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1
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Wang C, Zhang Y, Yang S, Savelkoul HFJ, Jansen CA, Liu G. Zn 2+ inhibits PEDV replication by inducing autophagy through the Akt-mTOR pathway. Vet Microbiol 2025; 301:110343. [PMID: 39708717 DOI: 10.1016/j.vetmic.2024.110343] [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: 10/31/2024] [Revised: 12/13/2024] [Accepted: 12/16/2024] [Indexed: 12/23/2024]
Abstract
Porcine epidemic diarrhea virus (PEDV) is a coronavirus that induces diarrhea in pigs, leading to severe economic losses in the global pig industry. Currently, effective antiviral treatments for porcine epidemic diarrhea (PED) are rarely available for clinical use. Zinc (Zn2+), an essential mineral, is known to reduce diarrhea in piglets transitioning from milk to solid feed by modulating immune system activity. In this study, the role of Zn2+ in regulating PEDV infection was investigated to explore its potential for reducing diarrhea. Our findings show that Zn2+ inhibits PEDV replication in Vero-E6 cells by inducing autophagy. Notably, we demonstrated that autophagy negatively regulates PEDV infection, as confirmed by the use of autophagy inhibitor (3-MA) and activator (RAPA). Further analysis revealed that PEDV infection activates the Akt-mTOR signaling pathway, while Zn2+ inhibits this pathway in Vero-E6 cells. Additionally, overexpression of Akt and AktSer473 plasmids in Vero-E6 cells highlights the role of Akt phosphorylation in the Zn2+ induced autophagy that inhibits PEDV replication. In summary, this study identifies a mechanism by which Zn2+ suppresses PEDV infection through the Akt-mTOR pathway by mediating autophagy. These findings provide valuable insights into the potential use of Zn2+ as an effective antiviral agent in vivo.
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Affiliation(s)
- Caiying Wang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Cell Biology and Immunology Group, Wageningen University and Research, Wageningen, the Netherlands
| | - Yue Zhang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
| | - Shanshan Yang
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China; Cell Biology and Immunology Group, Wageningen University and Research, Wageningen, the Netherlands
| | - Huub F J Savelkoul
- Cell Biology and Immunology Group, Wageningen University and Research, Wageningen, the Netherlands
| | - Christine A Jansen
- Cell Biology and Immunology Group, Wageningen University and Research, Wageningen, the Netherlands
| | - Guangliang Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China.
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Thomas A, Nair A, Chakraborty S, Jayarajan RO, Joseph J, Ajayaghosh A. A Pyridinium fluorophore for the detection of zinc ions under autophagy conditions. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY. B, BIOLOGY 2024; 259:113006. [PMID: 39128425 DOI: 10.1016/j.jphotobiol.2024.113006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 07/18/2024] [Accepted: 08/06/2024] [Indexed: 08/13/2024]
Abstract
Molecular probes for sensing and imaging of various analytes and biological specimens are of great importance in clinical diagnostics, therapy, and disease management. Since the cellular concentration of free Zn2+ varies from nanomolar to micromolar range during cellular processes and the high affinity Zn2+ imaging probes tend to saturate at lower concentrations of free Zn2+, fluorescence based probes with moderate binding affinity are desirable in distinguishing the occurrence of higher zinc concentrations in the cells. Herein, we report a new, pentacyclic pyridinium based probe, PYD-PA, having a pendant N,N-di(pyridin-2-ylmethyl)amine (DPA) for Zn2+ detection in the cellular environment. The designed probe is soluble in water and serves as a mitochondria targeting unit, whereas the pendent DPA acts as the coordination site for Zn2+. PYD-PA displayed a threefold enhancement in fluorescence intensity upon Zn2+ binding with a 1:1 binding stoichiometry. Further, the probe showed a selective response to Zn2+ over other biologically relevant metal ions with a moderate binding affinity (Ka = 6.29 × 104 M-1), good photostability, pH insensitivity, and low cytotoxicity. The demonstration of bioimaging in SK-BR-3 breast cancer cell lines confirmed the intracellular Zn ion sensing ability of the probe. The probe was successfully applied for real time monitoring of the fluctuation of intracellular free zinc ions during autophagy conditions, demonstrating its potential for cellular imaging of Zn2+ at higher intracellular concentrations.
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Affiliation(s)
- Anagha Thomas
- Photosciences and Photonics Section, Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695 019, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Anaga Nair
- Photosciences and Photonics Section, Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695 019, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Sandip Chakraborty
- Photosciences and Photonics Section, Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695 019, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Roopasree O Jayarajan
- Photosciences and Photonics Section, Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695 019, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India
| | - Joshy Joseph
- Photosciences and Photonics Section, Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695 019, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
| | - Ayyappanpillai Ajayaghosh
- Photosciences and Photonics Section, Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695 019, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad 201002, India.
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3
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Chen Y. Advances in Organic Fluorescent Probes for Intracellular Zn 2+ Detection and Bioimaging. Molecules 2024; 29:2542. [PMID: 38893419 PMCID: PMC11173588 DOI: 10.3390/molecules29112542] [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: 04/11/2024] [Revised: 05/13/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
Zinc ions (Zn2+) play a key role in maintaining and regulating protein structures and functions. To better understand the intracellular Zn2+ homeostasis and signaling role, various fluorescent sensors have been developed that allow the monitoring of Zn2+ concentrations and bioimaging in live cells in real time. This review highlights the recent development of organic fluorescent probes for the detection and imaging of intracellular Zn2+, including the design and construction of the probes, fluorescent response mechanisms, and their applications to intracellular Zn2+ detection and imaging on-site. Finally, the current challenges and prospects are discussed.
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Affiliation(s)
- Yi Chen
- Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China;
- University of Chinese Academy of Sciences, Beijing 100190, China
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Yang X, Li W, Ding M, Liu KJ, Qi Z, Zhao Y. Contribution of zinc accumulation to ischemic brain injury and its mechanisms about oxidative stress, inflammation, and autophagy: an update. Metallomics 2024; 16:mfae012. [PMID: 38419293 DOI: 10.1093/mtomcs/mfae012] [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: 09/11/2023] [Accepted: 02/27/2024] [Indexed: 03/02/2024]
Abstract
Ischemic stroke is a leading cause of death and disability worldwide, and presently, there is no effective neuroprotective therapy. Zinc is an essential trace element that plays important physiological roles in the central nervous system. Free zinc concentration is tightly regulated by zinc-related proteins in the brain under normal conditions. Disruption of zinc homeostasis, however, has been found to play an important role in the mechanism of brain injury following ischemic stroke. A large of free zinc releases from storage sites after cerebral ischemia, which affects the functions and survival of nerve cells, including neurons, astrocytes, and microglia, resulting in cell death. Ischemia-triggered intracellular zinc accumulation also disrupts the function of blood-brain barrier via increasing its permeability, impairing endothelial cell function, and altering tight junction levels. Oxidative stress and neuroinflammation have been reported to be as major pathological mechanisms in cerebral ischemia/reperfusion injury. Studies have showed that the accumulation of intracellular free zinc could impair mitochondrial function to result in oxidative stress, and form a positive feedback loop between zinc accumulation and reactive oxygen species production, which leads to a series of harmful reactions. Meanwhile, elevated intracellular zinc leads to neuroinflammation. Recent studies also showed that autophagy is one of the important mechanisms of zinc toxicity after ischemic injury. Interrupting the accumulation of zinc will reduce cerebral ischemia injury and improve neurological outcomes. This review summarizes the role of zinc toxicity in cellular and tissue damage following cerebral ischemia, focusing on the mechanisms about oxidative stress, inflammation, and autophagy.
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Affiliation(s)
- Xueqi Yang
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China
- Beijing Geriatric Medical Research Center, Beijing 100053, China
| | - Wei Li
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China
- Beijing Geriatric Medical Research Center, Beijing 100053, China
| | - Mao Ding
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China
| | - Ke Jian Liu
- Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Zhifeng Qi
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China
- Beijing Geriatric Medical Research Center, Beijing 100053, China
| | - Yongmei Zhao
- Institute of Cerebrovascular Disease Research, Xuanwu Hospital of Capital Medical University, 45 Changchun Street, Beijing 100053, China
- Beijing Geriatric Medical Research Center, Beijing 100053, China
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Salete-Granado D, Carbonell C, Puertas-Miranda D, Vega-Rodríguez VJ, García-Macia M, Herrero AB, Marcos M. Autophagy, Oxidative Stress, and Alcoholic Liver Disease: A Systematic Review and Potential Clinical Applications. Antioxidants (Basel) 2023; 12:1425. [PMID: 37507963 PMCID: PMC10376811 DOI: 10.3390/antiox12071425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 07/06/2023] [Accepted: 07/12/2023] [Indexed: 07/30/2023] Open
Abstract
Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and excess cytoplasmic organelles for lysosomal degradation and may counteract the harmful effects of ROS-induced oxidative stress. These effects include hepatotoxicity, mitochondrial damage, steatosis, endoplasmic reticulum stress, inflammation, and iron overload. In liver diseases, particularly ALD, macroautophagy has been implicated as a protective mechanism in hepatocytes, although it does not appear to play the same role in stellate cells. Beyond the liver, autophagy may also mitigate the harmful effects of alcohol on other organs, thereby providing an additional layer of protection against ALD. This protective potential is further supported by studies showing that drugs that interact with autophagy, such as rapamycin, can prevent ALD development in animal models. This systematic review presents a comprehensive analysis of the literature, focusing on the role of autophagy in oxidative stress regulation, its involvement in organ-organ crosstalk relevant to ALD, and the potential of autophagy-targeting therapeutic strategies.
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Affiliation(s)
- Daniel Salete-Granado
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
| | - Cristina Carbonell
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - David Puertas-Miranda
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Víctor-José Vega-Rodríguez
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
| | - Marina García-Macia
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Instituto de Biología Funcional y Genómica (IBFG), Universidad de Salamanca, 37007 Salamanca, Spain
| | - Ana Belén Herrero
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
| | - Miguel Marcos
- Instituto de Investigación Biomédica de Salamanca (IBSAL), 37007 Salamanca, Spain; (D.S.-G.); (C.C.); (D.P.-M.); (V.-J.V.-R.); (M.G.-M.); (A.B.H.)
- Hospital Universitario de Salamanca, 37007 Salamanca, Spain
- Unidad de Medicina Molecular, Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain
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Sun B, Ma J, Te L, Zuo X, Liu J, Li Y, Bi J, Wang S. Zinc-Deficient Diet Causes Imbalance in Zinc Homeostasis and Impaired Autophagy and Impairs Semen Quality in Mice. Biol Trace Elem Res 2023; 201:2396-2406. [PMID: 35713811 DOI: 10.1007/s12011-022-03324-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/09/2022] [Indexed: 11/02/2022]
Abstract
Zinc (Zn) is an essential trace element for human growth and its deficiency causes huge health impacts. The present study was conducted to examine the mechanisms by which Zn-deficient diet impairs reproductive function and its reversibility. Hence, SPF grade male Kunming (KM) mice were divided into three groups. Zn-normal diet group (ZN group) was provided with Zn-normal diet (Zn content = 30 mg/kg, DY19410Y) for 8 weeks. Zn-deficient diet group (ZD group) was provided with Zn-deficient diet (Zn content < 1 mg/kg, DY19401) for 8 weeks. Zn-deficient and Zn-normal diet group (ZDN group) was provided with 4 weeks Zn-deficient diet followed by 4 weeks Zn-normal diet. After 8 weeks, the overnight-fasted mice were sacrificed, and blood and organs were collected for further analysis. The results showed that Zn-deficient diet caused testicular structural disorders, decreased semen quality, imbalance in zinc homeostasis, and impaired autophagy. Semen quality, testosterone, serum Zn, testicular tissue Zn, testicular free Zn ions, alkaline phosphatase (ALP), zinc transporter 7(ZnT7), Beclin1, autophagy-related 5(ATG5), and the ratio of light chain 3(LC3) II/LC3I were significantly decreased, and ZnT4, Zrt-, Irt-like protein7 (ZIP7), and ZIP13 expression were significantly increased in ZD group mice, while the changes in above indicators caused by Zn-deficient diet were significantly alleviated in the ZDN group. It was concluded that Zn-deficient diet causes testicular structural disorders and decreased semen quality by causing imbalances in Zn homeostasis and impaired autophagy in male mice. Reproductive damages caused by Zn-deficient diet are reversible, and Zn-normal diet can alleviate them.
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Affiliation(s)
- Bo Sun
- Graduate School of Hebei Medical University, Shijiazhuang, 050017, China
| | - Jing Ma
- NHC Key Laboratory of Family Planning and Healthy, Hebei Key Laboratory of Reproductive Medicine, Hebei Institute of Reproductive Health Science and Technology, Shijiazhuang, 050071, China
| | - Liger Te
- Graduate School of Hebei Medical University, Shijiazhuang, 050017, China
| | - Xin Zuo
- School of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang, 050024, China
| | - Junsheng Liu
- Graduate School of Hebei Medical University, Shijiazhuang, 050017, China
| | - Yuejia Li
- Graduate School of Hebei Medical University, Shijiazhuang, 050017, China
| | - Jiajie Bi
- Chengde Medical University, Chengde, 067000, China
| | - Shusong Wang
- Graduate School of Hebei Medical University, Shijiazhuang, 050017, China.
- NHC Key Laboratory of Family Planning and Healthy, Hebei Key Laboratory of Reproductive Medicine, Hebei Institute of Reproductive Health Science and Technology, Shijiazhuang, 050071, China.
- School of Chemistry and Materials Science, Hebei Normal University, Shijiazhuang, 050024, China.
- Chengde Medical University, Chengde, 067000, China.
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Association of Serum Zinc and Inflammatory Markers with the Severity of COVID-19 Infection in Adult Patients. Nutrients 2023; 15:nu15020340. [PMID: 36678211 PMCID: PMC9861200 DOI: 10.3390/nu15020340] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 11/06/2022] [Accepted: 11/09/2022] [Indexed: 01/12/2023] Open
Abstract
COVID-19 infection can spread in the host body without any adequate immune response. Zinc is an essential trace element with strong immunoregulatory and antiviral properties and its deficiency might lead to inflammation and oxidative stress. The aim of the current study was to determine the association of serum zinc and inflammatory markers with the severity of COVID-19 infection. This was a prospective observational study in which 123 COVID-19-positive adult patients and 48 controls were recruited. The initial comparative analysis was conducted between COVID-19 patients and controls. COVID-19-positive patients were further divided into three different groups (mild, moderate, and severe) based on the severity of COVID-19 infection. COVID-19 patients showed significantly lower serum zinc levels (8.8 ± 2.3 µmol/L) compared to healthy controls (11.9 ± 1.8 µmol/L). There was a negative correlation between serum zinc levels and the severity of COVID-19 infection (r = −0.584, p < 0.0001) and this effect was independent of age (r = −0.361, p < 0.0001). Furthermore, inflammatory markers showed a positive correlation with the severity of COVID-19 infection and a negative correlation with the levels of serum zinc. The study demonstrated an association between COVID-19 infection with low serum zinc levels and elevated inflammatory markers. Further studies to assess the significance of this observation are needed, which may justify zinc supplementation to mitigate the severity of COVID-19 infection.
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Kim KR, Park SE, Hong JY, Koh JY, Cho DH, Hwang JJ, Kim YH. Zinc enhances autophagic flux and lysosomal function through transcription factor EB activation and V-ATPase assembly. Front Cell Neurosci 2022; 16:895750. [PMID: 36246521 PMCID: PMC9558701 DOI: 10.3389/fncel.2022.895750] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
The stimulation of autophagy or lysosomes has been considered therapeutic for neurodegenerative disorders because the accumulation of misfolded proteins is commonly observed in the brains of individuals with these diseases. Although zinc is known to play critical roles in the functions of lysosomes and autophagy, the mechanism behind this regulatory relationship remains unclear. Therefore, in this study, we examined which mechanism is involved in zinc-mediated activation of autophagy and lysosome. Exposure to zinc at a sub-lethal concentration activated autophagy in a concentration-dependent manner in mRFP-GFP-LC3-expressing H4 glioma cells. Zinc also rescued the blocking of autophagic flux arrested by pharmaceutical de-acidification. Co-treatment with zinc attenuated the chloroquine (CQ)-induced increase in the number and size of mRFP-GFP-LC3 puncta in H4 cells and accumulation of p62 by CQ or ammonium chloride in both H4 and mouse cerebrocortical cultures. Zinc rapidly induced the expression of cathepsin B (CTSB) and cathepsin D (CTSD), representative lysosomal proteases in neurons, which appeared likely to be mediated by transcription factor EB (TFEB). We observed the translocation of TFEB from neurite to nucleus and the dephosphorylation of TFEB by zinc. The addition of cycloheximide, a chemical inhibitor of protein synthesis, inhibited the activity of CTSB and CTSD at 8 h after zinc exposure but not at 1 h, indicating that only late lysosomal activation was dependent on the synthesis of CTSB and CTSD proteins. At the very early time point, the activation of cathepsins was mediated by an increased assembly of V-ATPase on lysosomes and resultant lysosomal acidification. Finally, considering that P301L mutation in tau protein causes frontotemporal dementia through aggressive tau accumulation, we investigated whether zinc reduces the accumulation of protein aggregates in SK-N-BE(2)-C neuroblastoma cells expressing wild-type tau or mutant P301L-tau. Zinc markedly attenuated the levels of phosphorylated tau and total tau as well as p62 in both wild-type and mutant tau-overexpressing cells. We also observed that zinc was more effective than rapamycin at inducing TFEB-dependent CTSB and CTSD expression and V-ATPase-dependent lysosomal acidification and CTSB/CTSD activation. These results suggest that the regulation of zinc homeostasis could be a new approach for developing treatments for neurodegenerative diseases, including Alzheimer’s and Parkinson’s.
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Affiliation(s)
- Ki-Ryeong Kim
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, South Korea
| | - Sang Eun Park
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
| | - Ji-Ye Hong
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
| | - Jae-Young Koh
- Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
- Neuronal Injury Lab, Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
| | - Dong-Hyung Cho
- BK21 FOUR KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, South Korea
| | - Jung Jin Hwang
- Asan Institute for Life Sciences, Asan Medical Center, Seoul, South Korea
- Jung Jin Hwang,
| | - Yang-Hee Kim
- Department of Integrative Bioscience and Biotechnology, Sejong University, Seoul, South Korea
- *Correspondence: Yang-Hee Kim,
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Arab HH, Eid AH, El-Sheikh AAK, Arafa ESA, Ashour AM. Irbesartan reprofiling for the amelioration of ethanol-induced gastric mucosal injury in rats: Role of inflammation, apoptosis, and autophagy. Life Sci 2022; 308:120939. [PMID: 36115582 DOI: 10.1016/j.lfs.2022.120939] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 08/28/2022] [Accepted: 09/05/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND Pronounced anti-inflammatory and anti-apoptotic features have been characterized for the angiotensin receptor blocker irbesartan. Yet, its effect on ethanol-induced gastropathy has not been studied. The present work explored the potential modulation of inflammatory, apoptotic, and autophagic events by irbesartan for the attenuation of ethanol-evoked gastric mucosal injury. METHODOLOGY Wistar rats were divided into control, control + irbesartan, ethanol, ethanol + irbesartan, and ethanol + omeprazole groups. Macroscopic examination, histopathology, immunohistochemistry, and biochemical assays were applied to examine the gastric tissues. KEY FINDINGS Irbesartan administration (50 mg/kg; by gavage) in ethanol-evoked gastropathy improved the gastric pathological manifestations (area of gastric lesion and ulcer index scores), histopathological changes, and microscopic damage scores. These beneficial effects were interceded by suppression of the HMGB1-associated inflammatory events and the linked downregulation of the nuclear NF-κBp65 protein expression. In the meantime, curtailing of the NLRP3 inflammasome by irbesartan was observed with consequent decline of the pro-inflammatory cytokine IL-1β. In tandem, upregulation of the antioxidant Nrf2 and the cytoprotective PPAR-γ were seen. Together, suppression of the pro-inflammatory cues and pro-oxidant signals attenuated the pro-apoptotic events as evidenced by Bcl-2 upregulation, Bax downregulation, and caspase 3 dampened activity. Regarding gastric autophagy signals, irbesartan diminished SQSTM-1/p62 accumulation and upregulated Beclin 1. This was associated with gastric AMPK/mTOR pathway activation evidenced by increased AMPK (Ser487) phosphorylation and lowered mTOR (Ser2448) phosphorylation. CONCLUSION Suppression of the inflammatory and apoptotic signals and upregulation of the pro-autophagy events may advocate the promising gastroprotective actions of irbesartan against ethanol-induced gastric injury.
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Affiliation(s)
- Hany H Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
| | - Ahmed H Eid
- Department of Pharmacology, Egyptian Drug Authority (EDA), formerly NODCAR, Giza, Egypt
| | - Azza A K El-Sheikh
- Basic Health Sciences Department, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
| | - El-Shaimaa A Arafa
- College of Pharmacy and Health Sciences, Ajman University, Ajman 346, United Arab Emirates; Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 346, United Arab Emirates
| | - Ahmed M Ashour
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia
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Kim SY, Lee JH, Kim SA. Zinc Deficiency Induces Autophagy in HT-22 Mouse Hippocampal Neuronal Cell Line. Int J Mol Sci 2022; 23:ijms23158811. [PMID: 35955944 PMCID: PMC9369147 DOI: 10.3390/ijms23158811] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/02/2022] [Accepted: 08/06/2022] [Indexed: 11/16/2022] Open
Abstract
Zinc is a trace metal vital for various functions in nerve cells, although the effect of zinc deficiency on neuronal autophagy remains unclear. This study aimed to elucidate whether zinc deficiency induced by treatment with N, N, N′, N′-tetrakis (2-pyridylmethyl) ethylenediamine (TPEN), a zinc chelator, affects and alters autophagy activity. In cell viability assays, TPEN showed cytotoxicity in HT-22 cells. TPEN treatment also increased LC3-II levels and the ratio of LC3-II to LC3-I. Western blot analysis showed that phospho-AMP-activated protein kinase levels and the ratio of phospho-AMP-activated protein kinase to total AMP-activated protein kinase increased. Protein levels of the mammalian target of rapamycin and sirtuin 1 decreased following TPEN treatment. When TPEN-treated HT-22 cells were cotreated with autophagy inhibitors, 3-methyladenine (1 mM), or bafilomycin A1 (3 nM), the TPEN-induced decrease in cell viability was exacerbated. Cotreatment with chloroquine (10 μM) partially restored cell viability. The study showed that zinc deficiency induces autophagy and may be cytoprotective in neurons. We expect our results to add a new perspective to our understanding of the neuronal pathology related to zinc deficiency.
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Teil M, Doudnikoff E, Thiolat ML, Bohic S, Bezard E, Dehay B. The Zinc Ionophore Clioquinol Reduces Parkinson's Disease Patient-Derived Brain Extracts-Induced Neurodegeneration. Mol Neurobiol 2022; 59:6245-6259. [PMID: 35915387 DOI: 10.1007/s12035-022-02974-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 07/20/2022] [Indexed: 11/25/2022]
Abstract
Parkinson's disease (PD) is pathologically characterized by intracellular α-synuclein-rich protein aggregates, named Lewy bodies (LB), and by the progressive loss of dopaminergic neurons in the substantia nigra. Several heavy metals, including zinc (Zn), have been suggested to play a role in PD progression, although the exact role of Zn in neurodegeneration remains to be fully elucidated. To address this gap, we investigated the effects of Zn modulation on the progression of degeneration in mice injected with PD patient-derived LB-extracts carrying toxic α-synuclein aggregates. Zn modulation was achieved using either a clioquinol-enriched diet, a Zn ionophore that redistributes cellular Zn, or a Zn-enriched diet that increases Zn levels. Clioquinol treatment significantly prevented dopaminergic neurodegeneration and reduced α-synuclein-associated pathology in LB-injected mice, while no differences were observed with Zn supplementation. Biochemical analyses further demonstrate that the expression levels of vesicle-specific Zn transporter ZnT3 in the striatum of LB-injected mice treated with clioquinol were decreased, suggesting an intracellular redistribution of Zn. Additionally, we found that clioquinol modulates the autophagy-lysosomal pathway by enhancing lysosomal redistribution within the neuronal compartments. Collectively, we found that in vivo pharmacological chelation of Zn, by dampening Zn-mediated cytotoxicity, can result in an overall attenuation of PD-linked lysosomal alterations and dopaminergic neurodegeneration. The results support zinc chelation as a disease-modifying strategy for treating PD.
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Affiliation(s)
- Margaux Teil
- Univ. Bordeaux, CNRS, IMN, UMR 5293, F-33000, Bordeaux, France
| | | | | | - Sylvain Bohic
- Synchrotron Radiation for Biomedicine (STROBE), Univ. Grenoble Alpes, Inserm, UA7, 38000, Grenoble, France
| | - Erwan Bezard
- Univ. Bordeaux, CNRS, IMN, UMR 5293, F-33000, Bordeaux, France
| | - Benjamin Dehay
- Univ. Bordeaux, CNRS, IMN, UMR 5293, F-33000, Bordeaux, France.
- Institut des Maladies Neurodégénératives, Université de Bordeaux, CNRS UMR 5293, Centre Broca Nouvelle-Aquitaine, 146 rue Léo Saignat, 33076, Bordeaux cedex, France.
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12
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Chen H, Yu Z, Ren S, Qiu Y. Fluorescent Probes Design Strategies for Imaging Mitochondria and Lysosomes. Front Pharmacol 2022; 13:915609. [PMID: 35928260 PMCID: PMC9343947 DOI: 10.3389/fphar.2022.915609] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/30/2022] [Indexed: 11/22/2022] Open
Abstract
Modern cellular biology faces several major obstacles, such as the determination of the concentration of active sites corresponding to chemical substances. In recent years, the popular small-molecule fluorescent probes have completely changed the understanding of cellular biology through their high sensitivity toward specific substances in various organisms. Mitochondria and lysosomes are significant organelles in various organisms, and their interaction is closely related to the development of various diseases. The investigation of their structure and function has gathered tremendous attention from biologists. The advanced nanoscopic technologies have replaced the diffraction-limited conventional imaging techniques and have been developed to explore the unknown aspects of mitochondria and lysosomes with a sub-diffraction resolution. Recent progress in this field has yielded several excellent mitochondria- and lysosome-targeted fluorescent probes, some of which have demonstrated significant biological applications. Herein, we review studies that have been carried out to date and suggest future research directions that will harness the considerable potential of mitochondria- and lysosome-targeted fluorescent probes.
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Affiliation(s)
- Huimin Chen
- Institute of Materia Medica, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
- Department of Biochemistry, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai’an, China
| | - Zhenjie Yu
- Institute of Materia Medica, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Shiwei Ren
- Institute of Materia Medica, Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
| | - Yuyu Qiu
- Department of Biochemistry, Shandong First Medical University and Shandong Academy of Medical Sciences, Tai’an, China
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13
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Zinc in Cognitive Impairment and Aging. Biomolecules 2022; 12:biom12071000. [PMID: 35883555 PMCID: PMC9312494 DOI: 10.3390/biom12071000] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 07/01/2022] [Accepted: 07/05/2022] [Indexed: 02/05/2023] Open
Abstract
Zinc, an essential micronutrient for life, was first discovered in 1869 and later found to be indispensable for the normal development of plants and for the normal growth of rats and birds. Zinc plays an important role in many physiological and pathological processes in normal mammalian brain development, especially in the development of the central nervous system. Zinc deficiency can lead to neurodegenerative diseases, mental abnormalities, sleep disorders, tumors, vascular diseases, and other pathological conditions, which can cause cognitive impairment and premature aging. This study aimed to review the important effects of zinc and zinc-associated proteins in cognitive impairment and aging, to reveal its molecular mechanism, and to highlight potential interventions for zinc-associated aging and cognitive impairments.
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14
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Sadeghsoltani F, Mohammadzadeh I, Safari MM, Hassanpour P, Izadpanah M, Qujeq D, Moein S, Vaghari-Tabari M. Zinc and Respiratory Viral Infections: Important Trace Element in Anti-viral Response and Immune Regulation. Biol Trace Elem Res 2022; 200:2556-2571. [PMID: 34368933 PMCID: PMC8349606 DOI: 10.1007/s12011-021-02859-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/28/2021] [Indexed: 12/15/2022]
Abstract
Influenza viruses, respiratory syncytial virus (RSV), and SARS-COV2 are among the most dangerous respiratory viruses. Zinc is one of the essential micronutrients and is very important in the immune system. The aim of this narrative review is to review the most interesting findings about the importance of zinc in the anti-viral immune response in the respiratory tract and defense against influenza, RSV, and SARS-COV2 infections. The most interesting findings on the role of zinc in regulating immunity in the respiratory tract and the relationship between zinc and acute respiratory distress syndrome (ARDS) are reviewed, as well. Besides, current findings regarding the relationship between zinc and the effectiveness of respiratory viruses' vaccines are reviewed. The results of reviewed studies have shown that zinc and some zinc-dependent proteins are involved in anti-viral defense and immune regulation in the respiratory tract. It seems that zinc can reduce the viral titer following influenza infection. Zinc may reduce RSV burden in the lungs. Zinc can be effective in reducing the duration of viral pneumonia symptoms. Zinc may enhance the effectiveness of hydroxychloroquine in reducing mortality rate in COVID-19 patients. Besides, zinc has a positive effect in preventing ARDS and ventilator-induced lung damage. The relationship between zinc levels and the effectiveness of respiratory viruses' vaccines, especially influenza vaccines, is still unclear, and the findings are somewhat contradictory. In conclusion, zinc has anti-viral properties and is important in defending against respiratory viral infections and regulating the immune response in the respiratory tract.
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Affiliation(s)
- Fatemeh Sadeghsoltani
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Daneshgah Street, P.O. Box 51666-14711, Tabriz, Iran
| | - Iraj Mohammadzadeh
- Non-Communicable Pediatric Diseases Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Mir-Meghdad Safari
- Virtual School of Medical Education and Management, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Hassanpour
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Daneshgah Street, P.O. Box 51666-14711, Tabriz, Iran
| | - Melika Izadpanah
- Department of Anatomy, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran
- Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mostafa Vaghari-Tabari
- Department of Clinical Biochemistry and Laboratory Medicine, School of Medicine, Tabriz University of Medical Sciences, Daneshgah Street, P.O. Box 51666-14711, Tabriz, Iran.
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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15
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Reddy SS, Addi UR, Pullakhandam R, Reddy GB. Dietary Zinc deficiency disrupts skeletal muscle proteostasis and mitochondrial biology in rats. Nutrition 2022; 98:111625. [DOI: 10.1016/j.nut.2022.111625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/30/2021] [Accepted: 01/27/2022] [Indexed: 10/19/2022]
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16
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Karim MM, Sultana S, Sultana R, Rahman MT. Possible Benefits of Zinc supplement in CVD and COVID-19 Comorbidity. J Infect Public Health 2021; 14:1686-1692. [PMID: 34649043 PMCID: PMC8489295 DOI: 10.1016/j.jiph.2021.09.022] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 09/09/2021] [Accepted: 09/29/2021] [Indexed: 12/31/2022] Open
Abstract
As far as comorbidity is concerned, cardiovascular diseases (CVD) appear to be accounted for the highest prevalence, severity, and fatality among COVID 19 patients. A wide array of causal links connecting CVD and COVID-19 baffle the overall prognosis as well as the efficacy of the given therapeutic interventions. At the centre of this puzzle lies ACE2 that works as a receptor for the SARS-CoV-2, and functional expression of which is also needed to minimize vasoconstriction otherwise would lead to high blood pressure. Furthermore, SARS-CoV-2 infection seems to reduce the functional expression of ACE2. Given these circumstances, it might be advisable to consider a treatment plan for COVID-19 patients with CVD in an approach that would neither aggravate the vasodeleterious arm of the renin-angiotensinogen-aldosterone system (RAAS) nor compromise the vasoprotective arm of RAAS but is effective to minimize or if possible, inhibit the viral replication. Given the immune modulatory role of Zn in both CVD and COVID-19 pathogenesis, zinc supplement to the selective treatment plan for CVD and COVID-19 comorbid conditions, to be decided by the clinicians depending on the cardiovascular conditions of the patients, might greatly improve the therapeutic outcome. Notably, ACE2 is a zinc metalloenzyme and zinc is also known to inhibit viral replication.
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Affiliation(s)
| | - Shahnaz Sultana
- Institute of National Analytical Research and Service (INARS), Bangladesh Council of Scientific and Industrial Research (BCSIR), New Elephant Road, Dhaka 1205, Bangladesh
| | - Rokaia Sultana
- Institute of National Analytical Research and Service (INARS), Bangladesh Council of Scientific and Industrial Research (BCSIR), New Elephant Road, Dhaka 1205, Bangladesh
| | - Mohammad Tariqur Rahman
- Faculty of Dentistry, University of Malaya, Kuala Lumpur 50603, Malaysia,Corresponding author
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17
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Arab HH, Ashour AM, Gad AM, Mahmoud AM, Kabel AM. Activation of AMPK/mTOR-driven autophagy and inhibition of NLRP3 inflammasome by saxagliptin ameliorate ethanol-induced gastric mucosal damage. Life Sci 2021; 280:119743. [PMID: 34166711 DOI: 10.1016/j.lfs.2021.119743] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 06/03/2021] [Accepted: 06/11/2021] [Indexed: 02/08/2023]
Abstract
AIMS Saxagliptin, a selective/potent dipeptidyl peptidase-4 inhibitor, has revealed remarkable anti-inflammatory features in murine models of nephrotoxicity, hepatic injury, and neuroinflammation. However, its potential effect on ethanol-induced gastric mucosal injury has not been examined. Hence, the present work investigated the prospect of saxagliptin to attenuate ethanol-evoked gastric injury, with emphasis on the AMPK/mTOR-driven autophagy and NLRP3/ASC/caspase-1 pathway. MATERIALS AND METHODS In ethanol-induced gastropathy, the gastric tissues were examined by immunohistochemistry, immunoblotting, histopathology, and ELISA. KEY FINDINGS The results demonstrated that saxagliptin (10 mg/kg; by gavage) suppressed the gastric pathological signs (area of gastric ulcer and ulcer index scores), histopathologic aberrations/damage scores, without provoking hypoglycemia in rats. These protective features were attributed to the enhancement of gastric mucosal autophagy flux, as proven with increased expression of LC3-II and Beclin 1, decreased accumulation of p62 SQSTM1, and activation of the autophagy-linked AMPK/mTOR pathway by increasing the expression of p-AMPK/AMPK and decreasing the expression of the autophagy suppressor p-mTOR/mTOR signal. In tandem, saxagliptin counteracted the ethanol-induced pro-apoptotic events by downregulating Bax, upregulating Bcl2 protein, and lowering the Bax/Bcl2 ratio. Equally important, saxagliptin suppressed the NLRP3 inflammasome in the gastric tissue by lowering the expression of NLRP3, ASC, and nuclear NF-κBp65, decreasing the activity of caspase-1, and diminishing the IL-1β levels. In the same regard, saxagliptin suppressed the mucosal oxidative stress by lowering lipid peroxide levels, increasing GSH and GPx antioxidants, and activating Nrf2/HO-1 pathway. SIGNIFICANCE Saxagliptin may be a promising intervention against ethanol-evoked gastropathy by activating AMPK/mTOR-driven autophagy and inhibiting NLRP3 inflammasome.
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Affiliation(s)
- Hany H Arab
- Department of Pharmacology and Toxicology, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.
| | - Ahmed M Ashour
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al Qura University, P.O. Box 13578, Makkah 21955, Saudi Arabia
| | - Amany M Gad
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, El Ismailia, Egypt; Department of Pharmacology, Egyptian Drug Authority (EDA), formerly NODCAR, Giza, Egypt
| | - Ayman M Mahmoud
- Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt; Biotechnology Department, Research Institute of Medicinal and Aromatic Plants, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed M Kabel
- Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
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18
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Abstract
Evidence for the importance of zinc for all immune cells and for mounting an efficient and balanced immune response to various environmental stressors has been accumulating in recent years. This article describes the role of zinc in fundamental biological processes and summarizes our current knowledge of zinc's effect on hematopoiesis, including differentiation into immune cell subtypes. In addition, the important role of zinc during activation and function of immune cells is detailed and associated with the specific immune responses to bacteria, parasites, and viruses. The association of zinc with autoimmune reactions and cancers as diseases with increased or decreased immune responses is also discussed. This article provides a broad overview of the manifold roles that zinc, or its deficiency, plays in physiology and during various diseases. Consequently, we discuss why zinc supplementation should be considered, especially for people at risk of deficiency. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Inga Wessels
- Institute of Immunology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany;
| | | | - Lothar Rink
- Institute of Immunology, Faculty of Medicine, RWTH Aachen University, 52074 Aachen, Germany;
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19
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Bittencourt TL, da Silva Prata RB, de Andrade Silva BJ, de Mattos Barbosa MG, Dalcolmo MP, Pinheiro RO. Autophagy as a Target for Drug Development Of Skin Infection Caused by Mycobacteria. Front Immunol 2021; 12:674241. [PMID: 34113346 PMCID: PMC8185338 DOI: 10.3389/fimmu.2021.674241] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/28/2021] [Indexed: 12/11/2022] Open
Abstract
Pathogenic mycobacteria species may subvert the innate immune mechanisms and can modulate the activation of cells that cause disease in the skin. Cutaneous mycobacterial infection may present different clinical presentations and it is associated with stigma, deformity, and disability. The understanding of the immunopathogenic mechanisms related to mycobacterial infection in human skin is of pivotal importance to identify targets for new therapeutic strategies. The occurrence of reactional episodes and relapse in leprosy patients, the emergence of resistant mycobacteria strains, and the absence of effective drugs to treat mycobacterial cutaneous infection increased the interest in the development of therapies based on repurposed drugs against mycobacteria. The mechanism of action of many of these therapies evaluated is linked to the activation of autophagy. Autophagy is an evolutionary conserved lysosomal degradation pathway that has been associated with the control of the mycobacterial bacillary load. Here, we review the role of autophagy in the pathogenesis of cutaneous mycobacterial infection and discuss the perspectives of autophagy as a target for drug development and repurposing against cutaneous mycobacterial infection.
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Affiliation(s)
| | | | | | | | - Margareth Pretti Dalcolmo
- Helio Fraga Reference Center, Sergio Arouca National School of Public Health, Fiocruz, Rio de Janeiro, Brazil
| | - Roberta Olmo Pinheiro
- Leprosy Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil
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20
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Choi HJ, Park JH, Kim OH, Kim KH, Hong HE, Seo H, Kim SJ. Combining Everolimus and Ku0063794 Promotes Apoptosis of Hepatocellular Carcinoma Cells via Reduced Autophagy Resulting from Diminished Expression of miR-4790-3p. Int J Mol Sci 2021; 22:ijms22062859. [PMID: 33799789 PMCID: PMC7998287 DOI: 10.3390/ijms22062859] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/09/2021] [Accepted: 03/09/2021] [Indexed: 11/16/2022] Open
Abstract
It is challenging to overcome the low response rate of everolimus in the treatment of patients with hepatocellular carcinoma (HCC). To overcome this challenge, we combined everolimus with Ku0063794, the inhibitor of mTORC1 and mTORC2, to achieve higher anticancer effects. However, the precise mechanism for the synergistic effects is not clearly understood yet. To achieve this aim, the miRNAs were selected that showed the most significant variation in expression according to the mono- and combination therapy of everolimus and Ku0063794. Subsequently, the roles of specific miRNAs were determined in the processes of the treatment modalities. Compared to individual monotherapies, the combination therapy significantly reduced viability, increased apoptosis, and reduced autophagy in HepG2 cells. The combination therapy led to significantly lower expression of miR-4790-3p and higher expression of zinc finger protein225 (ZNF225)—the predicted target of miR-4790-3p. The functional study of miR-4790-3p and ZNF225 revealed that regarding autophagy, miR-4790-3p promoted it, while ZNF225 inhibited it. In addition, regarding apoptosis, miR-4790-3p inhibited it, while ZNF225 promoted it. It was also found that HCC tissues were characterized by higher expression of miR-4790-3p and lower expression of ZNF225; HCC tissues were also characterized by higher autophagic flux. We, thus, conclude that the potentiated anticancer effect of the everolimus and Ku0063794 combination therapy is strongly associated with reduced autophagy resulting from diminished expression of miR-4790-3p, as well as higher expression of ZNF225.
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Affiliation(s)
- Ho Joong Choi
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (O.-H.K.); (H.E.H.); (H.S.); (S.-J.K.)
- Correspondence:
| | - Jung Hyun Park
- Department of Surgery, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 03312, Korea;
| | - Ok-Hee Kim
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (O.-H.K.); (H.E.H.); (H.S.); (S.-J.K.)
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Kee-Hwan Kim
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
- Department of Surgery, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 11765, Korea
| | - Ha Eun Hong
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (O.-H.K.); (H.E.H.); (H.S.); (S.-J.K.)
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Haeyeon Seo
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (O.-H.K.); (H.E.H.); (H.S.); (S.-J.K.)
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Say-June Kim
- Department of Surgery, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (O.-H.K.); (H.E.H.); (H.S.); (S.-J.K.)
- Catholic Central Laboratory of Surgery, Institute of Biomedical Industry, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
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21
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Luo Y, Fu Y, Huang Z, Li M. Transition metals and metal complexes in autophagy and diseases. J Cell Physiol 2021; 236:7144-7158. [PMID: 33694161 DOI: 10.1002/jcp.30359] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 02/19/2021] [Accepted: 02/27/2021] [Indexed: 12/19/2022]
Abstract
Transition metals refer to the elements in the d and ds blocks of the periodic table. Since the success of cisplatin and auranofin, transition metal-based compounds have become a prospective source for drug development, particularly in cancer treatment. In recent years, extensive studies have shown that numerous transition metal-based compounds could modulate autophagy, promising a new therapeutic strategy for metal-related diseases and the design of metal-based agents. Copper, zinc, and manganese, which are common components in physiological pathways, play important roles in the progression of cancer, neurodegenerative diseases, and cardiovascular diseases. Furthermore, enrichment of copper, zinc, or manganese can regulate autophagy. Thus, we summarized the current advances in elucidating the mechanisms of some metals/metal-based compounds and their functions in autophagy regulation, which is conducive to explore the intricate roles of autophagy and exploit novel therapeutic drugs for human diseases.
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Affiliation(s)
- Yuping Luo
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Yuanyuan Fu
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhiying Huang
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Min Li
- Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, Guangdong, China
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22
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Abstract
The current COVID-19 pandemic caused by SARS-CoV-2 has prompted investigators worldwide to search for an effective anti-viral treatment. A number of anti-viral drugs such as ribavirin, remdesivir, lopinavir/ritonavir, antibiotics such as azithromycin and doxycycline, and anti-parasite such as ivermectin have been recommended for COVID-19 treatment. In addition, sufficient pre-clinical rationale and evidence have been presented to use chloroquine for the treatment of COVID-19. Furthermore, Zn has the ability to enhance innate and adaptive immunity in the course of a viral infection. Besides, Zn supplement can favour COVID-19 treatment using those suggested and/or recommended drugs. Again, the effectiveness of Zn can be enhanced by using chloroquine as an ionophore while Zn inside the infected cell can stop SARS-CoV-2 replication. Given those benefits, this perspective paper describes how and why Zn could be given due consideration as a complement to the prescribed treatment of COVID-19.
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Affiliation(s)
| | - Syed Zahir Idid
- Faculty of Allied Health Sciences, International Islamic University Malaysia, 25200 Kuantan, Malaysia
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23
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Kouroumalis E, Voumvouraki A, Augoustaki A, Samonakis DN. Autophagy in liver diseases. World J Hepatol 2021; 13:6-65. [PMID: 33584986 PMCID: PMC7856864 DOI: 10.4254/wjh.v13.i1.6] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 12/10/2020] [Accepted: 12/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is the liver cell energy recycling system regulating a variety of homeostatic mechanisms. Damaged organelles, lipids and proteins are degraded in the lysosomes and their elements are re-used by the cell. Investigations on autophagy have led to the award of two Nobel Prizes and a health of important reports. In this review we describe the fundamental functions of autophagy in the liver including new data on the regulation of autophagy. Moreover we emphasize the fact that autophagy acts like a two edge sword in many occasions with the most prominent paradigm being its involvement in the initiation and progress of hepatocellular carcinoma. We also focused to the implication of autophagy and its specialized forms of lipophagy and mitophagy in the pathogenesis of various liver diseases. We analyzed autophagy not only in well studied diseases, like alcoholic and nonalcoholic fatty liver and liver fibrosis but also in viral hepatitis, biliary diseases, autoimmune hepatitis and rare diseases including inherited metabolic diseases and also acetaminophene hepatotoxicity. We also stressed the different consequences that activation or impairment of autophagy may have in hepatocytes as opposed to Kupffer cells, sinusoidal endothelial cells or hepatic stellate cells. Finally, we analyzed the limited clinical data compared to the extensive experimental evidence and the possible future therapeutic interventions based on autophagy manipulation.
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Affiliation(s)
- Elias Kouroumalis
- Liver Research Laboratory, University of Crete Medical School, Heraklion 71110, Greece
| | - Argryro Voumvouraki
- 1 Department of Internal Medicine, AHEPA University Hospital, Thessaloniki 54636, Greece
| | - Aikaterini Augoustaki
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece
| | - Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Crete, Heraklion 71110, Greece.
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24
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Acute Increases in Intracellular Zinc Lead to an Increased Lysosomal and Mitochondrial Autophagy and Subsequent Cell Demise in Malignant Melanoma. Int J Mol Sci 2021; 22:ijms22020667. [PMID: 33440911 PMCID: PMC7826594 DOI: 10.3390/ijms22020667] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 12/28/2020] [Accepted: 01/06/2021] [Indexed: 02/07/2023] Open
Abstract
Changes in zinc content and dysregulated zinc homeostatic mechanisms have been recognized in several solid malignancies such as prostate cancer, breast cancer, or pancreatic cancer. Moreover, it has been shown that zinc serum and/or tissue levels are altered in melanoma with varying effects on melanoma development and biology. This study was conducted to explore the effects of acute increases of intracellular zinc in a set of melanoma tissue explants obtained from clinical samples. Measurements of their zinc content showed an extant heterogeneity in total and free intracellular zinc pools associated with varying biological behavior of individual cells, e.g., autophagy levels and propensity to cell death. Use of zinc pyrithione elevated intracellular zinc in a short time frame which resulted in marked changes in mitochondrial activity and lysosomes. These alterations were accompanied by significantly enhanced autophagy flux and subsequent cell demise in the absence of typical apoptotic cell death markers. The present results show for the first time that acutely increased intracellular zinc in melanoma cells specifically enhances their autophagic activity via mitochondria and lysosomes which leads to autophagic cell death. While biologically relevant, this discovery may contribute to our understanding and exploration of zinc in relation to autophagy as a means of controlling melanoma growth and survival.
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Fang H, Geng S, Hao M, Chen Q, Liu M, Liu C, Tian Z, Wang C, Takebe T, Guan JL, Chen Y, Guo Z, He W, Diao J. Simultaneous Zn 2+ tracking in multiple organelles using super-resolution morphology-correlated organelle identification in living cells. Nat Commun 2021; 12:109. [PMID: 33397937 PMCID: PMC7782730 DOI: 10.1038/s41467-020-20309-7] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 11/25/2020] [Indexed: 12/19/2022] Open
Abstract
Zn2+ plays important roles in metabolism and signaling regulation. Subcellular Zn2+ compartmentalization is essential for organelle functions and cell biology, but there is currently no method to determine Zn2+ signaling relationships among more than two different organelles with one probe. Here, we report simultaneous Zn2+ tracking in multiple organelles (Zn-STIMO), a method that uses structured illumination microscopy (SIM) and a single Zn2+ fluorescent probe, allowing super-resolution morphology-correlated organelle identification in living cells. To guarantee SIM imaging quality for organelle identification, we develop a new turn-on Zn2+ fluorescent probe, NapBu-BPEA, by regulating the lipophilicity of naphthalimide-derived Zn2+ probes to make it accumulate in multiple organelles except the nucleus. Zn-STIMO with this probe shows that CCCP-induced mitophagy in HeLa cells is associated with labile Zn2+ enhancement. Therefore, direct organelle identification supported by SIM imaging makes Zn-STIMO a reliable method to determine labile Zn2+ dynamics in various organelles with one probe. Finally, SIM imaging of pluripotent stem cell-derived organoids with NapBu-BPEA demonstrates the potential of super-resolution morphology-correlated organelle identification to track biospecies and events in specific organelles within organoids. Subcellular Zn2+ compartmentalisation is essential for cell biology. Here the authors make a turn-on fluorescent Zn2+ probe that localises to multiple organelles, and correlate its location using organelle morphology derived from structured illumination microscopy.
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Affiliation(s)
- Hongbao Fang
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 210023, Nanjing, China.,Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.,Chemistry and Biomedicine Innovation Center, Nanjing University, 210023, Nanjing, China
| | - Shanshan Geng
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 210023, Nanjing, China
| | - Mingang Hao
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Qixin Chen
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Minglun Liu
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 210023, Nanjing, China
| | - Chunyan Liu
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA
| | - Zhiqi Tian
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Chengjun Wang
- Sinopec Shengli Petroleum Engineering Limited Company, Dongying, China
| | - Takanori Takebe
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA.,Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA.,Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45267, USA.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.,Institute of Research, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan
| | - Jun-Lin Guan
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA
| | - Yuncong Chen
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 210023, Nanjing, China. .,Chemistry and Biomedicine Innovation Center, Nanjing University, 210023, Nanjing, China.
| | - Zijian Guo
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 210023, Nanjing, China.,Chemistry and Biomedicine Innovation Center, Nanjing University, 210023, Nanjing, China
| | - Weijiang He
- State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 210023, Nanjing, China. .,Chemistry and Biomedicine Innovation Center, Nanjing University, 210023, Nanjing, China.
| | - Jiajie Diao
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, 45267, USA.
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Liuzzi JP, Pazos R. Interplay Between Autophagy and Zinc. J Trace Elem Med Biol 2020; 62:126636. [PMID: 32957075 DOI: 10.1016/j.jtemb.2020.126636] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Revised: 07/28/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022]
Abstract
Autophagy is a conserved catabolic process that plays an important role in cellular homeostasis. The study of the interplay between autophagy and zinc has gained interest over the last years. Multiple studies have indicated that zinc stimulates autophagy and is critical for basal and induced autophagy in mammalian cells. Conversely, autophagy is induced by zinc starvation in yeast. There are no studies analyzing the role of zinc in either Microautophagy or Chaperone-Mediated-Autophagy. The mechanisms by which zinc modulates autophagy are still poorly understood. Studies examining loss of function of genes involved in cellular zinc homeostasis have provided novel insights into the role of zinc in autophagy. Autophagy may help cells adapt to changes in zinc availability in medium by controlling zinc mobilization, recycling, and secretion. Zinc is a key player in toxic and protective autophagy.
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Affiliation(s)
- Juan P Liuzzi
- Department of Dietetics and Nutrition, Robert Stempel College of Public Health & Social Work, Florida International University, 11200 SW 8th Street, AHC5, Miami, FL 33199, USA.
| | - Rebecca Pazos
- Department of Dietetics and Nutrition, Robert Stempel College of Public Health & Social Work, Florida International University, 11200 SW 8th Street, AHC5, Miami, FL 33199, USA.
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Yuan F, Xu Y, You K, Zhang J, Yang F, Li YX. Calcitriol alleviates ethanol-induced hepatotoxicity via AMPK/mTOR-mediated autophagy. Arch Biochem Biophys 2020; 697:108694. [PMID: 33232716 DOI: 10.1016/j.abb.2020.108694] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/04/2020] [Accepted: 11/17/2020] [Indexed: 12/28/2022]
Abstract
Excessive ethanol consumption causes cellular damage, leading to fetal alcohol syndrome and alcohol liver diseases, which are frequently seen with vitamin D (VD) deficiency. A great deal of progress has been achieved in the mechanisms of ethanol-induced hepatocyte damage. However, there are limited intervention means to reduce or rescue hepatocytes damage caused by ethanol. On the basis of our preliminary limited screen process, calcitriol showed a positive effect on protecting hepatocyte viability. Therefore, the molecular basis is worth elucidating. We found that calcitriol pretreatment markedly improved the cell viability, decreased cell apoptosis and oxidative stress and alleviated the abnormal mitochondrial morphology and membrane potential of hepatocytes induced by ethanol. Notably, autophagy was significantly enhanced by calcitriol, as evident by the increasing number of autophagosomes and autolysosomes, upregulated LC3B-Ⅱ and ATG5 levels, and promotion of p62 degradation. Furthermore, calcitriol pretreatment increased the colocalization of GFP-LC3-labeled autophagosomes with mitochondria, suggesting that calcitriol effectively promoted ethanol-induced mitophagy in hepatocytes. In addition, the inhibition of autophagy attenuated the protective and preventive effect of calcitriol. Furthermore, the effect of calcitriol on autophagy was regulated by AMPK/mTOR signaling, and signaling transduction was dependent on the Vitamin D receptor (VDR). In conclusion, calcitriol ameliorates ethanol-induced hepatocyte damage by enhancing autophagy. It may offer a convenient preventive and hepatoprotective mean for people on occasional social drink.
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Affiliation(s)
- Fang Yuan
- School of Life Sciences, University of Science and Technology of China, 230027, Hefei, China; Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yingying Xu
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Kai You
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Jiaye Zhang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Fan Yang
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China
| | - Yin-Xiong Li
- Institute of Public Health, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China; Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China.
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von Pein JB, Stocks CJ, Schembri MA, Kapetanovic R, Sweet MJ. An alloy of zinc and innate immunity: Galvanising host defence against infection. Cell Microbiol 2020; 23:e13268. [PMID: 32975847 DOI: 10.1111/cmi.13268] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/31/2020] [Accepted: 09/03/2020] [Indexed: 12/16/2022]
Abstract
Innate immune cells such as macrophages and neutrophils initiate protective inflammatory responses and engage antimicrobial responses to provide frontline defence against invading pathogens. These cells can both restrict the availability of certain transition metals that are essential for microbial growth and direct toxic concentrations of metals towards pathogens as antimicrobial responses. Zinc is important for the structure and function of many proteins, however excess zinc can be cytotoxic. In recent years, several studies have revealed that innate immune cells can deliver toxic concentrations of zinc to intracellular pathogens. In this review, we discuss the importance of zinc status during infectious disease and the evidence for zinc intoxication as an innate immune antimicrobial response. Evidence for pathogen subversion of this response is also examined. The likely mechanisms, including the involvement of specific zinc transporters that facilitate delivery of zinc by innate immune cells for metal ion poisoning of pathogens are also considered. Precise mechanisms by which excess levels of zinc can be toxic to microorganisms are then discussed, particularly in the context of synergy with other antimicrobial responses. Finally, we highlight key unanswered questions in this emerging field, which may offer new opportunities for exploiting innate immune responses for anti-infective development.
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Affiliation(s)
- Jessica B von Pein
- Institute for Molecular Bioscience (IMB), The University of Queensland, St. Lucia, Queensland, Australia.,IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Queensland, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, Queensland, Australia
| | - Claudia J Stocks
- Institute for Molecular Bioscience (IMB), The University of Queensland, St. Lucia, Queensland, Australia.,IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Queensland, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, Queensland, Australia
| | - Mark A Schembri
- Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, Queensland, Australia.,School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, Queensland, Australia
| | - Ronan Kapetanovic
- Institute for Molecular Bioscience (IMB), The University of Queensland, St. Lucia, Queensland, Australia.,IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Queensland, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, Queensland, Australia
| | - Matthew J Sweet
- Institute for Molecular Bioscience (IMB), The University of Queensland, St. Lucia, Queensland, Australia.,IMB Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, Queensland, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, St. Lucia, Queensland, Australia
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Periyasamy KM, Ranganathan UD, Tripathy SP, Bethunaickan R. Vitamin D - A host directed autophagy mediated therapy for tuberculosis. Mol Immunol 2020; 127:238-244. [PMID: 33039674 DOI: 10.1016/j.molimm.2020.08.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 08/10/2020] [Accepted: 08/13/2020] [Indexed: 12/12/2022]
Abstract
According to the WHO report 2019, Tuberculosis (TB) is an ancient disease of humanity that is curable. TB has caused significant morbidity and mortality even in 2018. The etiological agent of TB, Mycobacterium tuberculosis (MTB) exploits its virulence factors to escape from host immunity and therapeutic drugs. Host Directed Therapy (HDT) is an adjunctive therapy where repurposed drugs, small molecules, vitamins, cytokines, and monoclonal antibodies are used to overcome the pathogen exploited pathways in the host. One of the HDTs, i.e. induction of autophagy is a highly regulated intracellular self-degradative process in which pathogens are sequestered in double-layered autophagosomes and targeted to the lysosome for degradation. Apart from the pathogen clearance, autophagy involves the release of nutrients during starvation, removal of damaged organelles and aggregated proteins, antigen presentation, tumor suppression, and anti-aging mechanisms. Xenophagy is a type of selective autophagy against microbes induced by ubiquitin receptors (p62/SQSTM1, NDP52, NBR1, OPTN, Parkin and Smurf proteins) after pathogen recognition. ULK1/2, Beclin-1, ATG5-ATG12-ATG16 L and LC-II-PE complexes along with two nutrient-sensing protein complexes, mTOR and AMPK activate autophagy mechanisms to limit infection. Pattern Recognition Receptors (PRRs) such as TLR2, recognize lipopolysaccharide (LPS) of MTB and triggers vitamin D3 activating enzymes. Activated vitamin D3 induces the synthesis of antimicrobial peptide, LL-37, which further enhances xenophagy. Apart from vitamin D, few micronutrients such as zinc and iron also regulate autophagy. In this review, we discuss current knowledge, advances and perspectives of autophagy against TB.
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Affiliation(s)
- Krisna Moorthi Periyasamy
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai. Affiliated to University of Madras, Chepauk, Chennai, India
| | - Uma Devi Ranganathan
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai. Affiliated to University of Madras, Chepauk, Chennai, India
| | | | - Ramalingam Bethunaickan
- Department of Immunology, ICMR-National Institute for Research in Tuberculosis, Chennai. Affiliated to University of Madras, Chepauk, Chennai, India; Department of Pathology and Microbiology, ICMR-National Institute of Nutrition, Hyderabad, India.
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Zinc and Autophagy in Age-Related Macular Degeneration. Int J Mol Sci 2020; 21:ijms21144994. [PMID: 32679798 PMCID: PMC7404247 DOI: 10.3390/ijms21144994] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/13/2020] [Accepted: 07/13/2020] [Indexed: 02/06/2023] Open
Abstract
Zinc supplementation is reported to slow down the progression of age-related macular degeneration (AMD), but there is no general consensus on the beneficiary effect on zinc in AMD. As zinc can stimulate autophagy that is declined in AMD, it is rational to assume that it can slow down its progression. As melanosomes are the main reservoir of zinc in the retina, zinc may decrease the number of lipofuscin granules that are substrates for autophagy. The triad zinc–autophagy–AMD could explain some controversies associated with population studies on zinc supplementation in AMD as the effect of zinc on AMD may be modulated by genetic background. This aspect was not determined in many studies regarding zinc in AMD. Zinc deficiency induces several events associated with AMD pathogenesis, including increased oxidative stress, lipid peroxidation and the resulting lipofuscinogenesis. The latter requires autophagy, which is impaired. This is a vicious cycle-like reaction that may contribute to AMD progression. Promising results with zinc deficiency and supplementation in AMD patients and animal models, as well as emerging evidence of the importance of autophagy in AMD, are the rationale for future research on the role of autophagy in the role of zinc supplementation in AMD.
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31
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Rahman MT. Potential benefits of combination of Nigella sativa and Zn supplements to treat COVID-19. J Herb Med 2020; 23:100382. [PMID: 32834942 PMCID: PMC7313527 DOI: 10.1016/j.hermed.2020.100382] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 04/23/2020] [Accepted: 06/22/2020] [Indexed: 02/06/2023]
Abstract
The COVID-19 has been declared a pandemic while there is no specific medicine against its causative agent SARS-CoV-2. As an complementary medicine Nigella sativa (black seed) could be considered for its bioactive components such as thymoquinone which was proven to have anti-viral activity. Further benefits to use N. sativa could be augmented by Zn supplement. Notably, Zn has been proven to improve innate and adaptive immunity in course of microbial infection. The effectiveness of the Zn salt supplement can be enhanced with N. sativa as its major bioactive component might work as ionophore to allow Zn2+ to enter pneumocytes and inhibit SARS-CoV-2 replication by stopping its replicase enzyme system. An effective vaccine to prevent the SARS-CoV-2 causing COVID-19 is yet to be approved. Further there is no drug that is specific to treat COVID-19. A number of antiviral drugs such as Ribavirin, Remdesivir, Lopinavir/ritonavir, Azithromycin and Doxycycline have been recommended or are being used to treat COVID-19 patients. In addition to these drugs, rationale and evidence have been presented to use chloroquine to treat COVID-19, arguably with certain precautions and criticism. In line with the proposed use of chloroquine, Nigella sativa (black seed) could be considered as a natural substitute that contains a number of bioactive components such as thymoquinone, dithymoquinone, thymohydroquinone, and nigellimine. Further benefits to use N. sativa could be augmented by Zn supplement. Notably, Zn has been proven to improve innate and adaptive immunity in the course of any infection, be it by pathogenic virus or bacteria. The effectiveness of the Zn salt supplement could also be enhanced with N. sativa as its major bioactive component might work as ionophore to allow Zn2+ to enter pneumocytes – the target cell for SARSCoV-2. Given those benefits, this review paper describes how N. sativa in combination with Zn could be useful as a complement to COVID-19 treatment.
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Maremanda KP, Srivalliputturu SB, Jena G. Zinc deficient diet exacerbates the testicular and epididymal damage in type 2 diabetic rat: Studies on oxidative stress-related mechanisms. Reprod Biol 2020; 20:191-201. [DOI: 10.1016/j.repbio.2020.03.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 02/13/2020] [Accepted: 03/14/2020] [Indexed: 01/20/2023]
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Jiang D, Deng J, Dong C, Ma X, Xiao Q, Zhou B, Yang C, Wei L, Conran C, Zheng SL, Ng IOL, Yu L, Xu J, Sham PC, Qi X, Hou J, Ji Y, Cao G, Li M. Knowledge-based analyses reveal new candidate genes associated with risk of hepatitis B virus related hepatocellular carcinoma. BMC Cancer 2020; 20:403. [PMID: 32393195 PMCID: PMC7216662 DOI: 10.1186/s12885-020-06842-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 04/07/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Recent genome-wide association studies (GWASs) have suggested several susceptibility loci of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) by statistical analysis at individual single-nucleotide polymorphisms (SNPs). However, these loci only explain a small fraction of HBV-related HCC heritability. In the present study, we aimed to identify additional susceptibility loci of HBV-related HCC using advanced knowledge-based analysis. METHODS We performed knowledge-based analysis (including gene- and gene-set-based association tests) on variant-level association p-values from two existing GWASs of HBV-related HCC. Five different types of gene-sets were collected for the association analysis. A number of SNPs within the gene prioritized by the knowledge-based association tests were selected to replicate genetic associations in an independent sample of 965 cases and 923 controls. RESULTS The gene-based association analysis detected four genes significantly or suggestively associated with HBV-related HCC risk: SLC39A8, GOLGA8M, SMIM31, and WHAMMP2. The gene-set-based association analysis prioritized two promising gene sets for HCC, cell cycle G1/S transition and NOTCH1 intracellular domain regulates transcription. Within the gene sets, three promising candidate genes (CDC45, NCOR1 and KAT2A) were further prioritized for HCC. Among genes of liver-specific expression, multiple genes previously implicated in HCC were also highlighted. However, probably due to small sample size, none of the genes prioritized by the knowledge-based association analyses were successfully replicated by variant-level association test in the independent sample. CONCLUSIONS This comprehensive knowledge-based association mining study suggested several promising genes and gene-sets associated with HBV-related HCC risks, which would facilitate follow-up functional studies on the pathogenic mechanism of HCC.
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Affiliation(s)
- Deke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaen Deng
- Department of Psychiatry, the University of Hong Kong, Pokfulam, Hong Kong
| | | | - Xiaopin Ma
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Qianyi Xiao
- Center for Genomic Translational Medicine and Prevention, School of Public Health, Fudan University, Shanghai, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chou Yang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lin Wei
- Program of Computational Genomics & Medicine, NorthShore University HealthSystem, Evanston, IL, USA
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | - Carly Conran
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Pritzker School of Medicine, University of Chicago, Evanston, IL, USA
| | - S Lilly Zheng
- Program of Computational Genomics & Medicine, NorthShore University HealthSystem, Evanston, IL, USA
| | - Irene Oi-Lin Ng
- Department of Pathology, the University of Hong Kong, Pokfulam, Hong Kong
- State Key Laboratory of Liver Research, the University of Hong Kong, Pokfulam, Hong Kong
| | - Long Yu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Jianfeng Xu
- Program of Computational Genomics & Medicine, NorthShore University HealthSystem, Evanston, IL, USA
| | - Pak C Sham
- The Centre for Genomic Sciences, the University of Hong Kong, Pokfulam, Hong Kong
| | - Xiaolong Qi
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuan Ji
- Department of Public Health Sciences, University of Chicago, Chicago, IL, USA
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China.
| | - Miaoxin Li
- Department of Psychiatry, the University of Hong Kong, Pokfulam, Hong Kong.
- The Centre for Genomic Sciences, the University of Hong Kong, Pokfulam, Hong Kong.
- State Key Laboratory for Cognitive and Brain Sciences, the University of Hong Kong, Pokfulam, Hong Kong.
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
- Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education, Guangzhou, China.
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Hernández-Camacho JD, Vicente-García C, Parsons DS, Navas-Enamorado I. Zinc at the crossroads of exercise and proteostasis. Redox Biol 2020; 35:101529. [PMID: 32273258 PMCID: PMC7284914 DOI: 10.1016/j.redox.2020.101529] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/25/2020] [Accepted: 03/27/2020] [Indexed: 12/11/2022] Open
Abstract
Zinc is an essential element for all forms of life, and one in every ten human proteins is a zinc protein. Zinc has catalytic, structural and signalling functions and its correct homeostasis affects many cellular processes. Zinc deficiency leads to detrimental consequences, especially in tissues with high demand such as skeletal muscle. Zinc cellular homeostasis is tightly regulated by different transport and buffer protein systems. Specifically, in skeletal muscle, zinc has been found to affect myogenesis and muscle regeneration due to its effects on muscle cell activation, proliferation and differentiation. In relation to skeletal muscle, exercise has been shown to modulate zinc serum and urinary levels and could directly affect cellular zinc transport. The oxidative stress induced by exercise may provide the basis for the mild zinc deficiency observed in athletes and could have severe consequences on health and sport performance. Proteostasis is induced during exercise and zinc plays an essential role in several of the associated pathways.
Zinc deficiency could be a crucial issue in sport performance for athletes. Exercise could modulate zinc serum and cellular homeostasis. Zinc is part of proteostatic systems critical during exercise.
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Affiliation(s)
- Juan Diego Hernández-Camacho
- Centro Andaluz de Biología del Desarrollo, CSIC-UPO-JA, Universidad Pablo de Olavide, Sevilla, 41013, Spain; CIBERER, Instituto de Salud Carlos III, Madrid, 28000, Spain
| | - Cristina Vicente-García
- Centro Andaluz de Biología del Desarrollo, CSIC-UPO-JA, Universidad Pablo de Olavide, Sevilla, 41013, Spain
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Li Y, Li Z, Cao Y, Zhou X, Li C. Chronic excessive Zn intake increases the testicular sensitivity to high ambient temperature in Bama miniature pigs. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2020; 257:113629. [PMID: 31806468 DOI: 10.1016/j.envpol.2019.113629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/13/2019] [Accepted: 11/13/2019] [Indexed: 06/10/2023]
Abstract
Zinc (Zn) can accumulate in the body of wild animal and human through bio-magnification effects in the food chain to pose chronic toxicity. Male spermatogenesis was sensitive to excessive Zn and elevated temperature. This study aimed to examine whether or not excessive Zn intake caused testicular toxicity and estimate the interaction between Zn and high temperature (HT) in testes of Bama miniature pigs. Six-month-old pigs were pre-fed with or without additional Zn at 1500 mg/kg diet for 30 d and afterward subjected to HT at 40 °C for 5 h daily for 8 consecutive days. Blood samples were collected on d 31 and d 38 and testes were obtained on d 38 immediately after HT exposure. Our data showed both scrotal surface temperature (T) and body surface T increased after 5-h HT exposure (p < 0.05). Pigs fed with additional Zn showed germ cell loss, the decreased testes weight (p < 0.01) and the elevated testicular H2O2 level (p < 0.05) as exposed to HT. In additional Zn groups, the autophagosomes or autolysosomes were more frequently observed in the Leydig cells and abnormal acrosomes increased in spermatids. Additional Zn diet increased p62 protein level (p < 0.05), decreased testicular Zn concentration (p < 0.01) and down-regulated the relative mRNA expression of heme oxygenase 1 (p < 0.05). There were significant interactions between T and Zn on testes weight, the relative weight of testes, testosterone concentration on d 31, and the relative mRNA expression of Zn transporters 1 and 2. In conclusion, chronic excessive Zn diet impacted testicular Zn concentration and made the testes more vulnerable to heat, leading to testicular toxicity in Bama miniature pigs.
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Affiliation(s)
- Yansen Li
- National Center for International Research on Animal Gut Nutrition, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; National Experimental Teaching Demonstration Center of Animal Science, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Zhaojian Li
- National Center for International Research on Animal Gut Nutrition, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Yun Cao
- National Center for International Research on Animal Gut Nutrition, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Xin Zhou
- National Center for International Research on Animal Gut Nutrition, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Chunmei Li
- National Center for International Research on Animal Gut Nutrition, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; National Experimental Teaching Demonstration Center of Animal Science, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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Zinc protects chondrocytes from monosodium iodoacetate-induced damage by enhancing ATP and mitophagy. Biochem Biophys Res Commun 2019; 521:50-56. [PMID: 31610916 DOI: 10.1016/j.bbrc.2019.10.066] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 10/06/2019] [Indexed: 01/20/2023]
Abstract
Osteoarthritis (OA) is characterized with articular cartilage degradation, and monosodium iodoacetate (MIA)-treated chondrocyte is the most commonly used model for mimicking OA progression. Zinc protects chondrocytes from MIA-induced damage. Here, we explored the protective effects of 25 μM zinc on 5 μM MIA-treated SW1353 cells (human chondrosarcoma cell line) through the analysis of energy metabolism- and autophagy-related parameters. We found that the exposure of SW1353 cells to MIA decreased ATP levels, expression of glycolysis-related proteins, including glucose transporter 1, hexokinase 2, and pyruvate dehydrogenase E1 component subunit alpha, and the levels of mitochondrial complex I, II, IV, and V subunits of the oxidative phosphorylation pathway. MIA treatment also decreased the expression of autophagy-related proteins, including autophagic elongation protein 5 (ATG5), ATG7, and microtubule-associated protein 1A/1B light chain 3B (LC3-II) and mitophagy-related proteins, including phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), ubiquitin, and p62. These results indicate that MIA interferes with energy metabolism and the autophagic clearance of dysfunctional mitochondria (so called mitophagy). Interestingly, zinc exposure could almost completely reverse the effects of MIA, suggesting its potential protective role against OA progression.
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Yan S, Khambu B, Hong H, Liu G, Huda N, Yin XM. Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions. Int J Mol Sci 2019; 20:ijms20205029. [PMID: 31614437 PMCID: PMC6834312 DOI: 10.3390/ijms20205029] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/02/2019] [Accepted: 10/09/2019] [Indexed: 02/06/2023] Open
Abstract
Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Honghai Hong
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Gang Liu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Nazmul Huda
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Tu Y, Zhu S, Wang J, Burstein E, Jia D. Natural compounds in the chemoprevention of alcoholic liver disease. Phytother Res 2019; 33:2192-2212. [PMID: 31264302 DOI: 10.1002/ptr.6410] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/29/2019] [Accepted: 05/21/2019] [Indexed: 12/17/2022]
Abstract
Alcoholic liver disease (ALD), caused by excessive consumption of alcohol, is a major cause of chronic liver disease worldwide. Much effort has been expended to explore the pathogenesis of ALD. Hepatic cell injury, oxidative stress, inflammation, regeneration, and bacterial translocation are all involved in the pathogenesis of ALD. Immediate abstinence is the most important therapeutic treatment for affected individuals. However, the medical treatment for ALD had not advanced in a long period. Intriguingly, an increasing body of research indicates the potential of natural compounds in the targeted therapy of ALD. A plethora of dietary natural products such as flavonoids, resveratrol, saponins, and β-carotene are found to exert protective effects on ALD. This occurs through various mechanisms composed of antioxidative, anti-inflammatory, iron chelation, pro-apoptosis, and/or antiproliferation of hepatic stellate cells and hepatocellular carcinoma cells. In this review, we will summarize current knowledge about the pathogenesis and treatments of ALD and focus on the potential of natural compounds in ALD therapies and underlying mechanisms.
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Affiliation(s)
- Yingfeng Tu
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Shu Zhu
- Chinese Academy of Science and Technology for Development, Ministry of Science and Technology, Institute of Foresight and Evaluation Research, Beijing, China
| | - Jing Wang
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
| | - Ezra Burstein
- Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA
| | - Da Jia
- Key Laboratory of Birth Defects and Related Diseases of Women and Children, Department of Paediatrics, West China Second University Hospital, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, China
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Yan S, Zhou J, Chen X, Dong Z, Yin XM. Diverse Consequences in Liver Injury in Mice with Different Autophagy Functional Status Treated with Alcohol. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1744-1762. [PMID: 31199920 DOI: 10.1016/j.ajpath.2019.05.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/01/2019] [Accepted: 05/07/2019] [Indexed: 02/07/2023]
Abstract
Alcoholic fatty liver disease is often complicated by other pathologic insults, such as viral infection or high-fat diet. Autophagy plays a homeostatic role in the liver but can be compromised by alcohol, high-fat diet, or viral infection, which in turn affects the disease process caused by these etiologies. To understand the full impact of autophagy modulation on alcohol-induced liver injury, several genetic models of autophagy deficiency, which have different levels of functional alterations, were examined after acute binge or chronic-plus-binge treatment. Mice given alcohol with either mode and induced with deficiency in liver-specific Atg7 shortly after the induction of Atg7 deletion had elevated liver injury, indicating the protective role of autophagy. Constitutive hepatic Atg7-deficient mice, in which Atg7 was deleted in embryos, were more susceptible with chronic-plus-binge but not with acute alcohol treatment. Constitutive hepatic Atg5-deficient mice, in which Atg5 was deleted in embryos, were more susceptible with acute alcohol treatment, but liver injury was unexpectedly improved with the chronic-plus-binge regimen. A prolonged autophagy deficiency may complicate the hepatic response to alcohol treatment, likely in part due to endogenous liver injury. The complexity of the relationship between autophagy deficiency and alcohol-induced liver injury can thus be affected by the timing of autophagy dysfunction, the exact autophagy gene being affected, and the alcohol treatment regimen.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jun Zhou
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Minimal Invasive Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaoyun Chen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Zheng Dong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China; Department of Cell Biology and Anatomy, Medical College of Georgia and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, China.
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Khambu B, Wang L, Zhang H, Yin XM. The Activation and Function of Autophagy in Alcoholic Liver Disease. Curr Mol Pharmacol 2019; 10:165-171. [PMID: 26278385 DOI: 10.2174/1874467208666150817112654] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/29/2015] [Accepted: 08/07/2015] [Indexed: 02/07/2023]
Abstract
Autophagy is an important lysosome-mediated intracellular degradation pathway required for tissue homeostasis. Dysregulation of liver autophagy is closely associated with different liver diseases including alcoholic liver disease. Studies now indicate that autophagy may be induced or suppressed depending on the amount and the duration of ethanol treatment. Autophagy induced by ethanol serves as a protective mechanism, probably by selective degradation of the damaged mitochondria (mitophagy) and excess lipid droplets (lipophagy) and in turn attenuates alcohol-induced steatosis and liver injury. However, the detailed molecular mechanism of selective targeting of mitochondria and lipid is still unclear. Autophagy may possess other functions that protect hepatocytes from ethanol. Understanding these molecular entities would be essential in order to therapeutically module autophagy for treatment of alcoholic liver disease.
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Affiliation(s)
- Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. United States
| | - Lin Wang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. United States
| | - Hao Zhang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. United States
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202. United States
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Sun W, Yang J, Wang W, Hou J, Cheng Y, Fu Y, Xu Z, Cai L. The beneficial effects of Zn on Akt-mediated insulin and cell survival signaling pathways in diabetes. J Trace Elem Med Biol 2018; 46:117-127. [PMID: 29413101 DOI: 10.1016/j.jtemb.2017.12.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Revised: 12/06/2017] [Accepted: 12/21/2017] [Indexed: 12/11/2022]
Abstract
Zinc is one of the essential trace elements and participates in numerous physiological processes. Abnormalities in zinc homeostasis often result in the pathogenesis of various chronic metabolic disorders, such as diabetes and its complications. Zinc has insulin-mimetic and anti-diabetic effects and deficiency has been shown to aggravate diabetes-induced oxidative stress and tissue injury in diabetic rodent models and human subjects with diabetes. Akt signaling pathway plays a central role in insulin-stimulated glucose metabolism and cell survival. Anti-diabetic effects of zinc are largely dependent on the activation of Akt signaling. Zn is also an inducer of metallothionein that plays important role in anti-oxidative stress and damage. However, the exact molecular mechanisms underlying zinc-induced activation of Akt signaling pathway remains to be elucidated. This review summarizes the recent advances in deciphering the possible mechanisms of zinc on Akt-mediated insulin and cell survival signaling pathways in diabetes conditions. Insights into the effects of zinc on epigenetic regulation and autophagy in diabetic nephropathy are also discussed in the latter part of this review.
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Affiliation(s)
- Weixia Sun
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
| | - Jiaxing Yang
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Wanning Wang
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China; Pediatric Research Institute, The Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, The University of Louisville, Louisville, KY 40202, USA
| | - Jie Hou
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Yanli Cheng
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Yaowen Fu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China
| | - Zhonggao Xu
- Department of Nephrology, The First Hospital of Jilin University, Changchun, Jilin, 130021, China.
| | - Lu Cai
- Pediatric Research Institute, The Departments of Pediatrics, Radiation Oncology, Pharmacology and Toxicology, The University of Louisville, Louisville, KY 40202, USA
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Liuzzi JP, Narayanan V, Doan H, Yoo C. Effect of zinc intake on hepatic autophagy during acute alcohol intoxication. Biometals 2018; 31:217-232. [PMID: 29392448 DOI: 10.1007/s10534-018-0077-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 01/26/2018] [Indexed: 01/20/2023]
Abstract
Autophagy is a conserved mechanism that plays a housekeeping role by eliminating protein aggregates and damaged organelles. Recent studies have demonstrated that acute ethanol intoxication induces hepatic autophagy in mice. The effect of dietary zinc intake on hepatic autophagic flux during ethanol intoxication has not been evaluated using animal models. Herein, we investigated whether zinc deficiency and excess can affect autophagic flux in the liver in mice and in human hepatoma cells acutely exposed to ethanol. A mouse model of binge ethanol feeding was utilized to analyze the effect of low, adequate, and high zinc intake on hepatic autophagic flux during ethanol intoxication. Autophagic flux was inferred by analyzing LC3II/LC3I ratio, protein levels of p62/SQSTM1, Beclin1 and Atg7, and phosphorylation of 4EBP1. In addition, the degradation of the fusion protein LC3-GFP and the formation of autophagosomes and autolysosomes were evaluated in cells. Ethanol treatment stimulated autophagy in mice and cells. High zinc intake resulted in enhanced autophagy in mice exposed to ethanol. Conversely, zinc deficiency was consistently associated with impaired ethanol-induced autophagy in mice and cells. Zinc-deficient mice exhibited a high degree of ethanol-driven steatosis. Furthermore, zinc depletion increased apoptosis in cells exposed to ethanol. The results of this study suggest that adequate zinc intake is necessary for proper stimulation of autophagy by ethanol. Poor zinc status is commonly found among alcoholics and could likely contribute to faulty autophagy.
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Affiliation(s)
- Juan P Liuzzi
- Department of Dietetics and Nutrition, Robert Stempel College of Public Health and Social Work, Florida International University, 11200 SW, 8ST, AHC5-325, Miami, FL, 33199, USA.
| | - Vijaya Narayanan
- Department of Dietetics and Nutrition, Robert Stempel College of Public Health and Social Work, Florida International University, 11200 SW, 8ST, AHC5-325, Miami, FL, 33199, USA
| | - Huong Doan
- Department of Dietetics and Nutrition, Robert Stempel College of Public Health and Social Work, Florida International University, 11200 SW, 8ST, AHC5-325, Miami, FL, 33199, USA
| | - Changwon Yoo
- Department of Biostatistics, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA
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Stocks CJ, Schembri MA, Sweet MJ, Kapetanovic R. For when bacterial infections persist: Toll-like receptor-inducible direct antimicrobial pathways in macrophages. J Leukoc Biol 2018; 103:35-51. [PMID: 29345056 DOI: 10.1002/jlb.4ri0917-358r] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Revised: 10/19/2017] [Accepted: 10/19/2017] [Indexed: 12/18/2022] Open
Abstract
Macrophages are linchpins of innate immunity, responding to invading microorganisms by initiating coordinated inflammatory and antimicrobial programs. Immediate antimicrobial responses, such as NADPH-dependent reactive oxygen species (ROS), are triggered upon phagocytic receptor engagement. Macrophages also detect and respond to microbial products through pattern recognition receptors (PRRs), such as TLRs. TLR signaling influences multiple biological processes including antigen presentation, cell survival, inflammation, and direct antimicrobial responses. The latter enables macrophages to combat infectious agents that persist within the intracellular environment. In this review, we summarize our current understanding of TLR-inducible direct antimicrobial responses that macrophages employ against bacterial pathogens, with a focus on emerging evidence linking TLR signaling to reprogramming of mitochondrial functions to enable the production of direct antimicrobial agents such as ROS and itaconic acid. In addition, we describe other TLR-inducible antimicrobial pathways, including autophagy/mitophagy, modulation of nutrient availability, metal ion toxicity, reactive nitrogen species, immune GTPases (immunity-related GTPases and guanylate-binding proteins), and antimicrobial peptides. We also describe examples of mechanisms of evasion of such pathways by professional intramacrophage pathogens, with a focus on Salmonella, Mycobacteria, and Listeria. An understanding of how TLR-inducible direct antimicrobial responses are regulated, as well as how bacterial pathogens subvert such pathways, may provide new opportunities for manipulating host defence to combat infectious diseases.
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Affiliation(s)
- Claudia J Stocks
- Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia
| | - Mark A Schembri
- Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.,School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Matthew J Sweet
- Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia
| | - Ronan Kapetanovic
- Institute for Molecular Bioscience (IMB) and IMB Centre for Inflammation and Disease Research, The University of Queensland, Brisbane, Queensland, Australia.,Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia
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Bian X, Teng T, Zhao H, Qin J, Qiao Z, Sun Y, Liun Z, Xu Z. Zinc prevents mitochondrial superoxide generation by inducing mitophagy in the setting of hypoxia/reoxygenation in cardiac cells. Free Radic Res 2017; 52:80-91. [PMID: 29216769 DOI: 10.1080/10715762.2017.1414949] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Zinc plays a role in autophagy and protects cardiac cells from ischemia/reperfusion injury. This study aimed to test if zinc can induce mitophagy leading to attenuation of mitochondrial superoxide generation in the setting of hypoxia/reoxygenation (H/R) in cardiac cells. H9c2 cells were subjected to 4 h hypoxia followed by 2 h reoxygenation. Under normoxic conditions, treatments of cells with ZnCl2 increased both the LC3-II/LC3-I ratio and GFP-LC3 puncta, implying that zinc induces autophagy. Further experiments showed that endogenous zinc is required for the autophagy induced by starvation and rapamycin. Zinc down-regulated TOM20, TIM23, and COX4 both in normoxic cells and the cells subjected to H/R, indicating that zinc can trigger mitophagy. Zinc increased ERK activity and Beclin1 expression, and zinc-induced mitophagy was inhibited by PD98059 and Beclin1 siRNA during reoxygenation. Zinc-induced Beclin1 expression was reversed by PD98059, implying that zinc promotes Beclin1 expression via ERK. In addition, zinc failed to induce mitophagy in cells transfected with PINK1 siRNA and stabilized PINK1 in mitochondria. Moreover, zinc-induced PINK1 stabilization was inhibited by PD98059. Finally, zinc prevented mitochondrial superoxide generation and dissipation of mitochondrial membrane potential (ΔΨm) at reoxygenation, which was blocked by both the Beclin1 and PINK1 siRNAs, suggesting that zinc prevents mitochondrial oxidative stress through mitophagy. In summary, zinc induces mitophagy through PINK1 and Beclin1 via ERK leading to the prevention of mitochondrial superoxide generation in the setting of H/R. Clearance of damaged mitochondria may account for the cardioprotective effect of zinc on H/R injury.
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Affiliation(s)
- Xiyun Bian
- a Department of Physiology and Pathophysiology , Tianjin Medical University , Tianjin , China
| | - Tianming Teng
- b Department of Cardiology , General Hospital, Tianjin Medical University , Tianjin , China
| | - Huanhuan Zhao
- a Department of Physiology and Pathophysiology , Tianjin Medical University , Tianjin , China
| | - Jiangyu Qin
- a Department of Physiology and Pathophysiology , Tianjin Medical University , Tianjin , China
| | - Zhen Qiao
- a Department of Physiology and Pathophysiology , Tianjin Medical University , Tianjin , China
| | - Yuemin Sun
- b Department of Cardiology , General Hospital, Tianjin Medical University , Tianjin , China
| | - Zhiqiang Liun
- a Department of Physiology and Pathophysiology , Tianjin Medical University , Tianjin , China
| | - Zhelong Xu
- a Department of Physiology and Pathophysiology , Tianjin Medical University , Tianjin , China
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Zinc deficiency as a mediator of toxic effects of alcohol abuse. Eur J Nutr 2017; 57:2313-2322. [PMID: 29177978 DOI: 10.1007/s00394-017-1584-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 11/20/2017] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To review data on the role of ethanol-induced alteration of Zn homeostasis in mediation of adverse effects of alcohol abuse. METHODS The scholarly published articles on the association between Zn metabolism and alcohol-associated disorders (liver, brain, lung, gut dysfunction, and fetal alcohol syndrome) have been reviewed. RESULTS It is demonstrated that alcohol-induced modulation of zinc transporters results in decreased Zn levels in lungs, liver, gut, and brain. Zn deficiency in the gut results in increased gut permeability, ultimately leading to endotoxemia and systemic inflammation. Similarly, Zn deficiency in lung epithelia and alveolar macrophages decreases lung barrier function resulting in respiratory distress syndrome. In turn, increased endotoxemia significantly contributes to proinflammatory state in alcoholic liver disease. Finally, impaired gut and liver functions may play a significant role in alcoholic brain damage, being associated with both increased proinflammatory signaling and accumulation of neurotoxic metabolites. It is also hypothesized that ethanol-induced Zn deficiency may interfere with neurotransmission. Similar changes may take place in the fetus as a result of impaired placental zinc transfer, maternal zinc deficiency, or maternal Zn sequestration, resulting in fetal alcoholic syndrome. Therefore, alcoholic Zn deficiency not only mediates the adverse effects of ethanol exposure, but also provides an additional link between different alcohol-induced disorders. CONCLUSIONS Generally, current findings suggest that assessment of Zn status could be used as a diagnostic marker of metabolic disturbances in alcohol abuse, whereas modulation of Zn metabolism may be a potential tool in the treatment of alcohol-associated disorders.
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Krizkova S, Kepinska M, Emri G, Eckschlager T, Stiborova M, Pokorna P, Heger Z, Adam V. An insight into the complex roles of metallothioneins in malignant diseases with emphasis on (sub)isoforms/isoforms and epigenetics phenomena. Pharmacol Ther 2017; 183:90-117. [PMID: 28987322 DOI: 10.1016/j.pharmthera.2017.10.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Metallothioneins (MTs) belong to a group of small cysteine-rich proteins that are ubiquitous throughout all kingdoms. The main function of MTs is scavenging of free radicals and detoxification and homeostating of heavy metals. In humans, 16 genes localized on chromosome 16 have been identified to encode four MT isoforms labelled by numbers (MT-1-MT-4). MT-2, MT-3 and MT-4 proteins are encoded by a single gene. MT-1 comprises many (sub)isoforms. The known active MT-1 genes are MT-1A, -1B, -1E, -1F, -1G, -1H, -1M and -1X. The rest of the MT-1 genes (MT-1C, -1D, -1I, -1J and -1L) are pseudogenes. The expression and localization of individual MT (sub)isoforms and pseudogenes vary at intra-cellular level and in individual tissues. Changes in MT expression are associated with the process of carcinogenesis of various types of human malignancies, or with a more aggressive phenotype and therapeutic resistance. Hence, MT (sub)isoform profiling status could be utilized for diagnostics and therapy of tumour diseases. This review aims on a comprehensive summary of methods for analysis of MTs at (sub)isoforms levels, their expression in single tumour diseases and strategies how this knowledge can be utilized in anticancer therapy.
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Affiliation(s)
- Sona Krizkova
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Marta Kepinska
- Department of Biomedical and Environmental Analysis, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland
| | - Gabriella Emri
- Department of Dermatology, Faculty of Medicine, University of Debrecen, Nagyerdei krt 98, H-4032 Debrecen, Hungary
| | - Tomas Eckschlager
- Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, V Uvalu 84, CZ-150 06 Prague 5, Czech Republic
| | - Marie Stiborova
- Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-128 40 Prague 2, Czech Republic
| | - Petra Pokorna
- Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, CZ-128 40 Prague 2, Czech Republic; Department of Oncology, 2nd Faculty of Medicine, Charles University, and University Hospital Motol, V Uvalu 84, CZ-150 06 Prague 5, Czech Republic
| | - Zbynek Heger
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic
| | - Vojtech Adam
- Central European Institute of Technology, Brno University of Technology, Technicka 3058/10, CZ-616 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00 Brno, Czech Republic.
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Zhou X, Li Y, Li C. Autophagy plays a positive role in zinc-induced apoptosis in intestinal porcine epithelial cells. Toxicol In Vitro 2017; 44:392-402. [DOI: 10.1016/j.tiv.2017.08.006] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 07/26/2017] [Accepted: 08/09/2017] [Indexed: 12/18/2022]
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48
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Zhu B, Wang JY, Zhou JJ, Zhou F, Cheng W, Liu YT, Wang J, Chen X, Chen DH, Luo L, Hua ZC. PML-RARα stabilized by zinc in human acute promyelocytic leukemia NB4 cells. J Inorg Biochem 2017; 175:92-100. [DOI: 10.1016/j.jinorgbio.2017.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 07/03/2017] [Accepted: 07/09/2017] [Indexed: 01/09/2023]
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49
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Abstract
Cells respond to deprivation of certain nutrients such as glucose or nitrogen by inducing autophagy, reclaiming pieces of proteins for use in critical functions. A recent study shows that, in yeast, zinc depletion acts in a similar fashion. Depletion of this essential nutrient induces non-selective autophagy by inhibiting TORC1, leading to release and recycling of zinc from degraded proteins.
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Affiliation(s)
- Binbin Ding
- Center for Autophagy Research, Department of Internal Medicine, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390
| | - Qing Zhong
- Center for Autophagy Research, Department of Internal Medicine, Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
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50
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Yan S, Huda N, Khambu B, Yin XM. Relevance of autophagy to fatty liver diseases and potential therapeutic applications. Amino Acids 2017; 49:1965-1979. [PMID: 28478585 DOI: 10.1007/s00726-017-2429-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2017] [Accepted: 04/21/2017] [Indexed: 12/19/2022]
Abstract
Autophagy is an evolutionarily conserved lysosome-mediated cellular degradation program. Accumulating evidence shows that autophagy is important to the maintenance of liver homeostasis. Autophagy involves recycling of cellular nutrients recycling as well as quality control of subcellular organelles. Autophagy deficiency in the liver causes various liver pathologies. Fatty liver disease (FLD) is characterized by the accumulation of lipids in hepatocytes and the dysfunction in energy metabolism. Autophagy is negatively affected by the pathogenesis of FLD and the activation of autophagy could ameliorate steatosis, which suggests a potential therapeutic approach to FLD. In this review, we will discuss autophagy and its relevance to liver diseases, especially FLD. In addition, we will discuss recent findings on potential therapeutic applications of autophagy modulators for FLD.
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Affiliation(s)
- Shengmin Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Nazmul Huda
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
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