Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets

Chen, Bonan; Yu, Peiyao; Chan, Wai Nok; Xie, Fuda; Zhang, Yigan; Liang, Li; Leung, Kam Tong; Lo, Kwok Wai; Yu, Jun; Tse, Gary M. K.; Kang, Wei; To, Ka Fai

doi:10.1038/s41392-023-01679-y

Cited by 54 publications

(8 citation statements)

References 695 publications

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“…The MT-zinc axis is closely associated with immune regulation in infectious diseases or atopies [29,39,40]. MT1 and MT2 are two major MTs involved in immune function [35]; however, the distinct roles of MT1 and MT2 have not been clarified.…”

Section: Discussionmentioning

confidence: 99%

Coccomyxa subellipsoidea KJ Components Enhance the Expression of Metallothioneins and Th17 Cytokines during Human T Cell Activation

Seki,

Ohshima,

Komatsu

et al. 2024

Microorganisms

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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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Section: Discussionmentioning

confidence: 99%

Coccomyxa subellipsoidea KJ Components Enhance the Expression of Metallothioneins and Th17 Cytokines during Human T Cell Activation

Seki,

Ohshima,

Komatsu

et al. 2024

Microorganisms

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“…MT3 is a Zn-binding protein that can bind up to seven Zn 2+ , and is involved in maintaining intracellular Zn 2+ homeostasis 16 , 53 . Our results demonstrated that under hypoxia treatment, MT3 knockdown reduced intracellular Zn 2+ levels and exogenous Zn 2+ supplementation largely reversed the inhibitory effects of MT3 knockdown on PASMCs.…”

Section: Discussionmentioning

confidence: 99%

Metallothionein 3 Potentiates Pulmonary Artery Smooth Muscle Cell Proliferation by Promoting Zinc-MTF1-ATG5 Axis-mediated Autophagosome Formation

Xiong,

Li,

Yang

et al. 2024

Int. J. Biol. Sci.

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Abnormal proliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the critical pathological mechanisms of pulmonary hypertension (PH), and therefore is gradually being adopted as an important direction for the treatment of PH. Metallothioneins (MTs) have been reported to be associated with PH, but the underlying mechanisms are not fully understood. Here, we demonstrated that the expression level of metallothionein 3 (MT3) was significantly increased in pulmonary arterioles from PH patients and chronic hypoxia-induced rat and mouse PH models, as well as in hypoxia-treated human PASMCs. Knockdown of MT3 significantly inhibited the proliferation of human PASMCs by arresting the cell cycle in the G1 phase, while overexpression of MT3 had the opposite effect. Mechanistically, we found that MT3 increased the intracellular zinc (Zn 2+ ) concentration to enhance the transcriptional activity of metal-regulated transcription factor 1 (MTF1), which promoted the expression of autophagy-related gene 5 (ATG5), facilitating autophagosome formation. More importantly, MT3-induced autophagy and proliferation of human PASMCs were largely prevented by knockdown of MTF1 and ATG5. Therefore, in this study, we identified MT3-Zinc-MTF1-ATG5 as a novel pathway that affects PASMC proliferation by regulating autophagosome formation, suggesting that MT3 may be a novel target for the treatment of PH.

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“…Zinc functions with calcium and iron enhancing site specific activities regulating plasma membrane and endosome receptors, effecting virus entry such as SARS-CoV-2. 204 Metallopeptidases can either be derived from microbes or host cells. Human zinc metallopeptidases support immune resistance, controlling inflammation including antigen recognition, processing and ultimately clearance of SARS-CoV-2.…”

Section: Bacterial and Viral Oral Pathogen Persistence In Oral Epithe...mentioning

confidence: 99%

SARS‐CoV‐2, periodontal pathogens, and host factors: The trinity of oral post‐acute sequelae of COVID‐19

Schwartz,

Capistrano,

Gluck

et al. 2024

Reviews in Medical Virology

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COVID‐19 as a pan‐epidemic is waning but there it is imperative to understand virus interaction with oral tissues and oral inflammatory diseases. We review periodontal disease (PD), a common inflammatory oral disease, as a driver of COVID‐19 and oral post‐acute‐sequelae conditions (PASC). Oral PASC identifies with PD, loss of teeth, dysgeusia, xerostomia, sialolitis‐sialolith, and mucositis. We contend that PD‐associated oral microbial dysbiosis involving higher burden of periodontopathic bacteria provide an optimal microenvironment for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. These pathogens interact with oral epithelial cells activate molecular or biochemical pathways that promote viral adherence, entry, and persistence in the oral cavity. A repertoire of diverse molecules identifies this relationship including lipids, carbohydrates and enzymes. The S protein of SARS‐CoV‐2 binds to the ACE2 receptor and is activated by protease activity of host furin or TRMPSS2 that cleave S protein subunits to promote viral entry. However, PD pathogens provide additional enzymatic assistance mimicking furin and augment SARS‐CoV‐2 adherence by inducing viral entry receptors ACE2/TRMPSS, which are poorly expressed on oral epithelial cells. We discuss the mechanisms involving periodontopathogens and host factors that facilitate SARS‐CoV‐2 infection and immune resistance resulting in incomplete clearance and risk for ‘long‐haul’ oral health issues characterising PASC. Finally, we suggest potential diagnostic markers and treatment avenues to mitigate oral PASC.

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Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets

Cited by 54 publications

References 695 publications

Coccomyxa subellipsoidea KJ Components Enhance the Expression of Metallothioneins and Th17 Cytokines during Human T Cell Activation

Coccomyxa subellipsoidea KJ Components Enhance the Expression of Metallothioneins and Th17 Cytokines during Human T Cell Activation

Metallothionein 3 Potentiates Pulmonary Artery Smooth Muscle Cell Proliferation by Promoting Zinc-MTF1-ATG5 Axis-mediated Autophagosome Formation

SARS‐CoV‐2, periodontal pathogens, and host factors: The trinity of oral post‐acute sequelae of COVID‐19

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