Dear colleagues,

I would like to extend my heartfelt congratulations on the launching of the first issue of Metallomics Research as an international official journal of the Japan Society for Biomedical Research on Trace Elements.

The Japan Society for Biomedical Research on Trace Elements has published Biomedical Research on Trace Elements as its official journal since its establishment in 1990. However, the study of metals in biological systems has recently re-emerged to become an increasingly important area of research. Considering the current activities in this research field, we have decided to launch the new journal, which is open access with global peer reviewing.

The term “metallomics" was coined by Professor Hiroki Haraguchi, a previous director of our Society. As you may know, the term has been officially defined by the International Union of Pure and Applied Chemistry. Japan is the cradle of metallomics, and metallomics is disseminated around the world. Therefore, the launching of Metallomics Research is a great pleasure and pride of our Society. In addition, the 8th International Symposium on Metallomics (ISM-8) is scheduled in Japan in the summer of 2022. The first ISM was held in Japan in 2007 with Professor Haraguchi as chair. That this will be the second time for ISM to be held in Japan indicates that the research field of metallomics has reached its second and more mature phase. This is also the best timing to launch the journal.

The Japan Society for Biomedical Research on Trace Elements brings together researchers from diverse areas, including medicine, biology, toxicology, analytical chemistry, environmental science, pharmaceutical science, and so on. I expect that the publication of Metallomics Research would further stimulate the international activities of our Society.

The Japan Society for Biomedical Research on Trace Elements decided to publish the new journal “Metallomics Research” from October, 2021, instead of their previous journal “Biomedical Research on Trace Elements”（BRTE）. On this occasion, the history of trace element study in Japan and the progress of metallomics as integrated biometal science proposed about 20 years ago are reviewed. In the latter part of this review, basic concepts of metallomics research are discussed in relation to homeostasis and all-present theory, and finally it is considered that metallomics research has a mission to contribute to our humans and nature through the SDGs (Sustainable Development Goals), mainly with focusing on health science and environmental/green science as multidisciplinary science.

Biopersistent nanofibers with specified physical dimension are unexpected human carcinogens whether they are natural or synthetic. Asbestos, a natural fibrous mineral, is classified as a definite human carcinogen (IARC Group 1) to cause malignant mesothelioma (MM) and lung cancer. Multi-walled carbon nanotube of 50 nm-diameter was defined in 2014 as a possible carcinogen (IARC Group 2B) toward MM, fortunately with no authorized patients thus far. Carcinogenic mechanism of asbestos has been a mystery for a long time. It is now recognized that asbestos goes through lung parenchyma by collecting hemoglobin-derived iron to reach pleural cavity, which takes several decades. Iron-loaded asbestos can induce oxidative damage directly to mesothelial cells, carcinogenesis-target cells lining somatic cavities. Recently, it was clarified that surrounding stromal environment are as important for mesothelial carcinogenesis. The novel concept here is ceaseless ferroptosis of macrophages, which forms a Fe(II)-dependent stromal mutagenic milieu indirectly for mesothelial cells and indeed is a revised understanding of frustrated phagocytosis. Deposition of foreign materials eventually causes iron accumulation in situ due to the innate characteristic of preserving iron inside cells. Nanofiber-induced carcinogenesis may be involved in other human carcinogenesis, including ovarian cancer. Alternatively, iron excess can be an optimal target of cancer prevention and cancer treatment.

Neuronal Zn²⁺ homeostasis is closely linked with not only cognitive function but also cognitive decline, while there is no hormone involved in zinc homeostasis unlike calcium homeostasis. Extracellular Zn²⁺ dynamics is modified by extracellular levels of glucocorticoids and glutamate, which are linked with stress response. Extracellular glucocorticoid signal is transmitted via not only glucocorticoid receptors but also mineralocorticoid receptors. Membrane corticosteroid receptors dynamically modifies synaptic Zn²⁺ dynamics in the hippocampus. Synaptic plasticity, i.e., long-term potentiation (LTP), which is a cellular mechanism of memory, is affected by rapid intracellular Zn²⁺ dysregulation via membrane corticosteroid receptor activation in the CA1; Corticosterone rapidly induces the increase in intracellular Zn²⁺ via membrane corticosteroid receptor activation, and decreases phosphorylated CaMKII level, resulting in attenuating CA1 LTP. The mechanism of intracellular Zn²⁺ dysregulation is different between membrane mineralocorticoid and glucocorticoid receptor-mediated signaling. In contrast, corticosterone-induced intracellular Ca²⁺ dysregulation is less crucial for affecting CA1 LTP. The basal concentration (~100 pM) of intracellular Zn²⁺ is much lower than that (~100 nM) of intracellular Ca²⁺. Therefore, the precise mechanism is required to regulate intracellular Zn²⁺ homeostasis because of more critical neurotoxicity of Zn²⁺. This review summarizes the physiological significance of intracellular Zn²⁺ homeostasis focused on signaling of corticosterone and glutamate in the extracellular compartment.

Extensive epidemiological studies in Taiwan, Chile, and Bangladesh have shown that chronic arsenic exposure is associated with increased incidence and prevalence of skin lesions, cancers, as well as non-malignant disorders such as hypertension, diabetes mellitus, cardiovascular diseases, and respiratory diseases. However, the underlying mechanisms of how arsenic facilitates vascular disorders and diabetes remained unclear. To understand biochemical mechanisms related to arsenic-induced non-malignant diseases, we have examined the relationships between disease-related blood biomarkers and arsenic exposure levels in the arsenic-contaminated area in the western region of Bangladesh. In this review, we presented a summary of the findings of our studies in Bangladesh and discussed their significances in comparison with epidemiological observations in Taiwan and Chile. We have identified arsenic-induced changes in the biomarkers reflecting oxidative stress, inflammation, dyslipidemia, vasoconstriction, monocyte adhesion, and angiogenesis, all related to promoting atherosclerosis and hypertension. Determinations of glucose intolerance, serum insulin and creatinine, and lean body mass suggested a potential role of arsenic-induced skeletal muscle atrophy and its association with insulin resistance. Respiratory function tests and measurements of serum immunoglobulin E and cytokines showed that arsenic-induced T helper 2 (Th2)-dominant immunomodulation might predispose to developing Th2-high type asthma. Thus, the investigation of disease-related biomarkers allowed us to provide novel insight into biochemical mechanisms of arsenic-associated increases in non-malignant diseases.

Aluminum (Al) is the third most abundant element in the earth’s crust. However, because of its specific chemical properties, Al is not essential for life, and it exerts various adverse effects on plants, animals, and humans. In particular, Al is a widely recognized neurotoxin. The association between Al and neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis and Parkinson’s disease dementia in the Kii Peninsula and Guam has been suspected. However, controversy has persisted for several decades. Based on recent epidemiological, analytical, and toxicological studies, we review the detailed characteristics of Al neurotoxicity and revisit its link to Alzheimer’s disease and other diseases. The daily intake of Al and its bioavailability linked with adverse effects on human health are also described.

Background: Nodular goiter (NG) is an internationally important health problem. The aim of this exploratory study was to evaluate whether significant changes in the thyroid tissue levels of fifty trace elements (TE) exist in the goitrous transformed thyroid.

Method: Thyroid tissue levels of fifty TE were prospectively evaluated in 46 patients with colloid NG and 105 healthy inhabitants. Measurements were performed using a combination of non-destructive and destructive methods: instrumental neutron activation analysis and inductively coupled plasma mass spectrometry, respectively. Tissue samples were divided into two portions. One was used for morphological study while the other was intended for TE analysis.

Results: It was found that contents of Ag, Al, Bi, Ce, Cr, Er, Fe, Hg, La, Li, Mn, Mo, Nd, Ni, Pr, Se, Sm, Tl, U, Y, and Zn in colloid NG tissue significantly increased whereas the levels of Cd, Ga, and Sn decrease in comparison with those in normal thyroid.

Conclusion: There are considerable changes in TE contents in the goitrous tissue of thyroid.

Selenophosphate is an important intermediate for selenoprotein synthesis. Despite its biological significance, the existence of selenophosphate in in vivo samples has not been corroborated by instrumental analyses, such as NMR spectroscopy and mass spectrometry. In this study, we synthesized selenophosphate and subjected it to detailed structural analyses, including ³¹P NMR, ⁷⁷Se NMR, and LC-ICP-MS/MS analyses. We confirmed that the structural information of the chemically synthesized selenophosphate was consistent with that of the product biologically synthesized by SelD, a bacterial selenophosphate synthetase. Based on these results, the structure of the SelD product was confirmed.

The effects of phytic acid on the absorption of several minerals including zinc, iron, copper, calcium, magnesium, manganese and molybdenum, the biosynthesis of uric acid, and the serum lipid components were examined. Weaning male Wistar rats were fed a basal AIN93G diet or the basal diet supplemented with 0.5% or 1.0% sodium phytate for 4 weeks. Phytic acid administration reduced the serum and femur zinc levels in a dose-dependent manner but did not affect the liver and kidney zinc levels. In addition, significant reductions with phytic acid administration were observed in the liver iron, serum and liver copper, liver and kidney calcium, kidney magnesium, and liver and kidney manganese concentrations. In phytic-acid-administered rats, the molybdenum concentration and xanthine oxidase activity in the liver and the serum uric acid decreased in a dose-dependent manner. In addition, phytic acid administration also reduced the serum lipid components including triacylglycerol and total cholesterol. Since phytic acid is hardly absorbed, these results indicate that phytic acid inhibits the absorption of several dietary components including minerals, and that the decrease in the serum uric acid concentration that occurs when phytic acid is ingested is due to the decrease in molybdenum absorption. When utilizing the functionality of phytic acid for health promotion, it is necessary to pay sufficient attention to the intake of minerals.

Laser ablation-single particle-ICP-mass spectrometry (LA-spICP-MS) was applied to define the size, position of silver nanoparticles (Ag NPs), and the concentration of ionic Ag (dissolved Ag) on a frozen section of mouse liver (6 hours after intraperitoneal administered 60 nm Ag NPs (0.2 mg per mouse)). For the accurate size calibration of Ag NPs and quantitative analysis of ionic Ag, a cellulose filter paper doped with Ag NPs suspension and a custom-made photocurable resin reference material containing ionic Ag were prepared in this study. From the imaging results of liver sample, preferential accumulation of the Ag NPs in certain regions was observed. Ionic Ag was also accumulated at regions where Ag NPs are. This suggests that there is a possible contribution of dissolution of Ag NPs through cell activity. This is supported by the detection of small Ag NPs (8–20 nm). The simultaneous imaging analyses of both Ag NPs and ionic Ag can become a useful tool to understand the mechanism of incorporation or metabolism of the NPs.

Distribution and concentration of certain organic compounds in drugs or biological tissue samples can provide key information to understand the behaviour and effect of that chemical species. In this study, we developed an analytical technique to perform mass spectrometry imaging for organic compounds under atmospheric pressure. The laser ablation technique was used as a sample introduction method to ablate a small amount of sample by focusing laser light onto the sample surface. Laser-induced sample particles were transferred by an argon gas stream to a newly developed plasma-based ion source for ionisation. The capability of this analytical method was demonstrated with the analysis of amino acids. Either protonated ([M+H]⁺) or ammoniated ([M+NH₄]⁺) ions, with slight fragments, were observed for the amino acids and sugar, suggesting a fairly soft ionisation was achieved. Analytical repeatability defined by nine times repeated analysis was better than 10%. More importantly, linear correlations between the signal intensities and concentration of analytes were obtained for three amino acids (valine, methionine, and phenylalanine). With the present analytical technique, imaging analysis of several amino acids and sugar was carried out with a tablet sample. The resulting imaging can be used to evaluate the homogeneity of drug components both the within and among the tablets.

We are delighted to introduce the first issue of Metallomics Research as a new official journal of the Japan Society for Biomedical Research on Trace Elements. In this first issue, Prof. Yasumitsu Ogra, a president of the Japan Society for Biomedical Research on Trace Elements, contributed an introduction about the start of Metallomics Research. Prof. Hiroki Haraguchi, the founder of “metallomics”, contributed the historical overviews and future perspectives about metallomics. Furthermore, many scientists have kindly contributed to this issue in their various fields including medicine, biology, toxicology, analytical chemistry, environmental science, pharmaceutical science, and so on. We thank all of the authors, reviewers, and executive office members for their significant contribution about this new journal. Metallomics Research is a small seed at the present time, however, we hope Metallomics Research will grow up into a big tree which connects numerous scientists in various research field and provide a good platform. We kindly ask to submit your valuable results to Metallomics Research.