen, China
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Abstract
Deadly diseases, such as cardiovascular diseases and cancer, remain the major health problems worldwide. Research in cardiovascular diseases and genome-wide association studies were successful in indentifying the gene loci associated with these threatening diseases. Yet, a substantial number of casual factors remain unexplained. Over the last decade, a better understanding of molecular and biochemical mechanisms of cardiac diseases led to developing a rationale for combining various protective agents, such as polyphenols, to target multiple signaling pathways. The present review article summarizes recent advances of the use of polyphenols against diseases, such as cardiac diseases.
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Angeletti F, Fossati G, Pattarozzi A, Würth R, Solari A, Daga A, Masiello I, Barbieri F, Florio T, Comincini S. Inhibition of the Autophagy Pathway Synergistically Potentiates the Cytotoxic Activity of Givinostat (ITF2357) on Human Glioblastoma Cancer Stem Cells. Front Mol Neurosci 2016; 9:107. [PMID: 27833530 PMCID: PMC5081386 DOI: 10.3389/fnmol.2016.00107] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Accepted: 10/07/2016] [Indexed: 12/13/2022] Open
Abstract
Increasing evidence highlighted the role of cancer stem cells (CSCs) in the development of tumor resistance to therapy, particularly in glioblastoma (GBM). Therefore, the development of new therapies, specifically directed against GBM CSCs, constitutes an important research avenue. Considering the extended range of cancer-related pathways modulated by histone acetylation/deacetylation processes, we studied the anti-proliferative and pro-apoptotic efficacy of givinostat (GVS), a pan-histone deacetylase inhibitor, on cell cultures enriched in CSCs, isolated from nine human GBMs. We report that GVS induced a significant reduction of viability and self-renewal ability in all GBM CSC cultures; conversely, GVS exposure did not cause a significant cytotoxic activity toward differentiated GBM cells and normal mesenchymal human stem cells. Analyzing the cellular and molecular mechanisms involved, we demonstrated that GVS affected CSC viability through the activation of programmed cell death pathways. In particular, a marked stimulation of macroautophagy was observed after GVS treatment. To understand the functional link between GVS treatment and autophagy activation, different genetic and pharmacological interfering strategies were used. We show that the up-regulation of the autophagy process, obtained by deprivation of growth factors, induced a reduction of CSC sensitivity to GVS, while the pharmacological inhibition of the autophagy pathway and the silencing of the key autophagy gene ATG7, increased the cell death rate induced by GVS. Altogether these findings suggest that autophagy represents a pro-survival mechanism activated by GBM CSCs to counteract the efficacy of the anti-proliferative activity of GVS. In conclusion, we demonstrate that GVS is a novel pharmacological tool able to target GBM CSC viability and its efficacy can be enhanced by autophagy inhibitory strategies.
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Affiliation(s)
| | - Gianluca Fossati
- Preclinical Research Department Italfarmaco Research Center, Italfarmaco S.p.A Cinisello Balsamo, Italy
| | - Alessandra Pattarozzi
- Department of Internal Medicine, Centre of Excellence for Biomedical Research, University of Genova Genova, Italy
| | - Roberto Würth
- Department of Internal Medicine, Centre of Excellence for Biomedical Research, University of Genova Genova, Italy
| | - Agnese Solari
- Department of Internal Medicine, Centre of Excellence for Biomedical Research, University of Genova Genova, Italy
| | - Antonio Daga
- Regenerative Medicine, IRCCS Azienda Ospedaliera Universitaria San Martino - IST Genova, Italy
| | - Irene Masiello
- Department of Biology and Biotechnology, University of Pavia Pavia, Italy
| | - Federica Barbieri
- Department of Internal Medicine, Centre of Excellence for Biomedical Research, University of Genova Genova, Italy
| | - Tullio Florio
- Department of Internal Medicine, Centre of Excellence for Biomedical Research, University of Genova Genova, Italy
| | - Sergio Comincini
- Department of Biology and Biotechnology, University of Pavia Pavia, Italy
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Pizarro M, Troncoso R, Martínez GJ, Chiong M, Castro PF, Lavandero S. Basal autophagy protects cardiomyocytes from doxorubicin-induced toxicity. Toxicology 2016; 370:41-48. [DOI: 10.1016/j.tox.2016.09.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Revised: 09/15/2016] [Accepted: 09/21/2016] [Indexed: 10/21/2022]
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Vavilis T, Delivanoglou N, Aggelidou E, Stamoula E, Mellidis K, Kaidoglou A, Cheva A, Pourzitaki C, Chatzimeletiou K, Lazou A, Albani M, Kritis A. Oxygen-Glucose Deprivation (OGD) Modulates the Unfolded Protein Response (UPR) and Inflicts Autophagy in a PC12 Hypoxia Cell Line Model. Cell Mol Neurobiol 2016; 36:701-12. [PMID: 26239244 PMCID: PMC11482405 DOI: 10.1007/s10571-015-0250-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 07/29/2015] [Indexed: 11/29/2022]
Abstract
Hypoxia is the lack of sufficient oxygenation of tissue, imposing severe stress upon cells. It is a major feature of many pathological conditions such as stroke, traumatic brain injury, cerebral hemorrhage, perinatal asphyxia and can lead to cell death due to energy depletion and increased free radical generation. The present study investigates the effect of hypoxia on the unfolded protein response of the cell (UPR), utilizing a 16-h oxygen-glucose deprivation protocol (OGD) in a PC12 cell line model. Expression of glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94), key players of the UPR, was studied along with the expression of glucose-regulated protein 75 (GRP75), heat shock cognate 70 (HSC70), and glyceraldehyde 3-phosphate dehydrogenase, all with respect to the cell death mechanism(s). Cells subjected to OGD displayed upregulation of GRP78 and GRP94 and concurrent downregulation of GRP75. These findings were accompanied with minimal apoptotic cell death and induction of autophagy. The above observation warrants further investigation to elucidate whether autophagy acts as a pro-survival mechanism that upon severe and prolonged hypoxia acts as a concerted cell response leading to cell death. In our OGD model, hypoxia modulates UPR and induces autophagy.
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Affiliation(s)
- Theofanis Vavilis
- Laboratory of Physiology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Nikoleta Delivanoglou
- Laboratory of Physiology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Eleni Aggelidou
- Laboratory of Physiology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Eleni Stamoula
- Laboratory of Physiology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Kyriakos Mellidis
- Laboratory of Physiology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Aikaterini Kaidoglou
- Laboratory of Histology, Embryology and Anthropology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Angeliki Cheva
- Department of Pathology, General Hospital of Thessaloniki "G. Papanikolaou", Thessaloniki, Greece
| | - Chryssa Pourzitaki
- Laboratory of Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Katerina Chatzimeletiou
- Unit of Human Reproduction, 1st Department of Obstetrics and Gynaecology, Aristotle University Medical School, Papageorgiou General Hospital, Thessaloniki, Greece
| | - Antigone Lazou
- Laboratory of Physiology, School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Maria Albani
- Laboratory of Physiology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece
| | - Aristeidis Kritis
- Laboratory of Physiology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece.
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Li D, Wang J, Hou J, Fu J, Chang D, Bensoussan A, Liu J. Ginsenoside Rg1 protects starving H9c2 cells by dissociation of Bcl-2-Beclin1 complex. Altern Ther Health Med 2016; 16:146. [PMID: 27228978 PMCID: PMC4881172 DOI: 10.1186/s12906-016-1112-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 05/13/2016] [Indexed: 12/12/2022]
Abstract
Background Autophagy can result in cellular adaptation, as well as cell survival or cell death. We investigated how ginsenoside Rg1(G-Rg1) regulates the relationship between autophagy and apoptosis induced by continuous starvation. Methods H9c2 cells under continuous starvation were treated with or without ginsenoside Rg1, and autophagy and apoptosis related proteins were assessed over a continuous time course by Western blot. Dynamic fluorescence intensity of green fluorescent protein (GFP)-LC3 was used to assess autophagosome formation by live cell imaging. Cyan fluorescent protein (CFP) -Beclin1(BECN1) and yellow fluorescent protein (YFP) -Bcl-2 were co-transfected into cells to observe ginsenoside Rg1 regulation of BECN1/Bcl-2 interaction using Fluorescence Resonance Energy Transfer (FRET). Immunoprecipitation was also used to assess BECN1/Bcl-2 interaction over a continuous time course. Results In H9c2 cells, starvation induced both apoptosis and autophagy. Cell apoptosis was significantly attenuated in ginsenoside Rg1-treated conditions, while autophagy was promoted. Ginsenoside Rg1 weakened the interaction between Beclin1 and Bcl-2, inhibiting apoptosis while promoting autophagy. Our results suggest that autophagy is beneficial to starved cardiac cells over a period of time. Furthermore, we describe the effect of ginsenoside Rg1 on the relationship between autophagy and apoptosis during starvation. Conclusions Our findings provide valuable evidence for employing ginsenoside Rg1 as a specific promoter of autophagy and inhibitor of apoptosis. Electronic supplementary material The online version of this article (doi:10.1186/s12906-016-1112-2) contains supplementary material, which is available to authorized users.
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