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Su K, Tang M, Wu J, Ye N, Jiang X, Zhao M, Zhang R, Cai X, Zhang X, Li N, Peng J, Lin L, Wu W, Ye H. Mechanisms and therapeutic strategies for NLRP3 degradation via post-translational modifications in ubiquitin-proteasome and autophagy lysosomal pathway. Eur J Med Chem 2025; 289:117476. [PMID: 40056798 DOI: 10.1016/j.ejmech.2025.117476] [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: 12/13/2024] [Revised: 02/20/2025] [Accepted: 03/03/2025] [Indexed: 03/10/2025]
Abstract
The NLRP3 inflammasome is crucial for immune responses. However, its overactivation can lead to severe inflammatory diseases, underscoring its importance as a target for therapeutic intervention. Although numerous inhibitors targeting NLRP3 exist, regulating its degradation offers an alternative and promising strategy to suppress its activation. The degradation of NLRP3 is primarily mediated by the proteasomal and autophagic pathways. The review not only elaborates on the traditional concepts of ubiquitination and NLRP3 degradation but also investigates the important roles of indirect regulatory modifications, such as phosphorylation, acetylation, ubiquitin-like modifications, and palmitoylation-key post-translational modifications (PTMs) that influence NLRP3 degradation. Additionally, we also discuss the potential targets that may affect NLRP3 degradation during the proteasomal and autophagic pathways. By unraveling these complex regulatory mechanisms, the review aims to enhance the understanding of NLRP3 regulation and its implications for developing therapeutic strategies to combat inflammatory diseases.
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Affiliation(s)
- Kaiyue Su
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minghai Tang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Wu
- Key Laboratory of Hydrodynamics (Ministry of Education), School of Ocean and Civil Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Neng Ye
- Scaled Manufacturing Center of Biological Products, Management Office of National Facility for Translational Medicine, West China Hospital, Sichuan University Chengdu 610041, China
| | - Xueqin Jiang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Min Zhao
- Laboratory of Metabolomics and Drug-induced Liver Injury, Department of Gastroenterology & Hepatology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Ruijia Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoying Cai
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinlu Zhang
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Na Li
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Peng
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lei Lin
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Wenshuang Wu
- Division of Thyroid Surgery, Department of General Surgery and Laboratory of Thyroid and Parathyroid Disease, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Haoyu Ye
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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Buj R, Cole AR, Danielson J, Xu J, Hurd D, Kishore A, Kedziora KM, Chen J, Yang B, Barras D, Uboveja A, Amalric A, Apiz Saab JJ, Wickramasinghe J, Tangudu NK, Levasseur E, Wang H, Minasyan A, Dadey RE, Sharrow AC, Kunning S, Vendetti FP, Rivadeneira DB, Bakkenist CJ, Bruno TC, Delgoffe GM, Hempel N, Snyder NW, Bao R, Soloff AC, Kirk-Wood JM, Dangaj Laniti D, Kossenkov AV, Muir A, Das J, Davar D, Mesaros C, Aird KM. CDKN2A Low cancer cells outcompete macrophages for microenvironmental zinc to drive immunotherapy resistance. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.02.08.637227. [PMID: 39975044 PMCID: PMC11839072 DOI: 10.1101/2025.02.08.637227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/21/2025]
Abstract
Approximately 50% of cancers exhibit decreased CDKN2A expression ( CDKN2A Low ), which is linked to immune checkpoint blockade (ICB) resistance. While CDKN2A is traditionally recognized as a tumor suppressor and cell cycle regulator, we have previously put forth a new paradigm demonstrating its role in intracellular metabolic reprogramming. Whether the metabolic derangement due to CDKN2A loss alters metabolites within the tumor microenvironment (TME) and how that affects the immune compartment and ICB response has never been investigated. Here we found that CDKN2A Low cancer cells reorganize zinc compartmentalization by upregulating the zinc importer SLC39A9 in the plasma membrane, leading to intracellular zinc accumulation in cancer cells and concurrent zinc depletion in the TME. This competition for zinc results in zinc-starved tumor-associated macrophages (TAMs), leading to reduced phagocytic activity. Increasing zinc in TAMs through multiple approaches, including a dietary intervention that increases availability of TME zinc, re-educates these TAMs to a pro-phagocytic phenotype. Remarkably, both knockdown of Slc39a9 in cancer cells or providing a high zinc diet sensitizes Cdkn2a Low tumors to ICB. TAMs, not T cells, are indispensable for ICB response. Clinically, TAMs from CDKN2A Low cancer patients have decreased zinc signatures, corresponding to reduced phagocytosis signatures. Moreover, patients with low circulating zinc levels have reduced time-to-event outcomes compared to those with higher zinc levels. Our work reveals a previously unrecognized mechanism through which CDKN2A Low cancer cells outcompete TAMs for zinc, directly disrupting their function and ICB efficacy.
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Li J, Tao L, Zhou Y, Zhu Y, Li C, Pan Y, Yao P, Qian X, Liu J. Identification of biomarkers in Alzheimer's disease and COVID-19 by bioinformatics combining single-cell data analysis and machine learning algorithms. PLoS One 2025; 20:e0317915. [PMID: 39965013 PMCID: PMC11835241 DOI: 10.1371/journal.pone.0317915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/07/2025] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Since its emergence in 2019, COVID-19 has become a global epidemic. Several studies have suggested a link between Alzheimer's disease (AD) and COVID-19. However, there is little research into the mechanisms underlying these phenomena. Therefore, we conducted this study to identify key genes in COVID-19 associated with AD, and evaluate their correlation with immune cells characteristics and metabolic pathways. METHODS Transcriptome analyses were used to identify common biomolecular markers of AD and COVID-19. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed on gene chip datasets (GSE213313, GSE5281, and GSE63060) from AD and COVID-19 patients to identify genes associated with both conditions. Gene ontology (GO) enrichment analysis identified common molecular mechanisms. The core genes were identified using machine learning. Subsequently, we evaluated the relationship between these core genes and immune cells and metabolic pathways. Finally, our findings were validated through single-cell analysis. RESULTS The study identified 484 common differentially expressed genes (DEGs) by taking the intersection of genes between AD and COVID-19. The black module, containing 132 genes, showed the highest association between the two diseases according to WGCNA. GO enrichment analysis revealed that these genes mainly affect inflammation, cytokines, immune-related functions, and signaling pathways related to metal ions. Additionally, a machine learning approach identified eight core genes. We identified links between these genes and immune cells and also found a association between EIF3H and oxidative phosphorylation. CONCLUSION This study identifies shared genes, pathways, immune alterations, and metabolic changes potentially contributing to the pathogenesis of both COVID-19 and AD.
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Affiliation(s)
- Juntu Li
- Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, Jiangsu, China
| | - Linfeng Tao
- Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, Jiangsu, China
| | - Yanyou Zhou
- Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, Jiangsu, China
| | - Yue Zhu
- Department of Breast and Thyroid Surgery, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou, Jiangsu, China
| | - Chao Li
- Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, Jiangsu, China
| | - Yiyuan Pan
- Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, Jiangsu, China
| | - Ping Yao
- Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, Jiangsu, China
| | - Xuefeng Qian
- Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, Jiangsu, China
| | - Jun Liu
- Department of Critical Care Medicine and Emergency, The Affiliated Suzhou Hospital of Nanjing Medical University (Suzhou Municipal Hospital), Gusu School, Nanjing Medical University, Suzhou Clinical Medical Center of Critical Care Medicine, Suzhou, Jiangsu, China
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Jimenez-Rondan FR, Ruggiero CH, Riva A, Yu F, Stafford LS, Cross TR, Larkin J, Cousins RJ. Deletion of metal transporter Zip14 reduces major histocompatibility complex II expression in murine small intestinal epithelial cells. Proc Natl Acad Sci U S A 2025; 122:e2422321121. [PMID: 39793074 PMCID: PMC11725848 DOI: 10.1073/pnas.2422321121] [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: 10/30/2024] [Accepted: 11/21/2024] [Indexed: 01/12/2025] Open
Abstract
Documented worldwide, impaired immunity is a cardinal signature resulting from loss of dietary zinc, an essential micronutrient. A steady supply of zinc to meet cellular requirements is regulated by an array of zinc transporters. Deletion of the transporter Zip14 (Slc39a14) in mice produced intestinal inflammation. Elevated fecal lipocalin-2, calprotectin, IgG levels, and dysbiosis support the inflammatory phenotype. Here, we show through RNA-sequencing, using purified intestinal epithelial cells (IECs), that Zip14 deletion produces markedly reduced expression of major histocompatibility complex class II (MHCII) molecules and the master MHCII transactivator (Ciita). qPCR, western analysis, and immunohistochemistry confirmed loss of MHCII. Spectrofluorimetry with zinc probe FluoZin-3 showed reduced labile zinc in IECs from knockout mice. Chromatin immunoprecipitation assays, using Ciita antibody and IEC chromatin, suggest decreased transcription accounts for depressed expression of specific MHCII genes. Assay for Transposase-Accessible Chromatin (ATAC) sequencing (ATAC-seq) demonstrated that H2-Aa, H2-Ab1 and other MHCII genes result from chromatin remodeling yielding closed chromatin at regulatory regions of these genes. In agreement, ATAC-seq showed peak density of the chromosomal regulatory region of Ciita is consistent with down regulation of specific MHCII genes in IECs with Zip14 loss. Finally, dietary zinc supplementation of knockout mice and zinc supplementation of intestinal organoids with Zip14 deletion restored transcript levels. Taken together, our data suggest that cellular zinc delivery, via Zip14, is necessary for proper chromatin occupancy, required for normal MHCII expression and effective immune functions, and to preclude inflammatory disorders of the small intestine.
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Affiliation(s)
- Felix R. Jimenez-Rondan
- Center for Nutritional Sciences, Food Science and Human Nutrition Department, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL32611
| | - Courtney H. Ruggiero
- Center for Nutritional Sciences, Food Science and Human Nutrition Department, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL32611
| | - Alberto Riva
- Bioinformatics Core Facility, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL32611
| | - Fahong Yu
- Bioinformatics Core Facility, Interdisciplinary Center for Biotechnology Research, University of Florida, Gainesville, FL32611
| | - Lauren S. Stafford
- Department of Microbiology and Cell Science, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL32611
| | - Tyler R. Cross
- Department of Microbiology and Cell Science, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL32611
| | - Joseph Larkin
- Department of Microbiology and Cell Science, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL32611
| | - Robert J. Cousins
- Center for Nutritional Sciences, Food Science and Human Nutrition Department, College of Agricultural and Life Sciences, University of Florida, Gainesville, FL32611
- Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL32611
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Yao JH, Ortega EF, Panda A. Impact of zinc on immunometabolism and its putative role on respiratory diseases. IMMUNOMETABOLISM (COBHAM, SURREY) 2025; 7:e00057. [PMID: 40051614 PMCID: PMC11882175 DOI: 10.1097/in9.0000000000000057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Accepted: 02/04/2025] [Indexed: 03/09/2025]
Abstract
Zinc is the second most abundant trace mineral in the human body and plays a critical role in immune cell function and metabolism. Zinc deficiency impairs immune cell function and is associated with increased susceptibility to respiratory diseases, including pneumonia, influenza, and COVID-19. Zinc homeostasis, maintained by numerous zinc transporters and metal-binding proteins (ie, metallothionein), is essential for coordinating immune cell signaling, gene expression, and enzymatic activities in response to respiratory infections. This article highlights the emerging role of zinc in various aspects of immune function, particularly through its influence on cellular metabolism. Given the significant global burden of respiratory diseases, there is a need to identify effective nutritional interventions that could be readily leveraged to prevent and/or mitigate respiratory disease risk, particularly in older adults who are prone to zinc deficiency. However, the immunometabolic mechanisms underlying zinc's protective effects remain poorly characterized. Future research should focus on elucidating how micronutrients, such as zinc, can support changes in immune cell metabolism in response to infections. Such efforts will help determine how zinc metabolism and zinc intervention strategies may best be leveraged to prevent or mitigate respiratory disease.
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Affiliation(s)
- Jonathan H. Yao
- Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Edwin F. Ortega
- Nutritional Immunology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
- Department of Microbiology and Immunology, University of California, San Francisco, CA, USA
| | - Alexander Panda
- Department of Immunology, Tufts University School of Medicine, Boston, MA, USA
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Li D, Wan M, Xue L, Zhang Z, Qiu Y, Mei F, Tang N, Yu C, Yu Y, Chen T, Ding X, Yang Q, Liu Q, Gu P, Jia W, Chen Y, Chen P. Zinc promotes microbial p-coumaric acid production that protects against cholestatic liver injury. Cell Host Microbe 2024; 32:2195-2211.e9. [PMID: 39610253 DOI: 10.1016/j.chom.2024.11.002] [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: 07/26/2024] [Revised: 09/30/2024] [Accepted: 11/01/2024] [Indexed: 11/30/2024]
Abstract
Cholestatic liver disease (CLD) is a common liver disorder with limited treatment options. Here, we demonstrate that zinc (Zn) supplementation can alter the gut microbiome to mitigate cholestatic liver injury. Oral Zn altered the microbiota of mice and humans (this study was registered at clinicaltrials.gov [NCT05597137]), increasing the abundance of Blautia producta (B. producta) and promoting the generation of p-coumaric acid. Additionally, p-coumaric acid concentrations were negatively correlated with liver injury parameters in CLD patients. In mice, the protective effects of Zn were partially mediated by p-coumaric acid, which directly bound to nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and suppressed the production of reactive oxygen species (ROS) in hepatocytes, thus preventing hepatocyte cell death and liver damage. Additionally, knocking out the histidine ammonia-lyase, which catalyzes the conversion of tyrosine to p-coumaric acid in B. producta, blunted the protective effects of Zn. These findings highlight a host-microbiota interaction that is stimulated by Zn supplementation, providing potential benefits for CLD.
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Affiliation(s)
- Dongping Li
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Meijuan Wan
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Lanfeng Xue
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan 528244, China
| | - Zhelin Zhang
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan 528244, China
| | - Yifeng Qiu
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical school, Shenzhen, Guangdong 518071, China
| | - Fengyi Mei
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Niexing Tang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Chunxiao Yu
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan 528244, China
| | - Yao Yu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Tianqi Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xing Ding
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qin Yang
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qiuyan Liu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Peng Gu
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Wei Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, School of Biomedical Engineering, Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China; Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong, China.
| | - Yu Chen
- Department of Gastroenterology, The Seventh Affiliated Hospital of Southern Medical University, Foshan 528244, China.
| | - Peng Chen
- Department of Pathophysiology, Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
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Aktay I, Billur D, Tuncay E, Turan B. An Overexpression of SLC30A6 Gene Contributes to Cardiomyocyte Dysfunction via Affecting Mitochondria and Inducing Activations in K-Acetylation and Epigenetic Proteins. Biochem Genet 2024; 62:3198-3214. [PMID: 38091184 DOI: 10.1007/s10528-023-10602-7] [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: 09/30/2023] [Accepted: 11/13/2023] [Indexed: 07/31/2024]
Abstract
Intracellular free Zn2+ ([Zn2+]i) is less than 1-nM in cardiomyocytes and its regulation is performed with Zn2+-transporters. However, the roles of Zn2+-transporters in cardiomyocytes are not defined exactly yet. Here, we aimed to examine the role of an overexpression and subcellular localization of a ZnT6 in insulin-resistance mimic H9c2 cardiomyoblasts (IR-cells; 50-μM palmitic acid for 24-h incubation). We used both IR-cells and ZnT6-overexpressed (ZnT6OE) cells in comparison to those of H9c2 cells (CON-cells). The IR-cells have higher ZnT6-protein levels than CON-cells while this level was similar to those of ZnT6OE-cells. The [Zn2+]i in IR-cells was increased significantly and mitochondrial localization of ZnT6 was demonstrated in these cells by using confocal microscopy visualization. Furthermore, electron microscopy analysis demonstrated abnormal morphological appearance in both IR-cells and ZnT6OE-cells characterized by irregular mitochondrion cristae and condensed and dilated cisterna in the sarcoplasmic reticulum. Mitochondria were similarly depolarized in both IR-cells and ZnT6OE-cells. The protein expression level of a mitofusin protein MFN2 in the IR-cells was decreased, significantly, whereas, it was found significantly upregulated in both ZnT6-OE-cells and IR-incubated ZnT6OE-cells, which demonstrates the role of ZnT6-overexpression but not IR. Additionally, the total protein level of a mitochondrial fission protein, dynamin-related protein 1, DRP1 was found to be increased over 1.5-fold in IR-cells while this increase was found to be higher in the ZnT6OE-cells than those of IR-cells, demonstrating an additional effect on IR-increase. ZnT6-overexpression induced also significant increases in K-acetylation, trimethylation of histone H3 lysine27, and mono-methylation of histone H3 lysine36, in a similar manner to those of IR-cells. Overall, our data point out an important contribution of ZnT6-overexpression to IR-induced cellular changes, such as alteration in mitochondria function and activation of epigenetic modifications.
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Affiliation(s)
- Irem Aktay
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Deniz Billur
- Department of Histology & Embryology, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Erkan Tuncay
- Department of Biophysics, Faculty of Medicine, Ankara University, Ankara, Turkey
| | - Belma Turan
- Department of Biophysics, Faculty of Medicine, Lokman Hekim University, Ankara, Turkey.
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Maywald M, Rink L. Zinc Deficiency and Zinc Supplementation in Allergic Diseases. Biomolecules 2024; 14:863. [PMID: 39062576 PMCID: PMC11274920 DOI: 10.3390/biom14070863] [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: 05/27/2024] [Revised: 07/17/2024] [Accepted: 07/18/2024] [Indexed: 07/28/2024] Open
Abstract
In recent decades, it has become clear that allergic diseases are on the rise in both Western and developing countries. The exact reason for the increase in prevalence has not been conclusively clarified yet. Multidimensional approaches are suspected in which diet and nutrition seem to play a particularly important role. Allergic diseases are characterized by a hyper-reactive immune system to usually harmless allergens, leading to chronic inflammatory diseases comprising respiratory diseases like asthma and allergic rhinitis (AR), allergic skin diseases like atopic dermatitis (AD), and food allergies. There is evidence that diet can have a positive or negative influence on both the development and severity of allergic diseases. In particular, the intake of the essential trace element zinc plays a very important role in modulating the immune response, which was first demonstrated around 60 years ago. The most prevalent type I allergies are mainly based on altered immunoglobulin (Ig)E and T helper (Th)2 cytokine production, leading to type 2 inflammation. This immune status can also be observed during zinc deficiency and can be positively influenced by zinc supplementation. The underlying immunological mechanisms are very complex and multidimensional. Since zinc supplements vary in dose and bioavailability, and clinical trials often differ in design and structure, different results can be observed. Therefore, different results are not surprising. However, the current literature suggests a link between zinc deficiency and the development of allergies, and shows positive effects of zinc supplementation on modulating the immune system and reducing allergic symptoms, which are discussed in more detail in this review.
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Affiliation(s)
| | - Lothar Rink
- Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, 52074 Aachen, Germany;
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Gori A, Brindisi G, Daglia M, del Giudice MM, Dinardo G, Di Minno A, Drago L, Indolfi C, Naso M, Trincianti C, Tondina E, Brunese FP, Ullah H, Varricchio A, Ciprandi G, Zicari AM. Exploring the Role of Lactoferrin in Managing Allergic Airway Diseases among Children: Unrevealing a Potential Breakthrough. Nutrients 2024; 16:1906. [PMID: 38931261 PMCID: PMC11206375 DOI: 10.3390/nu16121906] [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: 05/01/2024] [Revised: 06/08/2024] [Accepted: 06/09/2024] [Indexed: 06/28/2024] Open
Abstract
The prevalence of allergic diseases has dramatically increased among children in recent decades. These conditions significantly impact the quality of life of allergic children and their families. Lactoferrin, a multifunctional glycoprotein found in various biological fluids, is emerging as a promising immunomodulatory agent that can potentially alleviate allergic diseases in children. Lactoferrin's multifaceted properties make it a compelling candidate for managing these conditions. Firstly, lactoferrin exhibits potent anti-inflammatory and antioxidant activities, which can mitigate the chronic inflammation characteristic of allergic diseases. Secondly, its iron-binding capabilities may help regulate the iron balance in allergic children, potentially influencing the severity of their symptoms. Lactoferrin also demonstrates antimicrobial properties, making it beneficial in preventing secondary infections often associated with respiratory allergies. Furthermore, its ability to modulate the immune response and regulate inflammatory pathways suggests its potential as an immune-balancing agent. This review of the current literature emphasises the need for further research to elucidate the precise roles of lactoferrin in allergic diseases. Harnessing the immunomodulatory potential of lactoferrin could provide a novel add-on approach to managing allergic diseases in children, offering hope for improved outcomes and an enhanced quality of life for paediatric patients and their families. As lactoferrin continues to capture the attention of researchers, its properties and diverse applications make it an intriguing subject of study with a rich history and a promising future.
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Affiliation(s)
- Alessandra Gori
- Department of Mother-Child, Urological Science, Sapienza University of Rome, 00161 Rome, Italy; (A.G.); (G.B.)
| | - Giulia Brindisi
- Department of Mother-Child, Urological Science, Sapienza University of Rome, 00161 Rome, Italy; (A.G.); (G.B.)
| | - Maria Daglia
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (M.D.); (A.D.M.); (H.U.)
- International Research Center for Food Nutrition and Safety, Jiangsu University, Zhenjiang 212013, China
| | - Michele Miraglia del Giudice
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (M.M.d.G.); (G.D.); (C.I.)
| | - Giulio Dinardo
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (M.M.d.G.); (G.D.); (C.I.)
| | - Alessandro Di Minno
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (M.D.); (A.D.M.); (H.U.)
- CEINGE-Biotecnologie Avanzate, Via Gaetano Salvatore 486, 80145 Naples, Italy
| | - Lorenzo Drago
- Laboratory of Clinical Microbiology & Microbiome, Department of Biomedical Sciences for Health, University of Milan, 20122 Milan, Italy;
- UOC Laboratory of Clinical Medicine, MultiLab Department, IRCCS Multimedica, 20138 Milan, Italy
| | - Cristiana Indolfi
- Department of Woman, Child and General and Specialized Surgery, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (M.M.d.G.); (G.D.); (C.I.)
| | - Matteo Naso
- Allergy Center, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (M.N.); (C.T.)
| | - Chiara Trincianti
- Allergy Center, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy; (M.N.); (C.T.)
| | - Enrico Tondina
- Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | | | - Hammad Ullah
- Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Naples, Italy; (M.D.); (A.D.M.); (H.U.)
| | - Attilio Varricchio
- Department of Otolaryngology, University of Molise, 86100 Campobasso, Italy;
| | - Giorgio Ciprandi
- Allergy Clinic, Casa di Cura Villa Montallegro, 16145 Genoa, Italy;
| | - Anna Maria Zicari
- Department of Mother-Child, Urological Science, Sapienza University of Rome, 00161 Rome, Italy; (A.G.); (G.B.)
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10
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Li L, Chen J, Wang Z, Xu Y, Yao H, Lei W, Zhou X, Zheng M. NECA alleviates inflammatory responses in diabetic retinopathy through dendritic cell toll-like receptor signaling pathway. Front Immunol 2024; 15:1415004. [PMID: 38895119 PMCID: PMC11182989 DOI: 10.3389/fimmu.2024.1415004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
Introduction This study examined the impact of 5'-(N- ethylcarboxamido)adenosine (NECA) in the peripheral blood of healthy individuals, those with diabetes mellitus, diabetic retinopathy (DR), and C57BL/6 mice, both in vivo and in vitro. Methods Enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FCM) were used to evaluate the effects of NECA on dendritic cells (DCs) and mouse bone marrow-derived dendritic cells (BMDCs) and the effects of NECA-treated DCs on Treg and Th17 cells. The effect of NECA on the Toll-like receptor (TLR) pathway in DCs was evaluated using polymerase chain reaction (PCR) and western blotting (WB). Results FCM and ELISA showed that NECA inhibited the expression of surface markers of DCs and BMDCs, increased anti-inflammatory cytokines and decreased proinflammatory cytokines. PCR and WB showed that NCEA decreased mRNA transcription and protein expression in the TLR-4-MyD88-NF-kβ pathway in DCs and BMDCs. The DR severity in streptozocin (STZ) induced diabetic mice was alleviated. NECA-treated DCs and BMDCs were co-cultivated with CD4+T cells, resulting in modulation of Treg and Th17 differentiation, along with cytokine secretion alterations. Conclusion NECA could impair DCs' ability to present antigens and mitigate the inflammatory response, thereby alleviating the severity of DR.
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Affiliation(s)
| | | | | | | | | | | | - Xiyuan Zhou
- *Correspondence: Xiyuan Zhou, ; Minming Zheng,
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11
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Seki T, Ohshima S, Komatsu S, Yamada S, Kashiwagi H, Goto Y, Tsuda B, Kanno A, Yasuda A, Kuno H, Tsuji NM, Shiina T, Kametani Y. Coccomyxa subellipsoidea KJ Components Enhance the Expression of Metallothioneins and Th17 Cytokines during Human T Cell Activation. Microorganisms 2024; 12:741. [PMID: 38674685 PMCID: PMC11051862 DOI: 10.3390/microorganisms12040741] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/28/2024] [Accepted: 04/02/2024] [Indexed: 04/28/2024] Open
Abstract
Coccomyxa subellipsoidea KJ (C-KJ) is a green alga with unique immunoregulatory characteristics. Here, we investigated the mechanism underlying the modification of T cell function by C-KJ components. The water-soluble extract of C-KJ was fractionated into protein (P) and sugar (S) fractions acidic (AS), basic (BS), and neutral (NS). These fractions were used for the treatment of peripheral blood mononuclear cells stimulated with toxic shock syndrome toxin-1. Transcriptome analysis revealed that both P and AS enhanced the expression of the genes encoding metallothionein (MT) family proteins, inflammatory factors, and T helper (Th) 17 cytokine and suppressed that of those encoding Th2 cytokines in stimulated T cells. The kinetics of MT1 and MT2A gene expression showed a transient increase in MT1 and maintenance of MT2A mRNA after T cell stimulation in the presence of AS. The kinetics of Th17-related cytokine secretion in the early period were comparable to those of MT2A mRNA. Furthermore, our findings revealed that static, a STAT-3 inhibitor, significantly suppressed MT2A gene expression. These findings suggest that the expression of MTs is involved in the immune regulatory function of C-KJ components, which is partially regulated by Th17 responses, and may help develop innovative immunoregulatory drugs or functional foods.
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Affiliation(s)
- Toshiro Seki
- Department of Internal Medicine, Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara 259-1193, Japan; (T.S.); (A.Y.)
| | - Shino Ohshima
- Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara 259-1193, Japan; (S.O.); (T.S.)
| | - Satoko Komatsu
- DENSO CORPORATION, Kariya 448-0029, Japan; (S.K.); (H.K.)
| | - Soga Yamada
- Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara 259-1193, Japan; (S.O.); (T.S.)
| | - Hirofumi Kashiwagi
- Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Yumiko Goto
- Department of Obstetrics and Gynecology, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Banri Tsuda
- Department of Palliative Medicine, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Akiko Kanno
- DENSO CORPORATION, Kariya 448-0029, Japan; (S.K.); (H.K.)
| | - Atsushi Yasuda
- Department of Internal Medicine, Division of Nephrology, Endocrinology and Metabolism, Tokai University School of Medicine, Isehara 259-1193, Japan; (T.S.); (A.Y.)
| | - Hitoshi Kuno
- DENSO CORPORATION, Kariya 448-0029, Japan; (S.K.); (H.K.)
| | - Noriko M Tsuji
- Division of Immune Homeostasis, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 113-8602, Japan
- Division of Microbiology, Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo 113-8602, Japan
- Department of Food Science, Jumonji University, Niiza 352-8510, Japan
| | - Takashi Shiina
- Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara 259-1193, Japan; (S.O.); (T.S.)
- Institute of Advanced Biosciences, Tokai University, Hiratsuka 259-1207, Japan
| | - Yoshie Kametani
- Department of Molecular Life Science, Division of Basic Medical Science, Tokai University School of Medicine, Isehara 259-1193, Japan; (S.O.); (T.S.)
- Institute of Advanced Biosciences, Tokai University, Hiratsuka 259-1207, Japan
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12
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Abstract
This review provides a concise overview of the cellular and clinical aspects of the role of zinc, an essential micronutrient, in human physiology and discusses zinc-related pathological states. Zinc cannot be stored in significant amounts, so regular dietary intake is essential. ZIP4 and/or ZnT5B transport dietary zinc ions from the duodenum into the enterocyte, ZnT1 transports zinc ions from the enterocyte into the circulation, and ZnT5B (bidirectional zinc transporter) facilitates endogenous zinc secretion into the intestinal lumen. Putative promoters of zinc absorption that increase its bioavailability include amino acids released from protein digestion and citrate, whereas dietary phytates, casein and calcium can reduce zinc bioavailability. In circulation, 70% of zinc is bound to albumin, and the majority in the body is found in skeletal muscle and bone. Zinc excretion is via faeces (predominantly), urine, sweat, menstrual flow and semen. Excessive zinc intake can inhibit the absorption of copper and iron, leading to copper deficiency and anaemia, respectively. Zinc toxicity can adversely affect the lipid profile and immune system, and its treatment depends on the mode of zinc acquisition. Acquired zinc deficiency usually presents later in life alongside risk factors like malabsorption syndromes, but medications like diuretics and angiotensin-receptor blockers can also cause zinc deficiency. Inherited zinc deficiency condition acrodermatitis enteropathica, which occurs due to mutation in the SLC39A4 gene (encoding ZIP4), presents from birth. Treatment involves zinc supplementation via zinc gluconate, zinc sulphate or zinc chloride. Notably, oral zinc supplementation may decrease the absorption of drugs like ciprofloxacin, doxycycline and risedronate.
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Affiliation(s)
- Lucy I Stiles
- Faculty of Life Sciences and Medicine, GKT School of Medical Education, King's College London, London, UK
| | - Kevin Ferrao
- Faculty of Life Sciences and Medicine, GKT School of Medical Education, King's College London, London, UK
| | - Kosha J Mehta
- Faculty of Life Sciences and Medicine, Centre for Education, King's College London, London, UK.
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13
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Shao L, Yang M, Sun T, Xia H, Du D, Li X, Jie Z. Role of solute carrier transporters in regulating dendritic cell maturation and function. Eur J Immunol 2024; 54:e2350385. [PMID: 38073515 DOI: 10.1002/eji.202350385] [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: 07/02/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 02/27/2024]
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells that initiate and regulate innate and adaptive immune responses. Solute carrier (SLC) transporters mediate diverse physiological functions and maintain cellular metabolite homeostasis. Recent studies have highlighted the significance of SLCs in immune processes. Notably, upon activation, immune cells undergo rapid and robust metabolic reprogramming, largely dependent on SLCs to modulate diverse immunological responses. In this review, we explore the central roles of SLC proteins and their transported substrates in shaping DC functions. We provide a comprehensive overview of recent studies on amino acid transporters, metal ion transporters, and glucose transporters, emphasizing their essential contributions to DC homeostasis under varying pathological conditions. Finally, we propose potential strategies for targeting SLCs in DCs to bolster immunotherapy for a spectrum of human diseases.
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Affiliation(s)
- Lin Shao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
- School of Life Sciences, Fudan University, Shanghai, China
| | - Mengxin Yang
- School of Public Health, Xiamen University, Xiamen, Fujian, China
| | - Tao Sun
- Department of Laboratory Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Haotang Xia
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Dan Du
- Department of Stomatology, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian, China
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
| | - Xun Li
- Department of Laboratory Medicine, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Zuliang Jie
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, China
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14
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Yin Z, Wan B, Gong G, Yin J. ROS: Executioner of regulating cell death in spinal cord injury. Front Immunol 2024; 15:1330678. [PMID: 38322262 PMCID: PMC10844444 DOI: 10.3389/fimmu.2024.1330678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
The damage to the central nervous system and dysfunction of the body caused by spinal cord injury (SCI) are extremely severe. The pathological process of SCI is accompanied by inflammation and injury to nerve cells. Current evidence suggests that oxidative stress, resulting from an increase in the production of reactive oxygen species (ROS) and an imbalance in its clearance, plays a significant role in the secondary damage during SCI. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial regulatory molecule for cellular redox. This review summarizes recent advancements in the regulation of ROS-Nrf2 signaling and focuses on the interaction between ROS and the regulation of different modes of neuronal cell death after SCI, such as apoptosis, autophagy, pyroptosis, and ferroptosis. Furthermore, we highlight the pathways through which materials science, including exosomes, hydrogels, and nanomaterials, can alleviate SCI by modulating ROS production and clearance. This review provides valuable insights and directions for reducing neuronal cell death and alleviating SCI through the regulation of ROS and oxidative stress.
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Affiliation(s)
- Zhaoyang Yin
- Department of Orthopedics, the Affiliated Lianyungang Hospital of Xuzhou Medical University (The First People’s Hospital of Lianyungang), Lianyungang, China
| | - Bowen Wan
- Department of Orthopedics, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University/Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Ge Gong
- Department of Geriatrics, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
| | - Jian Yin
- Department of Orthopedics, the Affiliated Jiangning Hospital with Nanjing Medical University, Nanjing, China
- Department of Orthopedics, Jiangning Clinical Teaching Hospitals of Jiangsu Vocational College of Medicine, Nanjing, China
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15
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Yang F, Smith MJ. Metal profiling in coronary ischemia-reperfusion injury: Implications for KEAP1/NRF2 regulated redox signaling. Free Radic Biol Med 2024; 210:158-171. [PMID: 37989446 DOI: 10.1016/j.freeradbiomed.2023.11.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/18/2023] [Accepted: 11/07/2023] [Indexed: 11/23/2023]
Abstract
Coronary ischemia-reperfusion (IR) injury results from a blockage of blood supply to the heart followed by restoration of perfusion, leading to oxidative stress induced pathological processes. Nuclear factor erythroid 2-related factor 2 (NRF2), a master antioxidant transcription factor, plays a key role in regulating redox signaling. Over the past decades, the field of metallomics has provided novel insights into the mechanism of pro-oxidant and antioxidant pathological processes. Both redox-active (e.g. Fe and Cu) and redox-inert (e.g. Zn and Mg) metals play unique roles in establishing redox balance under IR injury. Notably, Zn protects against oxidative stress in coronary IR injury by serving as a cofactor of antioxidant enzymes such as superoxide dismutase [Cu-Zn] (SOD1) and proteins such as metallothionein (MT) and KEAP1/NRF2 mediated antioxidant defenses. An increase in labile Zn2+ inhibits proteasomal degradation and ubiquitination of NRF2 by modifying KEAP1 and glycogen synthase kinase 3β (GSK3β) conformations. Fe and Cu catalyse the formation of reactive oxygen species via the Fenton reaction and also serve as cofactors of antioxidant enzymes and can activate NRF2 antioxidant signaling. We review the evidence that Zn and redox-active metals Fe and Cu affect redox signaling in coronary cells during IR and the mechanisms by which oxidative stress influences cellular metal content. In view of the unique double-edged characteristics of metals, we aim to bridge the role of metals and NRF2 regulated redox signaling to antioxidant defenses in IR injury, with a long-term aim of informing the design and application of novel therapeutics.
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Affiliation(s)
- Fan Yang
- King's British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
| | - Matthew J Smith
- MSD R&D Innovation Centre, 120 Moorgate, London EC2M 6UR, United Kingdom.
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16
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Shaikh NA, Zhang XB, Abdalla MI, Baylink DJ, Tang X. Enhancing Human Treg Cell Induction through Engineered Dendritic Cells and Zinc Supplementation. Crit Rev Immunol 2024; 44:37-52. [PMID: 38421704 PMCID: PMC11015935 DOI: 10.1615/critrevimmunol.2023050325] [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] [Indexed: 03/02/2024]
Abstract
Regulatory T (Treg) cells hold promise for the ultimate cure of immune-mediated diseases. However, how to effectively restore Treg function in patients remains unknown. Previous reports suggest that activated dendritic cells (DCs) de novo synthesize locally high concentrations of 1,25-dihydroxy vitamin D, i.e., the active vitamin D or 1,25(OH)2D by upregulating the expression of 25-hydroxy vitamin D 1α-hydroxylase. Although 1,25(OH)2D has been shown to induce Treg cells, DC-derived 1,25(OH)2D only serves as a checkpoint to ensure well-balanced immune responses. Our animal studies have shown that 1,25(OH)2D requires high concentrations to generate Treg cells, which can cause severe side effects. In addition, our animal studies have also demonstrated that dendritic cells (DCs) overexpressing the 1α-hydroxylase de novo synthesize the effective Treg-inducing 1,25(OH)2D concentrations without causing the primary side effect of hypercalcemia (i.e., high blood calcium levels). This study furthers our previous animal studies and explores the efficacy of the la-hydroxylase-overexpressing DCs in inducing human CD4+FOXP3+regulatory T (Treg) cells. We discovered that the effective Treg-inducing doses of 1,25(OH)2D were within a range. Additionally, our data corroborated that the 1α-hydroxylase-overexpressing DCs synthesized 1,25(OH)2D within this concentration range in vivo, thus facilitating effective Treg cell induction. Moreover, this study demonstrated that 1α-hydroxylase expression levels were pivotal for DCs to induce Treg cells because physiological 25(OH)D levels were sufficient for the engineered but not parental DCs to enhance Treg cell induction. Interestingly, adding non-toxic zinc concentrations significantly augmented the Treg-inducing capacity of the engineered DCs. Our new findings offer a novel therapeutic avenue for immune-mediated human diseases, such as inflammatory bowel disease, type 1 diabetes, and multiple sclerosis, by integrating zinc with the 1α-hydroxylase-overexpressing DCs.
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Affiliation(s)
- Nisar Ali Shaikh
- Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY 11548, USA
| | - Xiao-Bing Zhang
- Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Peking Union Medical College, Tianjin, China
| | - Maisa I. Abdalla
- Division of Gastroenterology and Hepatology, University of Rochester Medical Center, New York 14642, USA
| | - David J. Baylink
- Division of Regenerative Medicine, Department of Medicine, Department of Basic Science, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Xiaolei Tang
- Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, Long Island University, Brookville, NY 11548, USA
- Division of Regenerative Medicine, Department of Medicine, Department of Basic Science, School of Medicine, Loma Linda University, Loma Linda, CA, USA
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Deng H, Liu Y, Shi Z, Yang J, Liu C, Mei X. Zinc regulates a specific subpopulation of VEGFA + microglia to improve the hypoxic microenvironment for functional recovery after spinal cord injury. Int Immunopharmacol 2023; 125:111092. [PMID: 37883817 DOI: 10.1016/j.intimp.2023.111092] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/05/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023]
Abstract
INTRODUCTION Spinal cord injury (SCI) is a central nervous system injury that is primarily traumatic and manifests as autonomic dysfunction below the level of injury. Our previous studies have found that zinc ions have important effects on the nervous system and nerve repair, promoting autophagy and reducing inflammatory responses. However, the role of zinc ions in vascular regeneration is unclear. AIMS We investigated the effect of zinc ions after spinal cord injury from the perspective of a hypoxic microenvironment, and elucidated the role of VEGF-A secreted by microglia for vascular regeneration after spinal cord injury, providing new ideas for the treatment of spinal cord injury. RESULTS Zinc promotes functional recovery after spinal cord injury by regulating VEGF-A secretion from microglia. On the one hand, VEGF-A secreted by microglia promotes angiogenesis through the PI3K/AKT/Bcl-2 pathway and improves the hypoxic microenvironment after spinal cord injury. On the other hand, VEGF-A secreted by microglia was positively correlated with platelet endothelial cell adhesion molecule-1 (CD31), and zinc could increase the association between microglia and blood vessels. CONCLUSION Zinc promoted microglia secretion of VEGF-A, increased vascular endothelial cell proliferation and migration through the PI3K/AKT/Bcl-2 pathway, and inhibited microglia apoptosis.
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Affiliation(s)
- Hao Deng
- Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Yu Liu
- Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Zuqiang Shi
- Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Jing Yang
- Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China
| | - Chang Liu
- First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China.
| | - Xifan Mei
- Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning Province, China.
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Liu Y, Li X, Liu S, Du J, Xu J, Liu Y, Guo L. The changes and potential effects of zinc homeostasis in periodontitis microenvironment. Oral Dis 2023; 29:3063-3077. [PMID: 35996971 DOI: 10.1111/odi.14354] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/28/2022] [Accepted: 08/14/2022] [Indexed: 11/29/2022]
Abstract
Zinc is a very important and ubiquitous element, which is present in oral environment, daily diet, oral health products, dental restorative materials, and so on. However, there is a lack of attention to the role of both extracellular or intracellular zinc in the progression of periodontitis and periodontal regeneration. This review summarizes the characteristics of immunological microenvironment and host cells function in several key stages of periodontitis progression, and explores the regulatory effect of zinc during this process. We find multiple evidence indicate that zinc may be involved and play a key role in the stages of immune defense, inflammatory response and bone remodeling. Zinc supplementation in an appropriate dose range or regulation of zinc transport proteins can promote periodontal regeneration by either enhancing immune defense or up-regulating local cells proliferation and differentiation functions. Therefore, zinc homeostasis is essential in periodontal remodeling and regeneration. More attention is suggested to be focused on zinc homeostasis regulation and consider it as a potential strategy in the studies on periodontitis treatment, periodontal-guided tissue regeneration, implant material transformation, and so on.
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Affiliation(s)
- Yitong Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaoyan Li
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Siyan Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Juan Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Junji Xu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Lijia Guo
- Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, China
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Kumar S, Ansari S, Narayanan S, Ranjith-Kumar CT, Surjit M. Antiviral activity of zinc against hepatitis viruses: current status and future prospects. Front Microbiol 2023; 14:1218654. [PMID: 37908540 PMCID: PMC10613677 DOI: 10.3389/fmicb.2023.1218654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 09/28/2023] [Indexed: 11/02/2023] Open
Abstract
Viral hepatitis is a major public health concern globally. World health organization aims at eliminating viral hepatitis as a public health threat by 2030. Among the hepatitis causing viruses, hepatitis B and C are primarily transmitted via contaminated blood. Hepatitis A and E, which gets transmitted primarily via the feco-oral route, are the leading cause of acute viral hepatitis. Although vaccines are available against some of these viruses, new cases continue to be reported. There is an urgent need to devise a potent yet economical antiviral strategy against the hepatitis-causing viruses (denoted as hepatitis viruses) for achieving global elimination of viral hepatitis. Although zinc was known to mankind for a long time (since before Christ era), it was identified as an element in 1746 and its importance for human health was discovered in 1963 by the pioneering work of Dr. Ananda S. Prasad. A series of follow up studies involving zinc supplementation as a therapy demonstrated zinc as an essential element for humans, leading to establishment of a recommended dietary allowance (RDA) of 15 milligram zinc [United States RDA for zinc]. Being an essential component of many cellular enzymes and transcription factors, zinc is vital for growth and homeostasis of most living organisms, including human. Importantly, several studies indicate potent antiviral activity of zinc. Multiple studies have demonstrated antiviral activity of zinc against viruses that cause hepatitis. This article provides a comprehensive overview of the findings on antiviral activity of zinc against hepatitis viruses, discusses the mechanisms underlying the antiviral properties of zinc and summarizes the prospects of harnessing the therapeutic benefit of zinc supplementation therapy in reducing the disease burden due to viral hepatitis.
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Affiliation(s)
- Shiv Kumar
- Virology Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
| | - Shabnam Ansari
- Virology Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
| | - Sriram Narayanan
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - C. T. Ranjith-Kumar
- University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi, India
| | - Milan Surjit
- Virology Laboratory, Centre for Virus Research, Therapeutics and Vaccines, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India
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Jiang D, Yang X, Ge M, Hu H, Xu C, Wen S, Deng H, Mei X. Zinc defends against Parthanatos and promotes functional recovery after spinal cord injury through SIRT3-mediated anti-oxidative stress and mitophagy. CNS Neurosci Ther 2023; 29:2857-2872. [PMID: 37063066 PMCID: PMC10493669 DOI: 10.1111/cns.14222] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 03/08/2023] [Accepted: 04/04/2023] [Indexed: 04/18/2023] Open
Abstract
INTRODUCTION Spinal cord injury (SCI) is a central nervous system injury that is primarily traumatic and manifests as motor, sensory, and autonomic dysfunction below the level of damage. Our previous studies confirmed the ability of zinc to protect mitochondria, protect neurons and promote spinal cord recovery. However, the role of zinc in Parthanatos is unknown. AIM We investigated the effects of zinc in Parthanatos from oxidative stress and mitophagy. We elucidated the role of SIRT3 in providing new ideas for treating spinal cord injury. THE RESULTS Zinc protected SCI mice by regulating Parthanatos. On the one hand, zinc eliminated ROS directly through SIRT3 deacetylation targeting SOD2 to alleviate Parthanatos. On the other hand, zinc eliminated ROS indirectly through SIRT3-mediated promotion of mitophagy to alleviate Parthanatos. CONCLUSION Zinc defends against Parthanatos and promotes functional recovery after spinal cord injury through SIRT3-mediated anti-oxidative stress and mitophagy.
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Affiliation(s)
- Dingyuan Jiang
- Suzhou Medical College of Soochow UniversitySuzhouChina
- Department of Spinal SurgeryZhuzhou 331 HospitalZhuzhouChina
| | - Xu Yang
- Suzhou Medical College of Soochow UniversitySuzhouChina
| | - Minghao Ge
- Department of OrthopedicsThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Hengshuo Hu
- Department of OrthopedicsThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Chang Xu
- Department of OrthopedicsThe First Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Shan Wen
- Department of OrthopedicsThe Third Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Hao Deng
- Department of OrthopedicsThe Third Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
| | - Xifan Mei
- Department of OrthopedicsThe Third Affiliated Hospital of Jinzhou Medical UniversityJinzhouChina
- Key Laboratory of Tissue Engineering of Liaoning ProvinceJinzhou Medical UniversityJinzhouChina
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21
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Figiel M, Górka AK, Górecki A. Zinc Ions Modulate YY1 Activity: Relevance in Carcinogenesis. Cancers (Basel) 2023; 15:4338. [PMID: 37686614 PMCID: PMC10487186 DOI: 10.3390/cancers15174338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/17/2023] [Accepted: 08/21/2023] [Indexed: 09/10/2023] Open
Abstract
YY1 is widely recognized as an intrinsically disordered transcription factor that plays a role in development of many cancers. In most cases, its overexpression is correlated with tumor progression and unfavorable patient outcomes. Our latest research focusing on the role of zinc ions in modulating YY1's interaction with DNA demonstrated that zinc enhances the protein's multimeric state and affinity to its operator. In light of these findings, changes in protein concentration appear to be just one element relevant to modulating YY1-dependent processes. Thus, alterations in zinc ion concentration can directly and specifically impact the regulation of gene expression by YY1, in line with reports indicating a correlation between zinc ion levels and advancement of certain tumors. This review concentrates on other potential consequences of YY1 interaction with zinc ions that may act by altering charge distribution, conformational state distribution, or oligomerization to influence its interactions with molecular partners that can disrupt gene expression patterns.
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Affiliation(s)
| | | | - Andrzej Górecki
- Faculty of Biochemistry, Biophysics and Biotechnology, Department of Physical Biochemistry, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland; (M.F.); (A.K.G.)
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22
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Uematsu T, Takano T, Matsui H, Kobayashi N, Ōmura S, Hanaki H. Prophylactic administration of ivermectin attenuates SARS-CoV-2 induced disease in a Syrian Hamster Model. J Antibiot (Tokyo) 2023; 76:481-488. [PMID: 37185581 PMCID: PMC10127164 DOI: 10.1038/s41429-023-00623-0] [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: 01/05/2023] [Revised: 03/22/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023]
Abstract
COVID-19, caused by SARS-CoV-2 infection, is currently among the most important public health concerns worldwide. Although several effective vaccines have been developed, there is an urgent clinical need for effective pharmaceutical treatments for treatment of COVID-19. Ivermectin, a chemical derivative of avermectin produced by Streptomyces avermitilis, is a macrocyclic lactone with antiparasitic activity. Recent studies have shown that ivermectin inhibits SARS-CoV-2 replication in vitro. In the present study, we investigated the in vivo effects of ivermectin in a hamster model of SARS-CoV-2 infection. The results of the present study demonstrate oral administration of ivermectin prior to SARS-CoV-2 infection in hamsters was associated with decreased weight loss and pulmonary inflammation. In addition, the administration of ivermectin reduced pulmonary viral titers and mRNA expression level of pro-inflammatory cytokines associated with severe COVID-19 disease. The administration of ivermectin rapidly induced the production of virus-specific neutralizing antibodies in the late stage of viral infection. Zinc concentrations leading to immune quiescence were also significantly higher in the lungs of ivermectin-treated hamsters compared to controls. These results indicate that ivermectin may have efficacy in reducing the development and severity of COVID-19 by affecting host immunity in a hamster model of SARS-CoV-2 infection.
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Affiliation(s)
- Takayuki Uematsu
- Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama, Japan.
| | - Tomomi Takano
- Laboratory of Veterinary Infectious Disease, Department of Veterinary Medicine, Kitasato University, Towada, Aomori, Japan
| | - Hidehito Matsui
- Infection Control Research Center, Ōmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo, Japan
| | - Noritada Kobayashi
- Biomedical Laboratory, Division of Biomedical Research, Kitasato University Medical Center, Kitamoto, Saitama, Japan
| | - Satoshi Ōmura
- Drug Discovery Project from Natural Products, Ōmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo, Japan
| | - Hideaki Hanaki
- Infection Control Research Center, Ōmura Satoshi Memorial Institute, Kitasato University, Minato-ku, Tokyo, Japan
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23
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Equey A, Berger MM, Gonseth-Nusslé S, Augsburger M, Rezzi S, Hodgson ACC, Estoppey S, Pantaleo G, Pellaton C, Perrais M, Lenglet S, Rousson V, D'Acremont V, Bochud M. Association of plasma zinc levels with anti-SARS-CoV-2 IgG and IgA seropositivity in the general population: A case-control study. Clin Nutr 2023; 42:972-986. [PMID: 37130500 PMCID: PMC10110932 DOI: 10.1016/j.clnu.2023.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/02/2023] [Accepted: 04/04/2023] [Indexed: 05/04/2023]
Abstract
INTRODUCTION Some micronutrients have key roles in immune defence, including mucosal defence mechanisms and immunoglobulin production. Altered micronutrient status has been linked with COVID-19 infection and disease severity. We assessed the associations of selected circulating micronutrients with anti-SARS-CoV-2 IgG and IgA seropositivity in the Swiss community using early pandemic data. METHODS Case-control study comparing the first PCR-confirmed COVID-19 symptomatic cases in the Vaud Canton (May to June 2020, n = 199) and controls (random population sample, n = 447), seronegative for IgG and IgA. The replication analysis included seropositive (n = 134) and seronegative (n = 152) close contacts from confirmed COVID-19 cases. Anti-SARS-CoV-2 IgG and IgA levels against the native trimeric spike protein were measured using the Luminex immunoassay. We measured plasma Zn, Se and Cu concentrations by ICP-MS, and 25-hydroxy-vitamin D3 (25(OH)D3) with LC-MS/MS and explored associations using multiple logistic regression. RESULTS The 932 participants (54.1% women) were aged 48.6 ± 20.2 years (±SD), BMI 25.0 ± 4.7 kg/m2 with median C-Reactive Protein 1 mg/l. In logistic regressions, log2(Zn) plasma levels were negatively associated with IgG seropositivity (OR [95% CI]: 0.196 [0.0831; 0.465], P < 0.001; replication analyses: 0.294 [0.0893; 0.968], P < 0.05). Results were similar for IgA. We found no association of Cu, Se, and 25(OH)D3 with anti-SARS-CoV-2 IgG or IgA seropositivity. CONCLUSION Low plasma Zn levels were associated with higher anti-SARS-CoV-2 IgG and IgA seropositivity in a Swiss population when the initial viral variant was circulating, and no vaccination available. These results suggest that adequate Zn status may play an important role in protecting the general population against SARS-CoV-2 infection. REGISTRY CORONA IMMUNITAS:: ISRCTN18181860.
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Affiliation(s)
- Antoine Equey
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Route de La Corniche 10, 1010, Lausanne, Switzerland
| | - Mette M Berger
- Service of Adult Intensive Care, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
| | - Semira Gonseth-Nusslé
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Route de La Corniche 10, 1010, Lausanne, Switzerland
| | - Marc Augsburger
- Forensic Toxicology and Chemistry Unit, University Centre of Legal Medicine, Lausanne-Geneva, Lausanne University Hospital and University of Lausanne - Geneva University Hospital and University of Geneva, Lausanne-Geneva, Switzerland
| | - Serge Rezzi
- Swiss Nutrition and Health Foundation, Épalinges, Switzerland
| | | | - Sandrine Estoppey
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Route de La Corniche 10, 1010, Lausanne, Switzerland
| | - Giuseppe Pantaleo
- Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Céline Pellaton
- Service of Immunology and Allergy, Department of Medicine, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Maïwenn Perrais
- Forensic Toxicology and Chemistry Unit, University Centre of Legal Medicine, Lausanne-Geneva, Lausanne University Hospital and University of Lausanne - Geneva University Hospital and University of Geneva, Lausanne-Geneva, Switzerland
| | - Sébastien Lenglet
- Forensic Toxicology and Chemistry Unit, University Centre of Legal Medicine, Lausanne-Geneva, Lausanne University Hospital and University of Lausanne - Geneva University Hospital and University of Geneva, Lausanne-Geneva, Switzerland
| | - Valentin Rousson
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Route de La Corniche 10, 1010, Lausanne, Switzerland
| | - Valérie D'Acremont
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Route de La Corniche 10, 1010, Lausanne, Switzerland
| | - Murielle Bochud
- Center for Primary Care and Public Health (Unisanté), University of Lausanne, Route de La Corniche 10, 1010, Lausanne, Switzerland
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24
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Chen Q, Wang M, Han M, Xu L, Zhang H. Molecular basis of Klebsiella pneumoniae colonization in host. Microb Pathog 2023; 177:106026. [PMID: 36773942 DOI: 10.1016/j.micpath.2023.106026] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 02/03/2023] [Accepted: 02/05/2023] [Indexed: 02/12/2023]
Abstract
Klebsiella pneumoniae (K. pneumoniae) is a common cause of nosocomial infection, which causing disseminated infections such as cystitis, pneumonia and sepsis. K. pneumoniae is intrinsic resistant to penicillin, and members of the population usually have acquired resistance to a variety of antibiotics, which makes it a major threat to clinical and public health. Bacteria can colonize on or within the hosts, accompanied by growth and reproduction of the organisms, but no clinical symptoms are presented. As the "first step" of bacterial infection, colonization in the hosts is of great importance. Colonization of bacteria can last from days to years, with resolution influenced by immune response to the organism, competition at the site from other organisms and, sometimes, use of antimicrobials. Colonized pathogenic bacteria cause healthcare-associated infections at times of reduced host immunity, which is an important cause of clinical occurrence of postoperative complications and increased mortality in ICU patients. Though, K. pneumoniae is one of the most common conditional pathogens of hospital-acquired infections, the mechanisms of K. pneumoniae colonization in humans are not completely clear. In this review, we made a brief summary of the molecular basis of K. pneumoniae colonization in the upper respiratory tract and intestinal niche, and provided new insights for understanding the pathogenesis of K. pneumoniae.
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Affiliation(s)
- Qi Chen
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Min Wang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Mingxiao Han
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Leyi Xu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Haifang Zhang
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China.
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25
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Bose S, Singh DV, Adhya TK, Acharya N. Escherichia coli, but Not Staphylococcus aureus, Functions as a Chelating Agent That Exhibits Antifungal Activity against the Pathogenic Yeast Candida albicans. J Fungi (Basel) 2023; 9:jof9030286. [PMID: 36983454 PMCID: PMC10057578 DOI: 10.3390/jof9030286] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/04/2023] [Accepted: 01/11/2023] [Indexed: 02/24/2023] Open
Abstract
Humans are colonized by diverse populations of microbes. Infections by Candida albicans, an opportunistic fungal pathogen, are a result of imbalances in the gut microbial ecosystem and are due to the suppressed immunity of the host. Here, we explored the potential effects of the polymicrobial interactions of C. albicans with Staphylococcus aureus, a Gram-positive bacterium, and Escherichia coli, a Gram-negative bacterium, in dual and triple in vitro culture systems on their respective growth, morphology, and biofilms. We found that S. aureus promoted the fungal growth and hyphal transition of C. albicans through cell-to-cell contacts; contrarily, both the cell and cell-free culture filtrate of E. coli inhibited fungal growth. A yet to be identified secretory metabolite of E. coli functionally mimicked EDTA and EGTA to exhibit antifungal activity. These findings suggested that E. coli, but not S. aureus, functions as a chelating agent and that E. coli plays a dominant role in regulating excessive growth and, potentially, the commensalism of C. albicans. Using animal models of systemic candidiasis, we found that the E. coli cell-free filtrate suppressed the virulence of C. albicans. In general, this study unraveled a significant antimicrobial activity and a potential role in the nutritional immunity of E. coli, and further determining the underlying processes behind the E. coli–C. albicans interaction could provide critical information in understanding the pathogenicity of C. albicans.
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Affiliation(s)
- Swagata Bose
- Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar 751023, India
- KIIT School of Biotechnology, Bhubaneswar 751021, India
| | - Durg Vijai Singh
- Department of Biotechnology, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya 824236, India
| | | | - Narottam Acharya
- Department of Infectious Disease Biology, Institute of Life Sciences, Bhubaneswar 751023, India
- Correspondence: ; Tel.: +91-674-230-4278; Fax: +91-674-230-0728
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26
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Peroni DG, Hufnagl K, Comberiati P, Roth-Walter F. Lack of iron, zinc, and vitamins as a contributor to the etiology of atopic diseases. Front Nutr 2023; 9:1032481. [PMID: 36698466 PMCID: PMC9869175 DOI: 10.3389/fnut.2022.1032481] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 12/14/2022] [Indexed: 01/11/2023] Open
Abstract
Micronutritional deficiencies are common in atopic children suffering from atopic dermatitis, food allergy, rhinitis, and asthma. A lack of iron, in particular, may impact immune activation with prolonged deficiencies of iron, zinc, vitamin A, and vitamin D associated with a Th2 signature, maturation of macrophages and dendritic cells (DCs), and the generation of IgE antibodies. In contrast, the sufficiency of these micronutrients establishes immune resilience, promotion of regulatory cells, and tolerance induction. As micronutritional deficiencies mimic an infection, the body's innate response is to limit access to these nutrients and also impede their dietary uptake. Here, we summarize our current understanding of the physiological function of iron, zinc, and vitamins A and D in relation to immune cells and the clinical consequences of deficiencies in these important nutrients, especially in the perinatal period. Improved dietary uptake of iron is achieved by vitamin C, vitamin A, and whey compounds, whereas zinc bioavailability improves through citrates and proteins. The addition of oil is essential for the dietary uptake of beta-carotene and vitamin D. As for vitamin D, the major source comes via sun exposure and only a small amount is consumed via diet, which should be factored into clinical nutritional studies. We summarize the prevalence of micronutritional deficiencies of iron, zinc, and vitamins in the pediatric population as well as nutritional intervention studies on atopic diseases with whole food, food components, and micronutrients. Dietary uptake via the lymphatic route seems promising and is associated with a lower atopy risk and symptom amelioration. This review provides useful information for clinical studies and concludes/emphasizes that a healthy, varied diet containing dairy products, fish, nuts, fruits, and vegetables as well as supplementing foods or supplementation with micronutrients as needed is essential to combat the atopic march.
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Affiliation(s)
- Diego G. Peroni
- Section of Paediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Karin Hufnagl
- Comparative Medicine, The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University of Vienna and University of Vienna, Vienna, Austria,Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
| | - Pasquale Comberiati
- Section of Paediatrics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Franziska Roth-Walter
- Comparative Medicine, The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University of Vienna and University of Vienna, Vienna, Austria,Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria,*Correspondence: Franziska Roth-Walter, ;
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27
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Secli V, Di Biagio C, Martini A, Michetti E, Pacello F, Ammendola S, Battistoni A. Localized Infections with P. aeruginosa Strains Defective in Zinc Uptake Reveal That Zebrafish Embryos Recapitulate Nutritional Immunity Responses of Higher Eukaryotes. Int J Mol Sci 2023; 24:ijms24020944. [PMID: 36674459 PMCID: PMC9862628 DOI: 10.3390/ijms24020944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/14/2022] [Accepted: 12/23/2022] [Indexed: 01/06/2023] Open
Abstract
The innate immune responses of mammals to microbial infections include strategies based on manipulating the local concentration of metals such as iron (Fe) and zinc (Zn), commonly described as nutritional immunity. To evaluate whether these strategies are also present in zebrafish embryos, we have conducted a series of heart cavity-localized infection experiments with Pseudomonas aeruginosa strains characterized by a different ability to acquire Zn. We have found that, 48 h after infection, the bacterial strains lacking critical components of the Zn importers ZnuABC and ZrmABCD have a reduced colonization capacity compared to the wild-type strain. This observation, together with the finding of a high level of expression of Zur-regulated genes, suggests the existence of antimicrobial mechanisms based on Zn sequestration. However, we have observed that strains lacking such Zn importers have a selective advantage over the wild-type strain in the early stages of infection. Analysis of the expression of the gene that encodes for a Zn efflux pump has revealed that at short times after infection, P. aeruginosa is exposed to high concentrations of Zn. At the same time, zebrafish respond to the infection by activating the expression of the Zn transporters Slc30a1 and Slc30a4, whose mammalian homologs mediate a redistribution of Zn in phagocytes aimed at intoxicating bacteria with a metal excess. These observations indicate that teleosts share similar nutritional immunity mechanisms with higher vertebrates, and confirm the usefulness of the zebrafish model for studying host-pathogen interactions.
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Affiliation(s)
- Valerio Secli
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy
| | - Claudia Di Biagio
- Laboratory of Experimental Ecology and Aquaculture, Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Arianna Martini
- Laboratory of Experimental Ecology and Aquaculture, Department of Biology, University of Rome Tor Vergata, 00133 Rome, Italy
- Council for Agricultural Research and Economics, Research, Centre for Animal Production and Aquaculture, Via Salaria 31, 00015 Monterotondo, Italy
| | - Emma Michetti
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy
| | - Francesca Pacello
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy
| | - Serena Ammendola
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy
| | - Andrea Battistoni
- Department of Biology, University of Rome Tor Vergata, Via della Ricerca Scientifica, 00133 Rome, Italy
- Correspondence:
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28
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Martínez D, Oyarzún-Salazar R, Quilapi AM, Coronado J, Enriquez R, Vargas-Lagos C, Oliver C, Santibañez N, Godoy M, Muñoz JL, Vargas-Chacoff L, Romero A. Live and inactivated Piscirickettsia salmonis activated nutritional immunity in Atlantic salmon ( Salmo salar). Front Immunol 2023; 14:1187209. [PMID: 37187753 PMCID: PMC10175622 DOI: 10.3389/fimmu.2023.1187209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
Nutritional immunity regulates the homeostasis of micronutrients such as iron, manganese, and zinc at the systemic and cellular levels, preventing the invading microorganisms from gaining access and thereby limiting their growth. Therefore, the objective of this study was to evaluate the activation of nutritional immunity in specimens of Atlantic salmon (Salmo salar) that are intraperitoneally stimulated with both live and inactivated Piscirickettsia salmonis. The study used liver tissue and blood/plasma samples on days 3, 7, and 14 post-injections (dpi) for the analysis. Genetic material (DNA) of P. salmonis was detected in the liver tissue of fish stimulated with both live and inactivated P. salmonis at 14 dpi. Additionally, the hematocrit percentage decreased at 3 and 7 dpi in fish stimulated with live P. salmonis, unchanged in fish challenged with inactivated P. salmonis. On the other hand, plasma iron content decreased during the experimental course in fish stimulated with both live and inactivated P. salmonis, although this decrease was statistically significant only at 3 dpi. Regarding the immune-nutritional markers such as tfr1, dmt1, and ireg1 were modulated in the two experimental conditions, compared to zip8, ft-h, and hamp, which were down-regulated in fish stimulated with live and inactivated P. salmonis during the course experimental. Finally, the intracellular iron content in the liver increased at 7 and 14 dpi in fish stimulated with live and inactivated P. salmonis, while the zinc content decreased at 14 dpi under both experimental conditions. However, stimulation with live and inactivated P. salmonis did not alter the manganese content in the fish. The results suggest that nutritional immunity does not distinguish between live and inactivated P. salmonis and elicits a similar immune response. Probably, this immune mechanism would be self-activated with the detection of PAMPs, instead of a sequestration and/or competition of micronutrients by the living microorganism.
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Affiliation(s)
- Danixa Martínez
- Laboratorio Institucional de Investigación, Facultad de Ciencias de la Naturaleza, Universidad San Sebastián, Puerto Montt, Chile
- Laboratorio de Inmunología y Estrés de Organismos Acuáticos, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
- *Correspondence: Danixa Martínez, ; Luis Vargas-Chacoff, ; Alex Romero,
| | - Ricardo Oyarzún-Salazar
- Laboratorio Institucional de Investigación, Facultad de Ciencias de la Naturaleza, Universidad San Sebastián, Puerto Montt, Chile
| | - Ana María Quilapi
- Escuela de Tecnología Médica, Facultad de la Salud, Universidad Santo Tomás, Osorno, Chile
| | - José Coronado
- Laboratorio de Inmunología y Estrés de Organismos Acuáticos, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Ricardo Enriquez
- Laboratorio de Inmunología y Estrés de Organismos Acuáticos, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Carolina Vargas-Lagos
- Escuela de Tecnología Médica, Facultad de la Salud, Universidad Santo Tomás, Osorno, Chile
| | - Cristian Oliver
- Laboratorio de Inmunología y Estrés de Organismos Acuáticos, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Natacha Santibañez
- Laboratorio de Inmunología y Estrés de Organismos Acuáticos, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Marcos Godoy
- Laboratorio Institucional de Investigación, Facultad de Ciencias de la Naturaleza, Universidad San Sebastián, Puerto Montt, Chile
- Centro de Investigaciones Biológicas Aplicadas (CIBA), Puerto Montt, Chile
| | - José Luis Muñoz
- Centro de Investigación y Desarrollo i~mar, Universidad de los Lagos, Puerto Montt, Chile
| | - Luis Vargas-Chacoff
- Instituto de Ciencias Marinas y Limnológicas, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile
- Centro Fondap de Investigación de Altas Latitudes (IDEAL), Universidad Austral de Chile, Valdivia, Chile
- Millennium Institute Biodiversity of Antarctic and Subantarctic Ecosystems, Biodiversity of Antarctic and Subantarctic Ecosystems (BASE), University Austral of Chile, Valdivia, Chile
- *Correspondence: Danixa Martínez, ; Luis Vargas-Chacoff, ; Alex Romero,
| | - Alex Romero
- Laboratorio de Inmunología y Estrés de Organismos Acuáticos, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
- Centro Fondap Interdisciplinary Center for Aquaculture Research (INCAR), Universidad de Concepción, Concepción, Chile
- *Correspondence: Danixa Martínez, ; Luis Vargas-Chacoff, ; Alex Romero,
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Association between Serum Zinc and Toll-like-Receptor- Related Innate Immunity and Infectious Diseases in Well-Nourished Children with a Low Prevalence of Zinc Deficiency: A Prospective Cohort Study. Nutrients 2022; 14:nu14245395. [PMID: 36558553 PMCID: PMC9782999 DOI: 10.3390/nu14245395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2022] [Revised: 12/03/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Existing reports focus on zinc-associated immunity and infection in malnourished children; however, whether zinc also plays an important role in the immune homeostasis of the non-zinc-deficient population remained unknown. This study aimed to investigate the association between zinc status and toll-like receptor (TLR)-related innate immunity and infectious outcome in well-nourished children. A total of 961 blood samples were collected from 1 through 5 years of age. Serum zinc was analyzed, and mononuclear cells isolated to assess TNF-α, IL-6, and IL-10 production by ELISA after stimulation with TLR ligands. Childhood infections were analyzed as binary outcomes with logistic regression. The prevalence of zinc deficiency was 1.4-9.6% throughout the first 5 years. There was significant association between zinc and TLR-stimulated cytokine responses. Higher serum zinc was associated with decreased risk of ever having pneumonia (aOR: 0.94; 95% CI: 0.90, 0.99) at 3 years, and enterocolitis (aOR: 0.96; 95% CI: 0.93, 0.99) at 5 years. Serum zinc was lower in children who have had pneumonia before 3 years of age (72.6 ± 9 vs. 81.9 ± 13 μg/dL), and enterocolitis before 5 years (89.3 ± 12 vs. 95.5 ± 13 μg/dL). We emphasize the importance of maintaining optimal serum zinc in the young population.
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Saravanan R, Balasubramanian V, Swaroop Balamurugan SS, Ezhil I, Afnaan Z, John J, Sundaram S, Gouthaman S, Pakala SB, Rayala SK, Venkatraman G. Zinc transporter LIV1: A promising cell surface target for triple negative breast cancer. J Cell Physiol 2022; 237:4132-4156. [PMID: 36181695 DOI: 10.1002/jcp.30880] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 08/22/2022] [Accepted: 08/30/2022] [Indexed: 11/05/2022]
Abstract
Breast cancer is one of the leading causes contributing to the global cancer burden. The triple negative breast cancer (TNBC) molecular subtype accounts for the most aggressive type. Despite progression in therapeutic options and prognosis in breast cancer treatment options, there remains a high rate of distant relapse. With advancements in understanding the role of zinc and zinc carriers in the prognosis and treatment of the disease, the scope of precision treatment/targeted therapy has been expanded. Zinc levels and zinc transporters play a vital role in maintaining cellular homeostasis, tumor surveillance, apoptosis, and immune function. This review focuses on the zinc transporter, LIV1, as an essential target for breast cancer prognosis and emerging treatment options. Previous studies give an insight into the role of LIV1 in fulfilling the most important hallmarks of cancer such as apoptosis, metastasis, invasion, and evading the immune system. Normal tissue expression of LIV1 is limited. Higher expression of LIV1 has been linked to Epithelial-Mesenchymal Transition, histological grade of cancer, and early node metastasis. LIV1 was found to be one of the attractive targets in the therapeutic hunt for TNBCs. TNBCs are an immunogenic breast cancer subtype. As zinc transporters are known to serve as the metabolic gatekeepers of immune cells, this review bridges tumor infiltrating lymphocytes, TNBC and LIV1. In addition, the suitability of LIV1 as an antibody-drug conjugate (Seattle genetics [SGN]-LIV1A) target in TNBC, represents a promising strategy for patients. Early clinical trial results reveal that this novel agent reduces tumor burden by inducing mitotic arrest, immunomodulation, and immunogenic cell death, warranting further investigation of SGN-LIV1A in combination with immuno-oncology agents. Priming the patient's immune response in combination with SGN-LIV1A could eventually change the landscape for the TNBC patient population.
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Affiliation(s)
- Roshni Saravanan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Vaishnavi Balasubramanian
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Srikanth Swamy Swaroop Balamurugan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Inemai Ezhil
- Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, Tamil Nadu, India
| | - Zeba Afnaan
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Jisha John
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Sandhya Sundaram
- Department of Pathology, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Shanmugasundaram Gouthaman
- Department of Surgical Oncology, Sri Ramachandra Medical College and Research Institute, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Suresh B Pakala
- Department of Biochemistry, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India
| | - Suresh Kumar Rayala
- Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, Tamil Nadu, India
| | - Ganesh Venkatraman
- Department of Human Genetics, Sri Ramachandra Faculty of Biomedical Sciences and Technology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
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Excess dietary zinc drives a Cushing's-like syndrome in ovariectomized mice - Implications for postmenopausal obesity. Biochem Biophys Res Commun 2022; 630:101-111. [PMID: 36152347 DOI: 10.1016/j.bbrc.2022.09.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 09/04/2022] [Accepted: 09/10/2022] [Indexed: 11/22/2022]
Abstract
Postmenopausal women have an increased risk of obesity, but the underlying cause is not clear. We unexpectedly found that excess dietary zinc induced severe obesity and a Cushing's-like syndrome without increased food intake in ovariectomized (Ovx) but not in sham-operated mice. Zinc accumulated in the adrenal glands and inhibited adrenal 17,20-lyase activity and steroid synthesis. As adrenal steroids are the only source of estrogen in Ovx mice, estrogen deficiency induced adrenal hyperplasia, glucocorticoid overproduction, and consequent development of a Cushing's-like syndrome. Adrenal steroid supplementation prevented the effects of zinc. Plasma zinc was positively correlated with cortisol level and negatively correlated with the levels of adrenal steroids and estrogen in obese postmenopausal women. The finding of a link between dietary zinc, estrogen deficiency, and postmenopausal obesity, implies that postmenopausal obesity might be prevented by supplementation with a adrenal steroid and avoiding excess dietary zinc.
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Aziz J, Vaithilingam RD, Radzi Z, Rahman MT. Inflammatory Responses in Periodontitis with or Without Rheumatoid Arthritis Alter Salivary Metallothionein and Zinc. Biol Trace Elem Res 2022; 201:3162-3174. [PMID: 36094693 DOI: 10.1007/s12011-022-03416-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Accepted: 09/06/2022] [Indexed: 11/26/2022]
Abstract
Periodontitis (PD) and rheumatoid arthritis (RA) are causally linked by their common inflammatory responses, yet it is largely unknown if these inflammatory responses might have an impact on salivary metallothionein (MT), zinc (Zn), and calcium (Ca) content. In this study, we analysed salivary concentrations of pro-inflammatory (IFN-γ, IL-6, and IL-17) and anti-inflammatory (IL-4 and IL-10) cytokines, as well as MT, Zn, and Ca in four groups of participants, namely control (without PD or RA, n = 21), PD (n = 21), RA (n = 21), or RAPD (n = 19). As expected, an increased amount of salivary pro-inflammatory cytokines were observed in the PD, RA, and RAPD groups. While Ca concentration was not significantly different between the groups, Zn concentration was lower in the PD, RA, and RAPD groups compared to the control group (p < 0.05). These groups also expressed higher MT/Zn ratios compared to the control group (p < 0.05). Unlike the control group, concentrations of inflammatory cytokines, MT, Zn, and Ca correlated with each other in the PD, RA, and RAPD groups (p < 0.05). Additionally, comorbidity of PD and RA appears to have a cumulative immuno-pathological impact that warrants further investigation. This study suggests that, in addition to inflammatory cytokines, salivary MT and Zn could reflect the severity of PD with or without RA, hence providing an important biomarker for diagnosis.
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Affiliation(s)
- Jazli Aziz
- Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
- Department of Oral & Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Rathna Devi Vaithilingam
- Department of Restorative Dentistry, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Zamri Radzi
- Department of Paediatric Dentistry & Orthodontics, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia
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Jacobs M, Geiger M, Summers S, Janes T, Boyea R, Zinn K, Aburashed R, Spence D. Interferon-β Decreases the Hypermetabolic State of Red Blood Cells from Patients with Multiple Sclerosis. ACS Chem Neurosci 2022; 13:2658-2665. [PMID: 35946788 DOI: 10.1021/acschemneuro.2c00332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Multiple sclerosis (MS) is an inflammatory disease characterized by damage to the myelin sheath surrounding axons in the central nervous system. While the exact mechanism of this destruction is unknown, excess nitric oxide (NO) and adenosine triphosphate (ATP) have been measured in tissues and fluids obtained from people with MS. Here, incubation of interferon-beta (IFN-β), an MS drug with an unknown mechanism of action, with red blood cells (RBCs) obtained from people with MS provide evidence of a potential hypermetabolic state in the MS RBC that is decreased with IFN-β intervention. Specifically, binding of all three components of an albumin/C-peptide/Zn2+ complex to MS RBCs was significantly increased in comparison to control RBCs. For example, the binding of C-peptide to MS RBCs was significantly increased (3.4 ± 0.1 nM) compared to control RBCs (1.6 ± 0.2 nM). However, C-peptide binding to MS RBCs was reduced to a value (1.6 ± 0.3 nM) statistically equal to that of control RBCs in the presence of 2 nM IFN-β. Similar trends were measured for albumin and Zn2+ binding to RBCs when in the presence of IFN-β. RBC function was also affected by incubation of cells with IFN-β. Specifically, RBC-derived ATP and measurable membrane GLUT1 were both significantly decreased (56 and 24%, respectively) in the presence of IFN-β. Collectively, our results suggest that IFN-β inhibits albumin binding to the RBC, thereby reducing its ability to deliver ligands such as C-peptide and Zn2+ to the cell and normalizing the basal hypermetabolic state.
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Affiliation(s)
- M Jacobs
- Department of Comparative Medicine and Integrative Biology, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - M Geiger
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - S Summers
- Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - T Janes
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | - R Boyea
- Department of Chemistry, Michigan State University, East Lansing, Michigan 48824, United States
| | - K Zinn
- Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
| | - R Aburashed
- Memorial Healthcare Institute for Neuroscience, Michigan State University, East Lansing, Michigan 48824, United States
| | - D Spence
- Department of Biomedical Engineering, Michigan State University, East Lansing, Michigan 48824, United States.,Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, Michigan 48824, United States
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Qiao H, Mei J, Yuan K, Zhang K, Zhou F, Tang T, Zhao J. Immune-regulating strategy against rheumatoid arthritis by inducing tolerogenic dendritic cells with modified zinc peroxide nanoparticles. J Nanobiotechnology 2022; 20:323. [PMID: 35836178 PMCID: PMC9281050 DOI: 10.1186/s12951-022-01536-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/28/2022] [Indexed: 11/10/2022] Open
Abstract
In hypoxic dendritic cells (DCs), a low level of Zn2+ can induce the activation of immunogenic DCs (igDCs), thereby triggering an active T-cell response to propel the immune progression of rheumatoid arthritis (RA). This finding indicates the crucial roles of zinc and oxygen homeostasis in DCs during the pathogenesis of RA. However, very few studies have focused on the modulation of zinc and oxygen homeostasis in DCs during RA treatment. Proposed herein is a DC-targeting immune-regulating strategy to induce igDCs into tolerogenic DCs (tDCs) and inhibit subsequent T-cell activation, referred to as ZnO2/Catalase@liposome-Mannose nanoparticles (ZnCM NPs). ZnCM NPs displayed targeted intracellular delivery of Zn2+ and O2 towards igDCs in a pH-responsive manner. After inactivating OTUB1 deubiquitination, the ZnCM NPs promoted CCL5 degradation via NF-κB signalling, thereby inducing the igDC-tDC transition to further inhibit CD4+ T-cell homeostasis. In collagen-induced arthritis (CIA) mice, this nanoimmunoplatform showed significant accumulation in the spleen, where immature DCs (imDCs) differentiated into igDCs. Splenic tDCs were induced to alleviate ankle swelling, improve walking posture and safely inhibit ankle/spleen inflammation. Our work pioneers the combination of DC-targeting nanoplatforms with RA treatments and highlights the significance of zinc and oxygen homeostasis for the immunoregulation of RA by inducing tDCs with modified ZnO2 NPs, which provides novel insight into ion homeostasis regulation for the treatment of immune diseases with a larger variety of distinct metal or nonmetal ions.
The DC-targeting immune-regulating nanostrategy was firstly employed to treat RA. The complex immune regulating effects was realized through a portable, convenient and green nanomaterial. Highlighting the significance of zinc and oxygen homeostasis for the immunoregulation of RA by inducing tDCs with modified ZnO2 NPs. Expanding the notion of ion homeostasis regulation with a larger variety of distinct metal or nonmetal ions.
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Affiliation(s)
- Han Qiao
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.,Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Jingtian Mei
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.,Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Kai Yuan
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.,Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Kai Zhang
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China.,Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China
| | - Feng Zhou
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, People's Republic of China
| | - Tingting Tang
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China. .,Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
| | - Jie Zhao
- Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhizaoju Road, Shanghai, 200011, People's Republic of China. .,Shanghai Key Laboratory of Orthopaedic Implants, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
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Chillon TS, Maares M, Demircan K, Hackler J, Sun Q, Heller RA, Diegmann J, Bachmann M, Moghaddam A, Haase H, Schomburg L. Serum Free Zinc Is Associated With Vaccination Response to SARS-CoV-2. Front Immunol 2022; 13:906551. [PMID: 35844578 PMCID: PMC9280661 DOI: 10.3389/fimmu.2022.906551] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 06/03/2022] [Indexed: 11/17/2022] Open
Abstract
Background Zinc (Zn) is an essential trace element with high relevance for the immune system, and its deficiency is associated with elevated infection risk and severe disease course. The association of Zn status with the immune response to SARS-CoV-2 vaccination is unknown. Methods A cohort of adult health care workers (n=126) received two doses of BNT162B2, and provided up to four serum samples over a time course of 6 months. Total SARS-CoV-2 IgG and neutralizing antibody potency was determined, along with total as well as free Zn concentrations. Results The SARS-CoV-2 antibodies showed the expected rise in response to vaccination, and decreased toward the last sampling point, with highest levels measured three weeks after the second dose. Total serum Zn concentrations were relatively stable over time, and showed no significant association with SARS-CoV-2 antibodies. Baseline total serum Zn concentration and supplemental intake of Zn were both unrelated to the antibody response to SARS-CoV-2 vaccination. Time resolved analysis of free Zn indicated a similar dynamic as the humoral response. A positive correlation was observed between free Zn concentrations and both the induced antibodies and neutralizing antibody potency. Conclusion While the biomarkers of Zn status and supplemental Zn intake appeared unrelated to the humoral immune response to SARS-CoV-2 vaccination, the observed correlation of free Zn to the induced antibodies indicates a diagnostic value of this novel biomarker for the immune system.
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Affiliation(s)
- Thilo Samson Chillon
- Institute for Experimental Endocrinology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Maria Maares
- Department of Food Chemistry and Toxicology, Technische Universität Berlin, Berlin, Germany
| | - Kamil Demircan
- Institute for Experimental Endocrinology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Julian Hackler
- Institute for Experimental Endocrinology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Qian Sun
- Institute for Experimental Endocrinology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Raban A. Heller
- Institute for Experimental Endocrinology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- Bundeswehr Hospital Berlin, Clinic of Traumatology and Orthopaedics, Berlin, Germany
- Department of General Practice and Health Services Research, Heidelberg University Hospital, Heidelberg, Germany
| | - Joachim Diegmann
- Aschaffenburg Trauma and Orthopaedic Research Group (ATORG), Center for Orthopaedics, Trauma Surgery and Sports Medicine, Hospital Aschaffenburg-Alzenau, Aschaffenburg, Germany
| | - Manuel Bachmann
- Aschaffenburg Trauma and Orthopaedic Research Group (ATORG), Center for Orthopaedics, Trauma Surgery and Sports Medicine, Hospital Aschaffenburg-Alzenau, Aschaffenburg, Germany
| | | | - Hajo Haase
- Department of Food Chemistry and Toxicology, Technische Universität Berlin, Berlin, Germany
- *Correspondence: Lutz Schomburg, ; Hajo Haase,
| | - Lutz Schomburg
- Institute for Experimental Endocrinology, Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- *Correspondence: Lutz Schomburg, ; Hajo Haase,
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Samuelson DR, Haq S, Knoell DL. Divalent Metal Uptake and the Role of ZIP8 in Host Defense Against Pathogens. Front Cell Dev Biol 2022; 10:924820. [PMID: 35832795 PMCID: PMC9273032 DOI: 10.3389/fcell.2022.924820] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/26/2022] [Indexed: 01/13/2023] Open
Abstract
Manganese (Mn) and Zinc (Zn) are essential micronutrients whose concentration and location within cells are tightly regulated at the onset of infection. Two families of Zn transporters (ZIPs and ZnTs) are largely responsible for regulation of cytosolic Zn levels and to a certain extent, Mn levels, although much less is known regarding Mn. The capacity of pathogens to persevere also depends on access to micronutrients, yet a fundamental gap in knowledge remains regarding the importance of metal exchange at the host interface, often referred to as nutritional immunity. ZIP8, one of 14 ZIPs, is a pivotal importer of both Zn and Mn, yet much remains to be known. Dietary Zn deficiency is common and commonly occurring polymorphic variants of ZIP8 that decrease cellular metal uptake (Zn and Mn), are associated with increased susceptibility to infection. Strikingly, ZIP8 is the only Zn transporter that is highly induced following bacterial exposure in key immune cells involved with host defense against leading pathogens. We postulate that mobilization of Zn and Mn into key cells orchestrates the innate immune response through regulation of fundamental defense mechanisms that include phagocytosis, signal transduction, and production of soluble host defense factors including cytokines and chemokines. New evidence also suggests that host metal uptake may have long-term consequences by influencing the adaptive immune response. Given that activation of ZIP8 expression by pathogens has been shown to influence parenchymal, myeloid, and lymphoid cells, the impact applies to all mucosal surfaces and tissue compartments that are vulnerable to infection. We also predict that perturbations in metal homeostasis, either genetic- or dietary-induced, has the potential to impact bacterial communities in the host thereby adversely impacting microbiome composition. This review will focus on Zn and Mn transport via ZIP8, and how this vital metal transporter serves as a "go to" conductor of metal uptake that bolsters host defense against pathogens. We will also leverage past studies to underscore areas for future research to better understand the Zn-, Mn- and ZIP8-dependent host response to infection to foster new micronutrient-based intervention strategies to improve our ability to prevent or treat commonly occurring infectious disease.
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Affiliation(s)
- Derrick R. Samuelson
- Division of Pulmonary, Critical Care, and Sleep, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE, United States
| | - Sabah Haq
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, United States
| | - Daren L. Knoell
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, United States,*Correspondence: Daren L. Knoell,
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What is the impact of zinc deficiency for pancreatectomies in patients with pancreatic ductal adenocarcinoma? Pancreatology 2022; 22:270-276. [PMID: 35012903 DOI: 10.1016/j.pan.2021.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/14/2021] [Accepted: 12/16/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND and purpose: Zinc is an essential element for human health and plays an important role in metabolic, immunological and other biological processes. The present study was conducted to investigate the association between zinc deficiency (ZD) and the perioperative clinical course in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS Of 216 patients with PDAC who underwent elective pancreatectomy between 2013 and 2017 at our institution, 206 patients with sufficient clinical data were retrospectively reviewed. The perioperative variables were compared and the risk factors associated with infectious complications were identified. RESULTS ZD was preoperatively present in 36 (17.5%) of 206 patients with PDAC. In the patients of the ZD group, a higher proportion of males, higher preoperative modified Glasgow prognostic scores, a higher neutrophil-to-lymphocyte ratio, and a higher occurrence of postoperative infectious complications after pancreatectomy were observed, compared to the non-ZD group. By a univariate analysis, three risk factors were significantly associated with infectious complications after pancreatectomy: ZD (vs non-ZD: p = 0.002), serum albumin <3.5 g/dl (vs ≥ 3.5 g/dl: p = 0.005), and the procedure of pancreaticoduodenectomy (vs others: p = 0.013). By multivariate logistic regression analysis, the occurrence of infectious complications was significantly associated with ZD (OR 3.430, 95%CI 1.570 to 7.490, p = 0.002) and the procedure of pancreaticoduodenectomy (OR 2.030, 95%CI 1.090 to 3.770, p = 0.025). CONCLUSIONS The current study newly demonstrated that ZD could serve as a preoperative predictor of infectious complications after pancreatectomies in the patients with PDAC.
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Baarz BR, Rink L. Rebalancing the unbalanced aged immune system - A special focus on zinc. Ageing Res Rev 2022; 74:101541. [PMID: 34915196 DOI: 10.1016/j.arr.2021.101541] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 11/18/2021] [Accepted: 12/09/2021] [Indexed: 02/08/2023]
Abstract
Nowadays, aging is understood as a dynamic and multifaceted dysregulation process that spares almost no human organ or cell. The immune system being among the most affected, it has been shown predominantly that its integrity determines the tightrope walk between the difference of escaping or suffering from age-related diseases. Next to drug-based anti-aging strategies, micronutrient intervention may represent an emerging but less radical way to slow immune aging. While a sufficient supply of a variety of micronutrients is undeniably important, adequate intake of the trace element zinc appears to tower over others in terms of reaching old age. Inconveniently, zinc deficiency prevalence among the elderly is high, which in turn contributes to increased susceptibility to infection, decreased anti-tumor immunity as well as attenuated response to vaccination. Driven by this research, this review aims to provide a comprehensive and up-to-date overview of the various rebalancing capabilities of zinc in the unbalanced immune system of the elderly. This includes an in-depth and cell type-centered discussion on the role of zinc in immunosenescence and inflammaging. We further address upcoming translational aspects e.g. how zinc deficiency promotes the flourishing of certain pathogenic taxa of the gut microbiome and how zinc supply counteracts such alterations in a manner that may contribute to longevity. In the light of the ongoing COVID-19 pandemic, we also briefly review current knowledge on the interdependency between age, zinc status, and respiratory infections. Based on two concrete examples and considering the latest findings in the field we conclude our remarks by outlining tremendous parallels between suboptimal zinc status and accelerated aging on the one hand and an optimized zinc status and successful aging on the other hand.
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Liu J, Yao S, Jia J, Chen Z, Yuan Y, He Y, Wasti B, Duan W, Li D, Wang G, Jia A, Sun W, Qiu S, Ma L, Li J, Liu Y, Zheng J, Xiang X, Zhang X, Liu S, He Z, Peng Z, Zhang H, Zhang D, Xiao B. Loss of MBD2 ameliorates LPS‐induced alveolar epithelial cell apoptosis and ALI in mice via modulating intracellular zinc homeostasis. FASEB J 2022; 36:e22162. [PMID: 35061304 DOI: 10.1096/fj.202100924rr] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Revised: 12/16/2021] [Accepted: 12/29/2021] [Indexed: 02/05/2023]
Affiliation(s)
- Jiqiang Liu
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Shuo Yao
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Jingsi Jia
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Zhifeng Chen
- Department of Respiratory Medicine Hunan Center for Evidence‐Based Medicine Research Unit of Respiratory Diseases The Second Xiangya Hospital of Central South University Changsha P.R. China
| | - Yu Yuan
- Department of Respiratory Medicine Hunan Center for Evidence‐Based Medicine Research Unit of Respiratory Diseases The Second Xiangya Hospital of Central South University Changsha P.R. China
| | - Yi He
- Department of Respiratory Medicine Hunan Center for Evidence‐Based Medicine Research Unit of Respiratory Diseases The Second Xiangya Hospital of Central South University Changsha P.R. China
| | - Binaya Wasti
- Department of Respiratory Medicine Hunan Center for Evidence‐Based Medicine Research Unit of Respiratory Diseases The Second Xiangya Hospital of Central South University Changsha P.R. China
| | - Wentao Duan
- Department of Respiratory Medicine Hunan Center for Evidence‐Based Medicine Research Unit of Respiratory Diseases The Second Xiangya Hospital of Central South University Changsha P.R. China
| | - Danhong Li
- Department of Respiratory Medicine Hunan Center for Evidence‐Based Medicine Research Unit of Respiratory Diseases The Second Xiangya Hospital of Central South University Changsha P.R. China
| | - Guyi Wang
- Department of Intensive Care Medicine The Second Xiangya Hospital of Central South University Changsha P.R. China
| | - Aijun Jia
- Department of the Third Emergency of Yuelushan Hospital District Hunan Provincial People's Hospital Changsha P.R. China
| | - Wenjin Sun
- Department of General Medicine West China Hospital, Sichuan University Chengdu P.R. China
| | - Shuangfa Qiu
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Libing Ma
- Department of Respiratory and Critical Care Medicine The Affiliated Hospital of Guilin Medical University Guangxi P.R. China
| | - Jianmin Li
- Department of Respiratory and Critical Care Medicine Hunan Provincial People's Hospital Changsha P.R. China
| | - Yi Liu
- Department of Respiratory Medicine Zhuzhou City Central Hospital Zhuzhou P.R. China
| | - Jianfei Zheng
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Xudong Xiang
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Xiufeng Zhang
- Department of Respiratory Medicine The Second Affiliated Hospital of Hainan Medical University Haikou P.R. China
| | - Shaokun Liu
- Department of Respiratory Medicine Hunan Center for Evidence‐Based Medicine Research Unit of Respiratory Diseases The Second Xiangya Hospital of Central South University Changsha P.R. China
| | - Zhibiao He
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Zhenyu Peng
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Hongliang Zhang
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Dongshan Zhang
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
| | - Bing Xiao
- Department of Emergency Medicine The Second Xiangya Hospital of Central South University, Emergency and Difficult Diseases Institute of Central South University Changsha P.R. China
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40
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Kim B, Kim HY, Yoon BR, Yeo J, In Jung J, Yu KS, Kim HC, Yoo SJ, Park JK, Kang SW, Lee WW. Cytoplasmic zinc promotes IL-1β production by monocytes and macrophages through mTORC1-induced glycolysis in rheumatoid arthritis. Sci Signal 2022; 15:eabi7400. [PMID: 35015571 DOI: 10.1126/scisignal.abi7400] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Bonah Kim
- Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, and BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Hee Young Kim
- Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, and BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Bo Ruem Yoon
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Jina Yeo
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Ji In Jung
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul 03080, Republic of Korea
| | - Hyeon Chang Kim
- Department of Preventive Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea
| | - Su-Jin Yoo
- Department of Internal Medicine, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea
| | - Jin Kyun Park
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
| | - Seong Wook Kang
- Department of Internal Medicine, Chungnam National University School of Medicine, 282 Munhwa-ro, Jung-gu, Daejeon 35015, Republic of Korea
| | - Won-Woo Lee
- Laboratory of Autoimmunity and Inflammation (LAI), Department of Biomedical Sciences, and BK21Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.,Cancer Research Institute, Ischemic/Hypoxic Disease Institute, and Institute of Infectious Diseases, Seoul National University College of Medicine, Seoul National University Hospital Biomedical Research Institute, Seoul 03080, Republic of Korea
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41
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Qu YY, Guo RY, Luo ML, Zhou Q. Pan-Cancer Analysis of the Solute Carrier Family 39 Genes in Relation to Oncogenic, Immune Infiltrating, and Therapeutic Targets. Front Genet 2021; 12:757582. [PMID: 34925450 PMCID: PMC8675640 DOI: 10.3389/fgene.2021.757582] [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: 08/12/2021] [Accepted: 11/12/2021] [Indexed: 12/28/2022] Open
Abstract
Background: Emerging pieces of evidence demonstrated that the solute carrier family 39 (SLC39A) members are critical for the oncogenic and immune infiltrating targets in multiple types of tumors. However, the precise relationship between the SLC39A family genes and clinical prognosis as well as the pan-cancer tumor cell infiltration has not been fully elucidated. Methods: In this study, the pan-cancer expression profile, genetic mutation, prognostic effect, functional enrichment, immune infiltrating, and potential therapeutic targets of the SLC39A family members were investigated by analyzing multiple public databases such as the Oncomine, TIMER, GEPIA, cBioPortal, KM-plotter, PrognoScan, GeneMANIA, STRING, DAVID, TIMER 2.0, and CellMiner databases. Results: The expression levels of most SLC39 family genes in the tumor tissues were found to be significantly upregulated compared to the normal group. In mutation analysis, the mutation frequencies of SLC39A4 and SLC39A1 were found to be higher among all the members (6 and 4%, respectively). Moreover, the overall mutation frequency of the SLC39A family genes ranged from 0.8 to 6% pan-cancer. Also, the function of the SLC39A highly related genes was found to be enriched in functions such as zinc II ion transport across the membrane, steroid hormone biosynthesis, and chemical carcinogenesis. In immune infiltration analysis, the expression level of the SLC39A family genes was found to be notably related to the immune infiltration levels of six types of immune cells in specific types of tumors. In addition, the SLC39A family genes were significantly related to the sensitivity or resistance of 63 antitumor drugs in a variety of tumor cell lines. Conclusion: These results indicate that the SLC39 family genes are significant for determining cancer progression, immune infiltration, and drug sensitivity in multiple cancers. This study, therefore, provides novel insights into the pan-cancer potential targets of the SLC39 family genes.
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Affiliation(s)
- Yi-Yuan Qu
- Department of Gynecology and Obstetrics, the People's Hospital of China Three Gorges University/The First People's Hospital of Yichang, Yichang, China
| | - Rong-Yan Guo
- Emergency Services Department, HanYang Hospital Affiliated of Wuhan University of Science and Technology, Wuhan, China
| | - Meng-Ling Luo
- Department of Gynecology and Obstetrics, the People's Hospital of China Three Gorges University/The First People's Hospital of Yichang, Yichang, China
| | - Quan Zhou
- Department of Gynecology and Obstetrics, the People's Hospital of China Three Gorges University/The First People's Hospital of Yichang, Yichang, China
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42
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Planeta Kepp K. Bioinorganic Chemistry of Zinc in Relation to the Immune System. Chembiochem 2021; 23:e202100554. [PMID: 34889510 DOI: 10.1002/cbic.202100554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 12/09/2021] [Indexed: 01/18/2023]
Abstract
Zinc is well-known to have a central role in human inflammation and immunity and is itself an anti-inflammatory and antiviral agent. Despite its massively documented role in such processes, the underlying chemistry of zinc in relation to specific proteins and pathways of the immune system has not received much focus. This short review provides an overview of this topic, with emphasis on the structures of key proteins, zinc coordination chemistry, and probable mechanisms involved in zinc-based immunity, with some focus points for future chemical and biological research.
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Affiliation(s)
- Kasper Planeta Kepp
- DTU Chemistry, Technical University of Denmark, Building 206, 2800, Kongens Lyngby, Denmark
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43
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Dai H, Wang L, Li L, Huang Z, Ye L. Metallothionein 1: A New Spotlight on Inflammatory Diseases. Front Immunol 2021; 12:739918. [PMID: 34804020 PMCID: PMC8602684 DOI: 10.3389/fimmu.2021.739918] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 10/18/2021] [Indexed: 01/15/2023] Open
Abstract
MT1 has been demonstrated to be an essential stress protein in maintaining physiological balance and regulating immune homeostasis. While the immunological involvement of MT1 in central nervous system disorders and cancer has been extensively investigated, mounting evidence suggests that MT1 has a broader role in inflammatory diseases and can shape innate and adaptive immunity. In this review, we will first summarize the biological features of MT1 and the regulators that influence MT1 expression, emphasizing metal, inflammation, and immunosuppressive factors. We will then focus on the immunoregulatory function of MT1 on diverse immune cells and the signaling pathways regulated by MT1. Finally, we will discuss recent advances in our knowledge of the biological role of MT1 in several inflammatory diseases to develop novel therapeutic strategies.
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Affiliation(s)
- Hanying Dai
- Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China
| | - Lu Wang
- Respiratory Medicine Department, Shenzhen University General Hospital, Shenzhen, China
| | - Lingyun Li
- Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China
| | - Zhong Huang
- Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China
| | - Liang Ye
- Department of Immunology, International Cancer Center, Shenzhen University Health Science Center, Shenzhen, China
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44
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Monteith AJ, Skaar EP. The impact of metal availability on immune function during infection. Trends Endocrinol Metab 2021; 32:916-928. [PMID: 34483037 PMCID: PMC8516721 DOI: 10.1016/j.tem.2021.08.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 12/16/2022]
Abstract
Nutrient transition metals are required cofactors for many proteins to perform functions necessary for life. As such, the concentration of nutrient metals is carefully maintained to retain critical biological processes while limiting toxicity. During infection, invading bacterial pathogens must acquire essential metals, such as zinc, manganese, iron, and copper, from the host to colonize and cause disease. To combat this, the host exploits the essentiality and toxicity of nutrient metals by producing factors that limit metal availability, thereby starving pathogens or accumulating metals in excess to intoxicate the pathogen in a process termed 'nutritional immunity'. As a result of inflammation, a heterogeneous environment containing both metal-replete and -deplete niches is created, in which nutrient metal availability may have an underappreciated role in regulating immune cell function during infection. How the host manipulates nutrient metal availability during infection, and the downstream effects that nutrient metals and metal-sequestering proteins have on immune cell function, are discussed in this review.
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Affiliation(s)
- Andrew J Monteith
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Eric P Skaar
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Institute for Infection, Immunology, & Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA.
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45
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Chen R, Chen L. Solute carrier transporters: emerging central players in tumour immunotherapy. Trends Cell Biol 2021; 32:186-201. [PMID: 34511324 DOI: 10.1016/j.tcb.2021.08.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/17/2021] [Accepted: 08/18/2021] [Indexed: 02/05/2023]
Abstract
Solute carrier transporters (SLCs) mediate nutrient and metabolite cellular homeostasis. Immune cells depend on SLCs to induce rapid and robust metabolic reprogramming, thereby controlling diverse immunological responses. Recent studies hint toward an important role of SLCs in immunity. Here, we review the emerging roles of SLCs in immunotherapy via modifying the metabolism and effector functions of immune cells. We focus on the roles of three major nutrient (glucose, amino acid, and lipid)-related transporters in immunity of representative cells [T cells, dendritic cells (DCs), natural killer (NK) cells, and macrophages) in innate and adaptive immunity. Other SLCs, such as ion transporters are also briefly discussed. Finally, we propose some potential strategies for targeting SLCs to augment tumour immunotherapy.
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Affiliation(s)
- Ruiqun Chen
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China
| | - Ligong Chen
- School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China; Collaborative Innovation Center for Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610065, China.
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46
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Affiliation(s)
| | - Ajay Gupta
- Division of Nephrology, Hypertension and Kidney Transplantation, Department of Medicine, University of California Irvine (UCI) School of Medicine, Irvine, California, USA
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47
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Alamir OF, Oladele RO, Ibe C. Nutritional immunity: targeting fungal zinc homeostasis. Heliyon 2021; 7:e07805. [PMID: 34466697 PMCID: PMC8384899 DOI: 10.1016/j.heliyon.2021.e07805] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/22/2021] [Accepted: 08/12/2021] [Indexed: 12/15/2022] Open
Abstract
Transition metals, such as Zn2+, are essential dietary constituents of all biological life, including mammalian hosts and the pathogens that infect them. Therefore, to thrive and cause infection, pathogens must successfully assimilate these elements from the host milieu. Consequently, mammalian immunity has evolved to actively restrict and/or pool metals to toxic concentrations in an effort to attenuate microbial pathogenicity - a process termed nutritional immunity. Despite host-induced Zn2+ nutritional immunity, pathogens such as Candida albicans, are still capable of causing disease and thus must be equipped with robust Zn2+ sensory, uptake and detoxification machinery. This review will discuss the strategies employed by mammalian hosts to limit Zn2+ during infection, and the subsequent fungal interventions that counteract Zn2+ nutritional immunity.
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Affiliation(s)
- Omran F Alamir
- Department of Natural Sciences, College of Health Sciences, The Public Authority for Applied Education and Training, Al Asimah, Kuwait
| | - Rita O Oladele
- Department of Medical Microbiology & Parasitology, College of Medicine, University of Lagos, Lagos State, Nigeria
| | - C Ibe
- Department of Microbiology, Abia State University, PMB 2000, Uturu, Abia State, Nigeria
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48
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Meshkini A. A Correlation Between Intracellular Zinc Content and Osteosarcoma. Biol Trace Elem Res 2021; 199:3222-3231. [PMID: 33150482 DOI: 10.1007/s12011-020-02466-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Accepted: 10/28/2020] [Indexed: 12/31/2022]
Abstract
Zinc is a trace element in human body involved in many biological processes. It is critical for cell growth and acts as a cofactor for the structure and function of a wide range of cellular proteins such as enzymes. Mounting evidence has shown the involvement of intracellular zinc in the bone-related biological processes such as bone growth, homeostasis, and regeneration; however, the molecular mechanism(s) whereby zinc impels tumorigenesis in bone remains largely unexplored. In this article, selective outline related to the content of intracellular zinc in osteosarcoma cells was provided, and its correlation with signaling molecules that are activated and consequently guide the cells toward tumorigenesis or osteogenesis was discussed. Based on preclinical and clinical evidence, dysregulation of zinc homeostasis, both at intracellular and tissue level, has the main role in the pathogenesis of osteosarcoma. Based on the intracellular zinc content, this element could have a direct role in the dynamics of bone cell transformation and tumor development and play an indirect role in the modulation of the inflammatory and pro/antitumorigenic responses in immune cells. In this context, zinc transporters and the proteins containing zinc domain are regulated by the availability of zinc, playing a crucial role in bone cell transformation and differentiation. According to recent studies, it seems that intracellular zinc levels could be considered as an early prognosis marker. Besides, identification and targeting of zinc-dependent signaling molecules could tilt the balance of life and death toward the latter in chemoresistant malignant cells and may pave a way for designing of the novel osteosarcoma treatment strategies.
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Affiliation(s)
- Azadeh Meshkini
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, P. O. Box 9177948974, Iran.
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49
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Hall SC, Smith DR, Dyavar SR, Wyatt TA, Samuelson DR, Bailey KL, Knoell DL. Critical Role of Zinc Transporter (ZIP8) in Myeloid Innate Immune Cell Function and the Host Response against Bacterial Pneumonia. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2021; 207:1357-1370. [PMID: 34380651 PMCID: PMC10575710 DOI: 10.4049/jimmunol.2001395] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 06/29/2021] [Indexed: 11/19/2022]
Abstract
Zinc (Zn) is required for proper immune function and host defense. Zn homeostasis is tightly regulated by Zn transporters that coordinate biological processes through Zn mobilization. Zn deficiency is associated with increased susceptibility to bacterial infections, including Streptococcus pneumoniae, the most commonly identified cause of community-acquired pneumonia. Myeloid cells, including macrophages and dendritic cells (DCs), are at the front line of host defense against invading bacterial pathogens in the lung and play a critical role early on in shaping the immune response. Expression of the Zn transporter ZIP8 is rapidly induced following bacterial infection and regulates myeloid cell function in a Zn-dependent manner. To what extent ZIP8 is instrumental in myeloid cell function requires further study. Using a novel, myeloid-specific, Zip8 knockout model, we identified vital roles of ZIP8 in macrophage and DC function upon pneumococcal infection. Administration of S. pneumoniae into the lung resulted in increased inflammation, morbidity, and mortality in Zip8 knockout mice compared with wild-type counterparts. This was associated with increased numbers of myeloid cells, cytokine production, and cell death. In vitro analysis of macrophage and DC function revealed deficits in phagocytosis and increased cytokine production upon bacterial stimulation that was, in part, due to increased NF-κB signaling. Strikingly, alteration of myeloid cell function resulted in an imbalance of Th17/Th2 responses, which is potentially detrimental to host defense. These results (for the first time, to our knowledge) reveal a vital ZIP8- and Zn-mediated axis that alters the lung myeloid cell landscape and the host response against pneumococcus.
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Affiliation(s)
- Sannette C Hall
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE
| | - Deandra R Smith
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE
| | - Shetty Ravi Dyavar
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE
| | - Todd A Wyatt
- Department of Environmental, Agricultural and Occupational Health, College of Public Health, University of Nebraska Medical Center, Omaha, NE
- Pulmonary Division, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE; and
- Department of Veterans Affairs Nebraska, University of Nebraska Medical Center, Western Iowa Health Care System, Omaha, NE
| | - Derrick R Samuelson
- Pulmonary Division, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE; and
| | - Kristina L Bailey
- Pulmonary Division, Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE; and
- Department of Veterans Affairs Nebraska, University of Nebraska Medical Center, Western Iowa Health Care System, Omaha, NE
| | - Daren L Knoell
- Department of Pharmacy Practice and Science, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE;
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50
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Story MJ. Essential sufficiency of zinc, ω-3 polyunsaturated fatty acids, vitamin D and magnesium for prevention and treatment of COVID-19, diabetes, cardiovascular diseases, lung diseases and cancer. Biochimie 2021; 187:94-109. [PMID: 34082041 PMCID: PMC8166046 DOI: 10.1016/j.biochi.2021.05.013] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 05/19/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023]
Abstract
Despite the development of a number of vaccines for COVID-19, there remains a need for prevention and treatment of the virus SARS-CoV-2 and the ensuing disease COVID-19. This report discusses the key elements of SARS-CoV-2 and COVID-19 that can be readily treated: viral entry, the immune system and inflammation, and the cytokine storm. It is shown that the essential nutrients zinc, ω-3 polyunsaturated fatty acids (PUFAs), vitamin D and magnesium provide the ideal combination for prevention and treatment of COVID-19: prevention of SARS-CoV-2 entry to host cells, prevention of proliferation of SARS-CoV-2, inhibition of excessive inflammation, improved control of the regulation of the immune system, inhibition of the cytokine storm, and reduction in the effects of acute respiratory distress syndrome (ARDS) and associated non-communicable diseases. It is emphasized that the non-communicable diseases associated with COVID-19 are inherently more prevalent in the elderly than the young, and that the maintenance of sufficiency of zinc, ω-3 PUFAs, vitamin D and magnesium is essential for the elderly to prevent the occurrence of non-communicable diseases such as diabetes, cardiovascular diseases, lung diseases and cancer. Annual checking of levels of these essential nutrients is recommended for those over 65 years of age, together with appropriate adjustments in their intake, with these services and supplies being at government cost. The cost:benefit ratio would be huge as the cost of the nutrients and the testing of their levels would be very small compared with the cost savings of specialists and hospitalization.
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Affiliation(s)
- Michael J Story
- Story Pharmaceutics Pty Ltd, PO Box 6086, Linden Park, South Australia, 5065, Australia.
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