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Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS)

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: 31 May 2026 | Viewed by 9558

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Special Issue Editors

Prof. Dr. Yoshinori Marunaka

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1. Medical Research Institute, Kyoto Industrial Health Association, Kyoto 604-8472, Japan
2. Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
3. Research Organization of Science and Technology, Ritsumeikan University, Kusatsu 525-8577, Japan
Interests: diabetes mellitus; cancer; ion environments; interstitial fluid pH; ion transporters; ion channels
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Prof. Dr. Masayuki Takahashi

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School of Life Science and Technology, Institute of Science Tokyo, Tokyo 152-8550, Japan
Interests: molecular mechanism of homologous recombination; anti-cancer drug design
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Prof. Dr. Yusaku Iwasaki

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Laboratory of Animal Science, Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan
Interests: feeding regulation; glucose metabolism; obesity; diabetes; vagal sensory nerve; hypothalamus; hormones; neuropeptides

Prof. Dr. Atsushi Shiozaki

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Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan
Interests: esophageal cancer, surgical oncology and cellular physiology

Prof. Dr. Akiyuki Taruno

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Department of Molecular Cell Physiology, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan
Interests: ion channels; signaling/ion transport in taste and intestinal epithelia
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue was created in collaboration with the 5th International Symposium on Frontiers in Molecular Science (ISFMS 2025)—Molecular Regulatory Mechanisms of Biological Function and Drug Discovery based on Protein Structure/Function Analysis, which will be held in Kyoto, Japan, from August 26 to 29, 2025. It comprises six sessions. The conference participants are cordially invited to contribute a full manuscript to this Special Issue and receive a 20% discount on the Article Processing Charge.

ISFMS 2025 Sessions:

S1. Protein Structure and Molecular Dynamics

S2. Enzymes

S3. Membrane Proteins

S4. Cancer Target Proteins

S5. Drug Design and Solution to Drug Resistance Problem

S6. Physiological Functions of Proteins and Organ Interactions

Prof. Dr. Yoshinori Marunaka
Prof. Dr. Masayuki Takahashi
Prof. Dr. Yusaku Iwasaki
Prof. Dr. Atsushi Shiozaki
Prof. Dr. Akiyuki Taruno
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

protein structure and function
multidomain proteins
drug design and drug resistance
enzymes
molecular biology of galectins
glycobiophysics
NMR spectroscopy
specific sensory systems
brain and systemic function

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Published Papers (9 papers)

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Research

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20 pages, 7395 KB

Open AccessArticle

Identification of ANT2 as a Druggable Target for Endocrine-Resistant ERα-Positive Breast Cancer

by Erika Iguchi, Motoki Watanabe, Kaito Kobayashi, Shogen Boku, Wataru Nishio, Chikage Kato, Midori Morita, Koichi Sakaguchi, Michihiro Mutoh, Tomoshi Kameda and Yasuto Naoi

Int. J. Mol. Sci. 2026, 27(8), 3704; https://doi.org/10.3390/ijms27083704 - 21 Apr 2026

Viewed by 167

Abstract

Endocrine therapy is the mainstay for estrogen receptor (ER) α-positive breast cancer (BC), yet many patients display acquired resistance. We then screened natural compounds using human ERα-positive BC cells and identified perillyl alcohol (POH), a monoterpene from perilla, that reduces ERα protein levels. Chemoproteome analysis using POH-immobilized nanomagnetic beads revealed adenine nucleotide translocase 2 (ANT2), a mitochondrial inner membrane protein, as a direct target of POH. Molecular dynamics (MD) simulations predicted POH binding to the central pore of ANT2, which functions in ATP transport. ANT2 depletion reduced ERα levels, and public datasets indicate that high ANT2 expression correlates with poor prognosis in ERα-positive BC. POH also inhibited the growth of Tamoxifen- and Fulvestrant-resistant BC cells. RNA sequencing showed that fatty acid elongation-related genes were upregulated in Fulvestrant-resistant cells but downregulated by ANT2 depletion. Both ANT2 depletion and POH treatment led to the accumulation of intracellular lipid droplets in Fulvestrant-resistant cells, consistent with impaired fatty acid elongation. Finally, in silico screening using MD simulations identified venetoclax and nystatin as potential ANT2 pore binders. Both compounds reduced ERα levels in ERα-positive BC cells and increased lipid droplet formation in Fulvestrant-resistant cells. These findings highlight ANT2 as a druggable target against endocrine-resistant BC. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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12 pages, 5067 KB

Open AccessArticle

In Situ Differential Analysis of α- and β-Glycosidase Activities in Lysosomes After Internalization Using Glucosylcerebroside-Based Liposomes

by Yi Wei and Osamu Kanie

Int. J. Mol. Sci. 2026, 27(6), 2749; https://doi.org/10.3390/ijms27062749 - 18 Mar 2026

Viewed by 376

Abstract

Fluorogenic glycosides are widely used substrates for assaying lysosomal glycosidase activities in vitro, but they do not provide subcellular information in living cells. In this study, we used glucosylceramide (GlcCer) liposomes as carriers to deliver fluorogenic substrates into live PC12 cells for confocal imaging. The α-4-methylumbelliferyl glucoside (α-4MUG) and β-glucosidase substrate β-4-(trifluoromethyl)umbelliferyl glucoside (β-4FMUG) were co-encapsulated in liposomes. The liposomes (approximately 100 nm in diameter) were taken up by PC12 cells after pulse exposure. Punctate fluorescence signals from both hydrolyzed substrates were observed. The relative intensity of two signals varied among puncta, as assessed by dual-channel imaging and line-scan analysis. These results show that GlcCer liposomes provide a practical platform for long-term and differential analyses of relative α- and β-glucosidase activities in living cells. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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22 pages, 2918 KB

Open AccessArticle

A Latent Autoantibody Axis Associated with Vascular Vulnerability in Ischemic Stroke: Integrated Statistical and Machine-Learning Analysis

by Tomohiro Sugiyama, Yoichi Yoshida, Takaki Hiwasa, Masaaki Kubota, Seiichiro Mine and Yoshinori Higuchi

Int. J. Mol. Sci. 2026, 27(5), 2465; https://doi.org/10.3390/ijms27052465 - 7 Mar 2026

Viewed by 407

Abstract

Ischemic stroke remains a major cause of mortality and long-term disability worldwide, and improved strategies for identifying individuals at elevated vascular risk are needed. Serum autoantibodies have emerged as potential biomarkers reflecting vascular injury and immune activation; however, their integrative biological significance and incremental predictive value beyond established clinical risk factors remain unclear. We analyzed 833 participants, including patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA) and healthy controls. Serum levels of anti-PDCD11 antibody (Ab), anti-DNAJC2 antibody, and anti-PAI-1 (SERPINE1) antibody were quantified, and multivariable logistic regression and machine-learning (ML) models (logistic regression and random forest) were constructed using clinical variables with and without antibody markers. Model performance was evaluated using cross-validation, bootstrap-derived confidence intervals, calibration metrics, and reclassification indices. Model interpretability analyses, principal component analysis (PCA), unsupervised clustering, and propensity score matching were performed to explore latent biological structures. Clinical-only models demonstrated excellent discrimination (bootstrap Area Under the Curve (AUC) 0.917 for random forest and 0.919 for logistic regression). The addition of antibody markers yielded similar performance (AUC 0.913 and 0.923, respectively) without evidence of meaningful improvement in reclassification. However, SHapley Additive exPlanations (SHAP) analysis identified antibody markers as influential contributors following major clinical risk factors. PCA revealed a dominant antibody component explaining approximately 79% of the variance, which remained independently associated with stroke after age adjustment. Unsupervised clustering further identified a high-risk subgroup characterized by consistently elevated antibody levels. These findings support the presence of a latent antibody axis associated with vascular vulnerability. Although antibody markers did not substantially enhance global predictive performance, they captured integrated biological signals reflecting cumulative vascular and immunological stress. Autoantibody profiling may complement conventional risk assessment by improving biological characterization of stroke susceptibility. Prospective validation in independent cohorts is required prior to clinical implementation. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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16 pages, 1538 KB

Open AccessArticle

GLP-1 Release by Rare Sugar D-Allulose Ameliorates Sucrose-Induced Obesity and Glucose Intolerance in Ovariectomized Mice

by Kengo Iba, Miharu Kyo, Hirotaka Ishihara, Aki Nagao, Misaki Kawabe, Kento Ohbayashi, Toshihiko Yada and Yusaku Iwasaki

Int. J. Mol. Sci. 2026, 27(4), 1651; https://doi.org/10.3390/ijms27041651 - 8 Feb 2026

Cited by 1 | Viewed by 1957

Abstract

Estrogen deficiency after menopause promotes visceral fat accumulation and insulin resistance, thereby increasing the risk of type 2 diabetes. Although hormone replacement therapy is partially effective, its use is limited by increased risks of cardiovascular disease and breast cancer, underscoring the need for safer preventive strategies. The rare sugar D-allulose has been reported to stimulate secretion of glucagon-like peptide-1 (GLP-1), a gut hormone, and improve obesity and glucose metabolism, suggesting its potential as a novel intervention for postmenopausal metabolic dysfunction. Here, we examined whether D-allulose improves obesity and glucose intolerance in a GLP-1-dependent manner under sucrose-fed conditions, using ovariectomized (OVX) female C57BL/6J mice as a model of menopause. OVX mice, but not sucrose-fed sham mice, developed exacerbated visceral obesity and glucose intolerance in response to dietary sucrose, despite similar total energy intake. Daily oral administration of D-allulose for two weeks significantly suppressed visceral fat accumulation, improved insulin resistance, and ameliorated glucose intolerance in sucrose-fed OVX mice. These beneficial effects were markedly attenuated in GLP-1 receptor knockout mice. Taken together, we found that sucrose intake after ovariectomy exacerbates visceral obesity and glucose intolerance, and that D-allulose effectively ameliorates these metabolic abnormalities. GLP-1-stimulating dietary components such as D-allulose may represent a safe and promising preventive strategy for metabolic dysfunction associated with menopause. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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23 pages, 7830 KB

Open AccessArticle

TRPA1 for Butterfly Eyespot Formation

by Momo Ozaki and Joji M. Otaki

Int. J. Mol. Sci. 2026, 27(3), 1420; https://doi.org/10.3390/ijms27031420 - 30 Jan 2026

Cited by 1 | Viewed by 540

Abstract

Butterfly wing color pattern formation is a process of two-dimensional morphogenesis involving long-range lateral signaling in pupal wing tissues. We hypothesized that TRP (transient receptor potential) channels, which are multimodal sensors for various stimuli, are involved in this developmental process. Using the blue pansy butterfly Junonia orithya, we injected the TRPA1 antagonists, AM0902 and AP-18, and an agonist, JT010, into pupae and observed that the eyespot core disk area in adult wings increased and decreased in response to AM0902 and JT010, respectively, although AP-18 did not induce any change. Furthermore, the eyespot outer black ring area increased in response to AM0902, and the orange ring area increased in response to JT010. We detected TRPA1 mRNA via RT-PCR in the pupal wing tissues of this species. An antibody against the J. orithya TRPA1 extracellular site induced unique aberrant color patterns with wing vein defects. These results suggest that TRPA1 is expressed in pupal wing tissue and may integrate signaling information to determine eyespot size and structure in butterfly wings. TRPA1 likely suppresses the black core disk and the outer black ring and enhances the nonblack orange ring in eyespots during development. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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18 pages, 2599 KB

Open AccessArticle

Structure-Functional Examination of Cysteine Synthase A (CysK) from Limosilactobacillus reuteri LR1

by Anastasia A. Pometun, Evgenii K. Les, Alla V. Chernobrovkina, Anastasiia V. Gorbovskaia, Natalia Yu Chikurova, Anastasia A. Loginova, Alexey N. Antipov, Nadezhda N. Mordkovich, Leonid A. Shaposhnikov, Svyatoslav S. Savin, Sergey Yu Kleymenov, Ilya O. Matyuta, Konstantin M. Boyko, Mikhail E. Minyaev, Dmitry M. Hushpulian, Evgenii V. Pometun and Vladimir I. Tishkov

Int. J. Mol. Sci. 2026, 27(1), 327; https://doi.org/10.3390/ijms27010327 - 28 Dec 2025

Viewed by 707

Abstract

This study presents a comprehensive analysis of cysteine synthase A (CysK) from Limosilactobacillus reuteri LR1 (LreCysK), an enzyme involved in the biosynthesis of L-cysteine. This protein supports crucial cellular functions such as sulfur metabolism, antioxidant defense, detoxification, and protein synthesis. Previously, the gene encoding LreCysK was cloned, and the enzyme with His-tag on the N-terminus was obtained in active and soluble form. Here, kinetic parameters of the enzyme were determined by the previously developed high-pressure liquid chromatography (HPLC) and ninhydrin methods. It was found that LreCysK has similar K_M^OAS and k_cat as CysKs from Escherichia coli and from the model plant Arabidopsis thaliana. The thermal stability of LreCysK was studied using differential scanning calorimetry. It was revealed that the melting point of the enzyme increases to almost 90°C when Pyridoxal-5 phosphate (PLP) is added, indicating that the stability of the enzyme complex with PLP is relatively high. Structural studies revealed that LreCysK is a dimer, and its active site is similar to those of other enzymes, but exhibits some features characteristic of lactobacilli CysKs (GISA), as well as unique residues, such as Ile50. Also, the potential biotechnological applications of LreCysK are discussed. These findings enhance our understanding of LreCysK’s biochemical versatility and its potential applications in biotechnology and medicine. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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22 pages, 5064 KB

Open AccessArticle

Discovery of Galloyl–Flavonoid Conjugates as SARS-CoV-2 3CL^pro Inhibitors: Understanding Binding Interactions Through Computational Approaches

by Nopawit Khamto, Panida Boontawee, Vachira Choommongkol, Kritsada Pruksaphon, Suwicha Patnin, Nuttee Suree, Panchika Prangkio and Puttinan Meepowpan

Int. J. Mol. Sci. 2025, 26(19), 9742; https://doi.org/10.3390/ijms26199742 - 7 Oct 2025

Cited by 2 | Viewed by 1807

Abstract

The emergence of SARS-CoV-2 in 2019 posed significant global public health challenges. One of the most promising targets for novel antiviral drug development is the SARS-CoV-2 main protease (3CL^pro). In this study, fragment molecular orbital (FMO) calculations were conducted to provide guidance for the structural modification of natural flavonoids, identifying the pyrogallol moiety as a key candidate. Natural flavonoids were chemically modified to generate 33 semi-synthetic derivatives through the introduction of various functional groups. Our findings revealed that the incorporation of a galloyl moiety significantly enhances anti-proteolytic activity against SARS-CoV-2 3CL^pro, achieving up to a 23-fold increase compared to the activity of the parent compounds. Notably, 7-O-galloyl-DMC (40) exhibited the highest anti-proteolytic activity in an enzymatic assay. Additionally, molecular dynamics simulations provided atomic-level insights into the interactions between the galloyl moiety and 3CL^pro. All galloylated flavonoid derivatives positioned their galloyl groups within the S1′ sub-pocket, facilitating hydrogen bonding and π-interactions, particularly with Thr26 and Leu27. These findings underscore the potential of the galloyl moiety as a crucial structural element for enhancing the binding affinity of flavonoids with inhibitory activity against SARS-CoV-2 3CL^pro. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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22 pages, 2876 KB

Open AccessReview

Pathophysiological Roles of Two Intracellular P-Type ATPases: The Cancer-Associated Na⁺,K⁺-ATPase α3 Isoform and the Parkinson’s Disease-Related ATP13A2

by Takuto Fujii, Takahiro Shimizu and Hideki Sakai

Int. J. Mol. Sci. 2026, 27(4), 1800; https://doi.org/10.3390/ijms27041800 - 13 Feb 2026

Viewed by 687

Abstract

P-type ATPases constitute a diverse superfamily of ATP-driven transporters essential for ion homeostasis, membrane asymmetry, and organelle function. Among them, the P2-type Na⁺,K⁺-ATPase and the P5-type ATP13A2 have recently emerged as key regulators of cancer progression and neurodegeneration, respectively. In this review, we highlight new insights into the pathological roles of the Na⁺,K⁺-ATPase α3 isoform (α3NaK) in malignant cells and ATP13A2 in Parkinson’s disease (PD). Cancer tissues frequently overexpress α3NaK which is aberrantly localized to intracellular vesicles and undergoes adhesion-dependent intracellular trafficking. Upon cell detachment, α3NaK translocates to the plasma membrane to sustain survival signaling, thereby promoting anoikis resistance and facilitating the persistence of circulating tumor cells (CTCs). Cardiac glycosides selectively inhibit α3NaK at nanomolar concentrations, suppressing cancer cell proliferation through GLUT1 endocytosis, metabolic inhibition, and downregulation of THADA and LAT1, ultimately inducing anoikis in CTCs and reducing metastasis in vivo. Conversely, ATP13A2 is genetically linked to early-onset parkinsonism and regulates lysosomal integrity, polyamine homeostasis, and neuronal resilience. Recent animal studies demonstrate that adult-onset ATP13A2 loss causes progressive nigrostriatal degeneration, while heterozygous deficiency produces distinct age-dependent cognitive and α-synuclein phenotypes. Beyond its established role in polyamine transport, emerging evidence suggests that ATP13A2 can function as an H⁺,K⁺-ATPase-like transporter, contributing to proton and cation handling within the endolysosomal system. Together, these findings underscore the broader physiological and pathological significance of intracellular P-type K⁺-ATPases and highlight α3NaK and ATP13A2 as promising therapeutic targets in cancer metastasis and PD. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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12 pages, 251 KB

Open AccessConference Report

Report of the 5th International Symposium on Frontiers in Molecular Science (ISFMS 2025)

by Yoshinori Marunaka, Antonello Merlino, Maria Hrmova, Ye Chun Ruan, Atsushi Shiozaki, Masayuki Takahashi and Yusaku Iwasaki

Int. J. Mol. Sci. 2025, 26(18), 9239; https://doi.org/10.3390/ijms26189239 - 22 Sep 2025

Cited by 1 | Viewed by 1525

Abstract

The 5th International Symposium on Frontiers in Molecular Science was held on 26–29 August 2025 in Kyoto (Japan), with the support of Kyoto Prefectural University and Kyoto Prefectural University of Medicine. It is evident that the event has proven to be significant, showcasing presentations of pioneering research achievements by internationally renowned researchers and fostering numerous stimulating discussions. The symposium’s objective was to identify and select key research themes within the domain of molecular science. Three plenary lecturers and numerous researchers of outstanding merit were invited by chairs to deliver keynote and invited lectures across six fields: S1. Protein Structure and Molecular Dynamics; S2. Enzymes; S3. Membrane Proteins; S4. Cancer Target Proteins; S5. Drug Design and Solution to Drug Resistance Problem; S6. Physiological Functions of Proteins and Organ Interactions. A total of 185 scientists from 31 countries/regions participated in the symposium with 139 presentations. We would like to express our sincere gratitude to the 31 members of the Scientific Committee and the seven members of the Local Organizing Committee who contributed to enhancing the quality of this symposium, ensuring its smooth operation, and dedicating considerable effort to the selection of each award. Full article

(This article belongs to the Special Issue Selected Papers from the 5th International Symposium on Frontiers in Molecular Science (ISFMS))

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