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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Endocrinology & Metabolism".

Deadline for manuscript submissions: closed (10 March 2021) | Viewed by 26271

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Prof. Dr. Masahiro Sugimoto

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Research and Development Center for Minimally Invasive Therapies, Institute of Medical Science, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan
Interests: bioinformatics; metabolomics

Special Issue Information

Dear Colleagues,

Metabolomics, one of the established omics technologies, has been utilized to understand the metabolic pathways in various cells. This method enables us to evaluate systemic health status and metabolic diseases through high-dimensional metabolomics data.

This Special Issue aims to provide an update regarding the current topics in metabolomics related to health and diseases. Therefore, we would like to invite original research, state-of-the-art reviews, and viewpoints. In particular, we would like to encourage the submission of manuscripts covering biomarker discovery, mechanism elucidation, technology development, and data analysis.

We look forward to your submissions!

Prof. Dr. Masahiro Sugimoto
Guest Editor

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Keywords

metabolomics
metabolites
chromatography
mass spectrometry
data processing
health
diseases
biomarkers

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Editorial

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2 pages, 171 KiB

Open AccessEditorial

Editorial of Special Issue “Metabolomic Analysis in Health and Diseases”

by Masahiro Sugimoto

J. Clin. Med. 2021, 10(16), 3491; https://doi.org/10.3390/jcm10163491 - 7 Aug 2021

Viewed by 1332

Abstract

Metabolomics, a quantitative omics technology that simultaneously profiles hundreds of metabolites, has been used to explore new biomarkers and elucidate the metabolic pathways perturbed by various stimuli at a system level [...] Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

Research

Jump to: Editorial

10 pages, 996 KiB

Open AccessArticle

Time-Course of Salivary Metabolomic Profiles during Radiation Therapy for Head and Neck Cancer

by Wakako Yatsuoka, Takao Ueno, Kanako Miyano, Ayame Enomoto, Sana Ota, Masahiro Sugimoto and Yasuhito Uezono

J. Clin. Med. 2021, 10(12), 2631; https://doi.org/10.3390/jcm10122631 - 15 Jun 2021

Cited by 14 | Viewed by 2890

Abstract

Oral mucositis (OM) is one of the most frequently observed adverse oral events in radiation therapy for patients with head and neck cancer. Thus, objective evaluation of OM severity is needed for early and timely intervention. Here, we analyzed the time-course of salivary metabolomic profiles during the radiation therapy. The severity of OM (National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0) of nine patients with head and neck cancer was evaluated. Partial least squares regression-discriminant analysis, using samples collected before radiation therapy, showed that histidine and tyrosine highly discriminated high-grade OM from low-grade OM before the start of radiation therapy (significant difference, p = 0.048 for both metabolites). Further, the pretreatment concentrations of gamma-aminobutyric acid and 2-aminobutyric acids were higher in the high-grade OM group. Although further validations are still necessary, this study showed potentially associated metabolites with worse radiotherapy-related OM among patients with head and neck cancer. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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15 pages, 4287 KiB

Open AccessArticle

Correlation of Plasma Amino Acid and Anthropometric Profiles with Brown Adipose Tissue Density in Humans

by Miyuki Kuroiwa, Sayuri Hamaoka-Fuse, Masahiro Sugimoto, Yuko Kurosawa, Yasuko Aita, Atsumi Tomita, Mikiko Anjo, Riki Tanaka, Tasuki Endo, Ryotaro Kime and Takafumi Hamaoka

J. Clin. Med. 2021, 10(11), 2339; https://doi.org/10.3390/jcm10112339 - 27 May 2021

Cited by 2 | Viewed by 2857

Abstract

This study examined the relationship between plasma amino acid (AA) concentrations, including branched-chain AAs, and brown adipose tissue density (BAT-d). One hundred and seventy-three subjects (69 men, 104 women) aged 22–68 years were recruited during the winter season. AAs were comprehensively quantified using liquid chromatography-time-of-flight-mass spectrometry. The total hemoglobin concentration in the supraclavicular region ([total-Hb]sup), an indicator of BAT-d, was assessed using near-infrared time-resolved spectroscopy. Anthropometric parameters, including age, percentage of body fat, and visceral fat, were evaluated. Factors associated with higher (≥74 µM) or lower (<74 µM) [total-Hb]sup were investigated by multiple logistic regression models that included AA concentrations alone (model 1) or AA concentrations and anthropometric parameters (model 2) as independent variables. When adjusted for the false discovery rate, [total-Hb]sup was positively correlated with glycine and asparagine levels in men and with the serine level in both men and women and was negatively correlated with the branched-chain AA concentration in men. Models 1 and 2 correlated with higher or lower BAT-d for men (r = 0.73, p = 0.015) and women (r = 0.58, p = 0.079) and for men (r = 0.82, p = 0.0070) and women (r = 0.70, p = 0.020), respectively. A combination of anthropometric parameters and plasma AA concentrations could be a reliable biomarker for higher and lower BAT-d. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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13 pages, 2183 KiB

Open AccessArticle

Multi-Omics Analysis of Anti-Inflammatory Action of Alkaline Extract of the Leaves of Sasa sp.

by Hiroshi Sakagami, Sachie Nakatani, Ayame Enomoto, Sana Ota, Miku Kaneko, Masahiro Sugimoto, Misaki Horiuchi, Kazuki Toeda and Takaaki Oizumi

J. Clin. Med. 2021, 10(10), 2100; https://doi.org/10.3390/jcm10102100 - 13 May 2021

Cited by 5 | Viewed by 2129

Abstract

Efficient utilization of alkaline extracts of several plants for the treatment of oral diseases has been reported. To investigate the mechanism of anti-inflammatory activity of alkaline extract of the leaves of Sasa sp. (SE), multi-omics analysis using metabolomics and DNA array was performed. Human gingival fibroblasts (HGFs) were treated for IL-1β to induce inflammation (detected by PGE₂ production in culture medium) in the presence or absence of SE. Both IL-1β and SE showed slight hormetic growth stimulation against HGF. SE inhibited PGE₂ production dose- and time-dependently. Its inhibitory action was more pronounced by first treating the cells with SE, rather than with IL-1β. At 3 h after IL-1β treatment, 18 amino acids (except cysteine and glutamic acid), total glutathione (GSH, GSSG, Cys-GSH disulfide), Met-sulfoxide, 5-oxoproline, and SAM declined, whereas DNA expressions of AKT, CASP3, and CXCL3 were elevated. These changes were reversed by simultaneous treatment with SE. The present study suggests that the anti-inflammatory action of SE is mediated via various metabolic pathways for cell survival, apoptosis, and leukocyte recruitment. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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18 pages, 4140 KiB

Open AccessArticle

Quality Assessment of Untargeted Analytical Data in a Large-Scale Metabolomic Study

by Rintaro Saito, Masahiro Sugimoto, Akiyoshi Hirayama, Tomoyoshi Soga, Masaru Tomita and Toru Takebayashi

J. Clin. Med. 2021, 10(9), 1826; https://doi.org/10.3390/jcm10091826 - 22 Apr 2021

Cited by 7 | Viewed by 2768

Abstract

Large-scale metabolomic studies have become common, and the reliability of the peak data produced by the various instruments is an important issue. However, less attention has been paid to the large number of uncharacterized peaks in untargeted metabolomics data. In this study, we tested various criteria to assess the reliability of 276 and 202 uncharacterized peaks that were detected in a gathered set of 30 plasma and urine quality control samples, respectively, using capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS). The linear relationship between the amounts of pooled samples and the corresponding peak areas was one of the criteria used to select reliable peaks. We used samples from approximately 3000 participants in the Tsuruoka Metabolome Cohort Study to investigate patterns of the areas of these uncharacterized peaks among the samples and clustered the peaks by combining the patterns and differences in the migration times. Our assessment pipeline removed substantial numbers of unreliable or redundant peaks and detected 35 and 74 reliable uncharacterized peaks in plasma and urine, respectively, some of which may correspond to metabolites involved in important physiological processes such as disease progression. We propose that our assessment pipeline can be used to help establish large-scale untargeted clinical metabolomic studies. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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12 pages, 2048 KiB

Open AccessArticle

Cognitive Dysfunction in a Mouse Model of Cerebral Ischemia Influences Salivary Metabolomics

by Masahiro To, Masahiro Sugimoto, Juri Saruta, Yuko Yamamoto, Wakako Sakaguchi, Akira Kawata, Masato Matsuo and Keiichi Tsukinoki

J. Clin. Med. 2021, 10(8), 1698; https://doi.org/10.3390/jcm10081698 - 15 Apr 2021

Cited by 8 | Viewed by 2499

Abstract

Vascular dementia, caused by cerebrovascular disease, is associated with cognitive impairment and reduced hippocampal metabolite levels. Specifically, cognitive impairment can be induced by decreased hippocampal brain-derived neurotrophic factor (BDNF) expression. The development of low or non-invasive biomarkers to characterize these diseases is an urgent task. Disturbance of metabolic pathways has been frequently observed in cognitive impairment, and salivary molecules also showed the potentials to reflect cognitive impairment. Therefore, we evaluated salivary metabolic profiles associated with altered hippocampal BDNF expression levels in a cerebral ischemia mouse model using metabolomic analyses. The effect of tacrine (a cholinesterase inhibitor) administration was also examined. The arteries of ICR mice were occluded with aneurysm clips to generate the cerebral ischemia model. Learning and memory performance was assessed using the elevated plus maze (EPM) test. Hippocampal and blood BDNF levels were quantified using an enzyme-linked immunosorbent assay. Glutamate decarboxylase 1 (GAD1) mRNA expression, is associated with cognitive impairment, was quantified by a real-time polymerase chain reaction. The EPM test revealed impaired spatial working memory in the cerebral ischemia mouse model; tacrine administration ameliorated this memory impairment. Cerebral ischemia suppressed GAD1 expression by decreasing hippocampal BDNF expression. In total, seven salivary metabolites, such as trimethylamine N-oxide and putrescine, were changed by cognitive impairment and tacrine administration. Our data suggest that salivary metabolite patterns were associated with cognitive function. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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12 pages, 1495 KiB

Open AccessArticle

Metabolomic Alteration of Oral Keratinocytes and Fibroblasts in Hypoxia

by Hiroko Kato, Masahiro Sugimoto, Ayame Enomoto, Miku Kaneko, Yuko Hara, Naoaki Saito, Aki Shiomi, Hisashi Ohnuki and Kenji Izumi

J. Clin. Med. 2021, 10(6), 1156; https://doi.org/10.3390/jcm10061156 - 10 Mar 2021

Cited by 4 | Viewed by 2697

Abstract

The oxygen concentration in normal human tissue under physiologic conditions is lower than the atmospheric oxygen concentration. The more hypoxic condition has been observed in the cells with wound healing and cancer. Somatic stem cells reside in a hypoxic microenvironment in vivo and prefer hypoxic culture conditions in vitro. Oral mucosa contains tissue-specific stem cells, which is an excellent tissue source for regenerative medicine. For clinical usage, maintaining the stem cell in cultured cells is important. We previously reported that hypoxic culture conditions maintained primary oral keratinocytes in an undifferentiated and quiescent state and enhanced their clonogenicity. However, the metabolic mechanism of these cells is unclear. Stem cell biological and pathological findings have shown that metabolic reprogramming is important in hypoxic culture conditions, but there has been no report on oral mucosal keratinocytes and fibroblasts. Herein, we conducted metabolomic analyses of oral mucosal keratinocytes and fibroblasts under hypoxic conditions. Hypoxic oral keratinocytes and fibroblasts showed a drastic change of metabolite concentrations in urea cycle metabolites and polyamine pathways. The changes of metabolic profiles in glycolysis and the pentose phosphate pathway under hypoxic conditions in the oral keratinocytes were consistent with those of other somatic stem cells. The metabolic profiles in oral fibroblasts showed only little changes in any pathway under hypoxia except for a significant increase in the antioxidant 2-oxoglutaric acid. This report firstly provides the holistic changes of various metabolic pathways of hypoxic cultured oral keratinocytes and fibroblasts. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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11 pages, 1162 KiB

Open AccessArticle

Positive Effects of Saliva on Oral Candidiasis: Basic Research on the Analysis of Salivary Properties

by Norishige Kawanishi, Noriyuki Hoshi, Takuya Adachi, Narumi Ichigaya and Katsuhiko Kimoto

J. Clin. Med. 2021, 10(4), 812; https://doi.org/10.3390/jcm10040812 - 17 Feb 2021

Cited by 5 | Viewed by 3199

Abstract

The major causes of oral candidiasis include decreased salivary flow rate and the use of ill-fitting dentures. However, the relationships among prosthetic treatment, saliva, and Candida albicans have not been elucidated. This study aimed to examine the effects of prosthetic treatment and changes in saliva (mainly the salivary flow rate) on oral candidiasis symptoms. Participants requiring prosthetic treatment underwent testing for C. albicans, salivary flow rate, intraoral symptoms, and bite force at the initial visit and four months after treatment to evaluate pretreatment and post-treatment changes. The relationships among C. albicans, salivary flow rate, dentures, and intraoral symptoms were analyzed using multiple regression analysis. Denture treatment improved activity against C. albicans as well as the salivary flow rate, intraoral symptoms, and masticatory function. Multiple regression analysis revealed that changes in the stimulated salivary flow rate due to prosthetic treatment significantly improved C. albicans detection (p = 0.011), intraoral symptoms (p = 0.037), and bite force (p = 0.031). This study showed that prosthetic treatment improved salivary flow and intraoral symptoms and confirmed the influence of stimulated salivary flow rate changes. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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8 pages, 405 KiB

Open AccessArticle

Relationship between Standard Uptake Values of Positron Emission Tomography/Computed Tomography and Salivary Metabolites in Oral Cancer: A Pilot Study

by Shigeo Ishikawa, Toshitada Hiraka, Kazukuni Kirii, Masahiro Sugimoto, Hiroaki Shimamoto, Ayako Sugano, Kenichiro Kitabatake, Yuuki Toyoguchi, Masafumi Kanoto, Kenji Nemoto, Tomoyoshi Soga, Masaru Tomita and Mitsuyoshi Iino

J. Clin. Med. 2020, 9(12), 3958; https://doi.org/10.3390/jcm9123958 - 7 Dec 2020

Cited by 11 | Viewed by 2106

Abstract

¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT) is usually used for staging or evaluation of treatment response rather than for cancer screening. However, ¹⁸F-FDG PET/CT has also been used in Japan for cancer screening in people with no cancer symptoms, and accumulating evidence supports this application of ¹⁸F-FDG PET/CT. Previously, we have observed a correlation between the saliva and tumor metabolomic profiles in patients with oral cancer. Hence, if salivary metabolites demonstrate a significant correlation with PET parameters such as the maximum standardized uptake value (SUV_max), they may have the potential to be used as a screening tool before PET/CT to identify patients with high SUV_max. Hence, in this study, we aimed to explore the relationship between salivary metabolites and SUV_max of ¹⁸F-FDG PET/CT using previously collected data. ¹⁸F-FDG PET/CT was performed for staging 26 patients with oral cancer. The collected data were integrated and analyzed along with quantified salivary hydrophilic metabolites obtained from the same patients with oral cancer and controls (n = 44). In total, 11 metabolites showed significant correlations with SUV_max in the delayed phases. A multiple logistic regression model of the two metabolites showed the ability to discriminate between patients with oral cancer and controls, with an area under the receiver operating characteristic curve of 0.738 (p = 0.001). This study uniquely confirmed a relationship between salivary metabolites and SUV_max of PET/CT in patients with oral cancer; salivary metabolites were significantly correlated with SUV_max. These salivary metabolites can be used as a screening tool before PET/CT to identify patients with high SUV_max, i.e., to detect the presence of oral cancer. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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10 pages, 1577 KiB

Open AccessArticle

Serum Metabolomic Profiling of Patients with Non-Infectious Uveitis

by Hiroyuki Shimizu, Yoshihiko Usui, Masaki Asakage, Naoya Nezu, Ryo Wakita, Kinya Tsubota, Masahiro Sugimoto and Hiroshi Goto

J. Clin. Med. 2020, 9(12), 3955; https://doi.org/10.3390/jcm9123955 - 6 Dec 2020

Cited by 16 | Viewed by 2446

Abstract

The activities of various metabolic pathways can influence the pathogeneses of autoimmune diseases, and intrinsic metabolites can potentially be used to diagnose diseases. However, the metabolomic analysis of patients with uveitis has not yet been conducted. Here, we profiled the serum metabolomes of patients with three major forms of uveitis (Behҫet’s disease (BD), sarcoidosis, and Vogt-Koyanagi-Harada disease (VKH)) to identify potential biomarkers. This study included 19 BD, 20 sarcoidosis, and 15 VKH patients alongside 16 healthy control subjects. The metabolite concentrations in their sera were quantified using liquid chromatography with time-of-flight mass spectrometry. The discriminative abilities of quantified metabolites were evaluated by four comparisons: control vs. three diseases, and each disease vs. the other two diseases (such as sarcoidosis vs. BD + VKH). Among 78 quantified metabolites, 24 kinds of metabolites showed significant differences in these comparisons. Four multiple logistic regression models were developed and validated. The area under the receiver operating characteristic (ROC) curve (AUC) in the model to discriminate disease groups from control was 0.72. The AUC of the other models to discriminate sarcoidosis, BD, and VKH from the other two diseases were 0.84, 0.83, and 0.73, respectively. This study provides potential diagnostic abilities of sarcoidosis, BD, and VKH using routinely available serum samples that can be collected with minimal invasiveness. Full article

(This article belongs to the Special Issue Metabolomic Analysis in Health and Disease)

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