International Journal of Molecular Sciences

16 pages, 2610 KB

Open AccessArticle

Syntaphilin Regulates Epithelial-Mesenchymal Transition and Metastasis in Gastric Cancer via the FAK/NF-κB/MMP-9 Signaling Pathway

by Hye Jin Choi and Jong Min Park

Int. J. Mol. Sci. 2026, 27(15), 6564; https://doi.org/10.3390/ijms27156564 (registering DOI) - 23 Jul 2026

Abstract

Syntaphilin (SNPH), initially considered a neuron-specific protein, has recently been found to be widely expressed across various cancers. Mechanistically, SNPH inhibits mitochondrial transport to the cortical cytoskeleton, thereby suppressing cancer cell migration and metastasis. Although SNPH is known to participate in the metastatic [...] Read more.

Syntaphilin (SNPH), initially considered a neuron-specific protein, has recently been found to be widely expressed across various cancers. Mechanistically, SNPH inhibits mitochondrial transport to the cortical cytoskeleton, thereby suppressing cancer cell migration and metastasis. Although SNPH is known to participate in the metastatic progression of multiple malignancies, its precise underlying mechanism remains obscure. In this study, we investigated the role of SNPH in the epithelial–mesenchymal transition (EMT) and invasiveness of gastric cancer cells. Knockdown of SNPH in SNU-638 gastric cancer cells significantly enhanced their migratory and invasive capacities by approximately 1.4-fold and 2.5-fold, respectively. This knockdown concurrently increased focal adhesion kinase (FAK) phosphorylation, upregulated the EMT marker vimentin, and increased the expression of key EMT-related transcription factors, including Snail, Slug, and Twist. Furthermore, SNPH depletion induced the phosphorylation of nuclear factor kappa B (NF-κB), a transcription factor regulating matrix metalloproteinase-9 (MMP-9), which subsequently upregulated MMP-9 mRNA expression. This cascade promotes extracellular matrix degradation, thereby increasing metastatic potential. Notably, these phenotypic and molecular changes were completely reversed upon SNPH overexpression in SNU-638 cells. Taken together, our results demonstrate that SNPH deficiency enhances the migration and metastatic potential of gastric cancer cells by driving EMT and invasion via the FAK/NF-κB/MMP-9 signaling pathway. Consequently, we propose that SNPH represents a novel biomarker and a promising therapeutic target for mitigating gastric cancer metastasis. Full article

(This article belongs to the Special Issue Molecular and Signaling Pathways in Pathological Changes of Esophageal, Gastric and Intestinal Epithelial Cells and Methods of Cell Protective Treatment)

35 pages, 1961 KB

Open AccessArticle

Amphiphilic Semisynthetic Triterpenoids Impair Survival Pathways and Suppress Clonogenic Growth in Multidrug-Resistant High-Risk Neuroblastoma

by Silvana Alfei, Cinzia Domenicotti, Sara Tirendi, Elaheh Khaledizadeh, Dafni Graikioti, Constantinos M. Athanassopoulos, Guendalina Zuccari, Caterina Reggio and Barbara Marengo

Int. J. Mol. Sci. 2026, 27(15), 6563; https://doi.org/10.3390/ijms27156563 (registering DOI) - 23 Jul 2026

Abstract

High-risk neuroblastoma (HR-NB) remains a major clinical challenge due to the emergence of therapy resistance. In this study, the anticancer effects of seven previously synthesized betulin (BET), betulinic acid (BA) and ursolic acid (UA) derivatives (1–7) and of their [...] Read more.

High-risk neuroblastoma (HR-NB) remains a major clinical challenge due to the emergence of therapy resistance. In this study, the anticancer effects of seven previously synthesized betulin (BET), betulinic acid (BA) and ursolic acid (UA) derivatives (1–7) and of their natural precursors BET, BA and UA (8–10) were investigated in HTLA NB cells, selected as the experimental model by MTT assay, to find a possible solution to drugs that have lost their effect. Dynamic light scattering (DLS) analysis showed that amphiphilic compounds 1 and 4–7 form nanovesicles (240–448 nm) in water, while all compounds have high positive ζ-potential (ζ-p, +28.5–+83.1 mV), supporting favourable membrane interaction and cellular uptake. Cytotoxic experiment results and related IC₅₀ values were expressed as the mean ± SD of four independent experiments run in triplicate. Most derivatives exhibited a cytotoxic activity higher than that of their natural precursors and outperformed etoposide; they were particularly effective against the multidrug resistant (MDR) HTLA ER cells. Among them, the ursolic acid (UA) derivative 7 emerged as the most active compound, displaying sub-micromolar to low micromolar IC₅₀ values and markedly improving the activity of native UA. Functional studies revealed that it induces complete suppression of clonogenic growth at low micromolar concentrations in both HTLA ER and parental HTLA 230 NB cells. In addition, a concentration-dependent downregulation of Akt, p-Akt, BMI1 and PARP, was observed consistently with a marked suppression of survival pathways and loss of cellular homeostasis. Collectively, our experiments, which need further direct investigation to confirm subsequent assumption, could suggest that compound 7 could kill cancer cells via a non-apoptotic, bioenergetic collapse mechanism. All of these findings suggest compound 7 as a promising mitochondria-targeted lead candidate and support amphiphilic triterpenoid derivatives as attractive platforms for overcoming multidrug resistance in high-risk NB. Full article

(This article belongs to the Collection Feature Papers in Molecular Oncology)

24 pages, 4042 KB

Open AccessArticle

α2-3-Sialylated Glycoproteins Attenuate Streptococcus mutans Virulence and Associated Host Inflammatory Responses

by Xiameng Ren, Lingyun Wei, Tao Liu, Min Wang, Ziyi Chang, Jian Shu and Zheng Li

Int. J. Mol. Sci. 2026, 27(15), 6562; https://doi.org/10.3390/ijms27156562 (registering DOI) - 23 Jul 2026

Abstract

Glycans attached to host glycoproteins play an important role in regulating oral microbial colonization and maintaining community balance. Our previous studies revealed that children exhibit lower levels of α2-3 sialylated glycan structures (SAα2-3Gal) than adults, raising the possibility that this age-associated glycan deficiency [...] Read more.

Glycans attached to host glycoproteins play an important role in regulating oral microbial colonization and maintaining community balance. Our previous studies revealed that children exhibit lower levels of α2-3 sialylated glycan structures (SAα2-3Gal) than adults, raising the possibility that this age-associated glycan deficiency contributes to the heightened cariogenicity of Streptococcus mutans. In this study, sialylated glycoproteins (Sia-GP) and corresponding desialylated controls (DeSia-GP and α2,3-DeSia-GP) were prepared from bovine milk-derived glycoproteins to investigate the functional contribution of SAα2-3Gal. Their effects on S. mutans were evaluated by assessing bacterial growth, acid production, biofilm formation and extracellular polysaccharide synthesis, while a human oral keratinocytes (HOK cells) infection model was used to examine epithelial cell viability, wound healing, and infection-associated inflammatory responses. The results showed that Sia-GP exerted only a transient inhibitory effect on early bacterial growth without affecting final biomass, but significantly attenuated acidogenic activity, biofilm formation, and extracellular polysaccharides production in a concentration-dependent manner. These inhibitory effects were markedly attenuated following removal of α2-3-linked sialic acids, demonstrating the essential role of SAα2-3Gal. In addition, Sia-GP alleviated S. mutans-induced cellular damage in HOK cells by improving cell viability, colony formation, and migration, while suppressing infection-associated inflammatory signaling. Collectively, these findings demonstrate that SAα2-3Gal effectively limits multiple virulence traits of S. mutans and attenuates S. mutans-induced damage in oral epithelial cells. This study provides mechanistic insights into glycan-mediated regulation of host–microbe interactions and suggests that the naturally low abundance of SAα2-3Gal in children may increase their susceptibility to S. mutans infection and caries development. Full article

(This article belongs to the Section Molecular Biology)

23 pages, 2968 KB

Open AccessArticle

Komagataella phaffii Encodes Two Functional Pho4 Transcription Factors

by Marcel Albacar, Asier González, Rui Wang, Antonio Casamayor and Joaquín Ariño

Int. J. Mol. Sci. 2026, 27(15), 6561; https://doi.org/10.3390/ijms27156561 (registering DOI) - 23 Jul 2026

Abstract

The transcription factor Pho4 is crucial for the response to phosphate starvation in many fungi, and it has been linked to tolerance to alkalinization of the medium and to pathogenicity. It is widely accepted that it is encoded by a single gene. However, [...] Read more.

The transcription factor Pho4 is crucial for the response to phosphate starvation in many fungi, and it has been linked to tolerance to alkalinization of the medium and to pathogenicity. It is widely accepted that it is encoded by a single gene. However, the industrially relevant yeast Komagataella phaffii might contain two Pho4-encoding genes (PAS_chr1-1_0265 and PAS_chr2-1_0177, designated here PHO4(A) and PHO4(B), respectively), which have never been functionally characterized. The phenotypic analysis of single and double mutants suggests that Pho4(B) plays a major role in the adaptation to Pi scarcity. While single mutants exhibited limited and non-overlapping phenotypic defects, the pho4(A) pho4(B) strain was sensitive to multiple types of stress, including phosphate starvation and alkaline pH. Transcriptomic analysis confirms that Pho4(B) is crucial for the transcriptional response to phosphate starvation, including induction of typical gene markers (PHO5, PHO89, VTC1, etc.). However, by using a GFP reporter, we found that PHO4(A) also participates in the induction of PHO89 under high pH stress. Expression of both PHO4(A) and PHO4(B) in Saccharomyces cerevisiae complemented the pho4 mutation under phosphate limitation by restoring growth, expression of the Pho84 transporter, and secreted phosphatase activity. Therefore, both transcription factors display partially overlapping functions, respond differently to diverse stimuli, and together constitute a key component in the adaptation to multiple stresses. Full article

(This article belongs to the Section Molecular Microbiology)

22 pages, 3136 KB

Open AccessArticle

Intracellular Ca²⁺ Modulates PKA Compartmentalization and Dynamics in Human iPSC-Derived Cardiomyocytes

by Anat Rotschield, Savyon Mazgaoker, Sofia Segal, Ido Weiser-Bitoun, Inbar Brosh, Ofer Binah and Yael Yaniv

Int. J. Mol. Sci. 2026, 27(15), 6559; https://doi.org/10.3390/ijms27156559 (registering DOI) - 23 Jul 2026

Abstract

The automaticity of human-induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) is governed by coupled Ca²⁺ and membrane clocks, coordinated through local Ca²⁺ releases (LCRs) and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling. We investigated the role of PKA in hiPSC-CM energetics [...] Read more.

The automaticity of human-induced Pluripotent Stem Cell-derived cardiomyocytes (hiPSC-CMs) is governed by coupled Ca²⁺ and membrane clocks, coordinated through local Ca²⁺ releases (LCRs) and cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling. We investigated the role of PKA in hiPSC-CM energetics by measuring its dynamics in the cytosol and mitochondria, and its crosstalk with Ca²⁺. We tested three hypotheses: (i) Ca²⁺-activated PKA signaling regulates energy balance; (ii) adenylyl cyclase activity correlates with spontaneous beating; and (iii) PKA compartmentalization is Ca²⁺-dependent. We also compared hiPSC-CMs with rabbit sinoatrial node cells (SANCs). The key findings are: (i) PKA inhibition (H-89), Ca²⁺ chelation (BAPTA), or mitochondrial Ca²⁺ blockade (Ru360) led to energy imbalance; (ii) H-89 induced compartmentalized PKA activity in the cytosol, mitochondrial matrix, and outer mitochondrial membrane; (iii) Ca²⁺ chelation with BAPTA reduced PKA activity globally; and (iv) PKA dynamics and Ca²⁺-dependent regulation were similar in hiPSC-CMs and rabbit SANCs. In conclusion, intracellular Ca²⁺-mediated PKA compartmentalization is present in hiPSC-CMs and rabbit SANCs. Full article

(This article belongs to the Collection Calcium Homeostasis and Dynamics in Life and Health)

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12 pages, 1660 KB

Open AccessArticle

Alpha2-Antiplasmin Limits Fibrinolysis by Tenecteplase and Enhances Brain Injury After Reperfusion in Ischemic Stroke

by Satish Singh, Sofiyan Saleem, Ryan D. Sullivan and Guy L. Reed

Int. J. Mol. Sci. 2026, 27(15), 6558; https://doi.org/10.3390/ijms27156558 (registering DOI) - 23 Jul 2026

Abstract

A bioengineered version of recombinant tissue plasminogen activator, i.e., tenecteplase (TNK-tPA), was designed to have a longer half-life, resistance to plasminogen activator inhibitor-1, and fibrin-targeted plasminogen activation. By comparison to tPA, clinical trials suggest that TNK-tPA may be less susceptible to the effects [...] Read more.

A bioengineered version of recombinant tissue plasminogen activator, i.e., tenecteplase (TNK-tPA), was designed to have a longer half-life, resistance to plasminogen activator inhibitor-1, and fibrin-targeted plasminogen activation. By comparison to tPA, clinical trials suggest that TNK-tPA may be less susceptible to the effects of alpha2-antiplasmin (α2AP), the primary inhibitor of thrombus dissolution. However, preclinical studies are limited, and whether α2AP affects TNK-tPA’s fibrinolytic activity or efficacy in experimental ischemic stroke is unknown. We examined the effects of TNK-tPA and α2AP on the dissolution of human plasma clots (in vitro) and experimental ischemic brain injury from stroke induced by transient middle cerebral artery ischemia. TNK-tPA induced a dose-dependent increase in plasma clot dissolution; inhibition of α2AP with a specific monoclonal antibody caused a synergistic increase in TNK-tPA-mediated clot dissolution. In experimental ischemic stroke with ischemia and reperfusion, TNK-tPA treatment of α2AP^−/− mice significantly reduced ischemic infarct volume, brain swelling, brain hemorrhage, and neurobehavioral disability vs. TNK-tPA-treated α2AP^+/+ (C57BL/6 background) mice with normal α2AP levels (p < 0.05 to p < 0.0001). α2AP impairs the dissolution of human clots in vitro by TNK-tPA and significantly exacerbates ischemic brain injury, swelling, hemorrhage, and neurobehavioral disability after experimental stroke, even with reperfusion. Targeting α2AP may improve the efficacy of TNK-tPA and reduce hemorrhagic complications. Full article

(This article belongs to the Special Issue The Role of Fibrinolytic Factors in Disease)

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22 pages, 47799 KB

Open AccessArticle

Genome-Wide Identification of the GELP Family in Juglans mandshurica Reveals Their Potential Roles in Seed Development and Stress Responses

by Meng Dang, Rui Wang, Zhenlin Shen, Fan Wu, Changcong Yan, Qianyu Wang and Huijuan Zhou

Int. J. Mol. Sci. 2026, 27(15), 6557; https://doi.org/10.3390/ijms27156557 (registering DOI) - 23 Jul 2026

Abstract

GDSL esterase/lipases (GELPs) are important regulators of plant growth and development, lipid metabolism, and stress responses. However, their genomic characteristics and expression patterns have not been systematically characterized for Juglans mandshurica, a woody oil crop species of significant ecological and economic value. [...] Read more.

GDSL esterase/lipases (GELPs) are important regulators of plant growth and development, lipid metabolism, and stress responses. However, their genomic characteristics and expression patterns have not been systematically characterized for Juglans mandshurica, a woody oil crop species of significant ecological and economic value. Here, we identified 61 JmGELP genes in J. mandshurica through genome-wide analysis. Phylogenetic analysis classified them into seven major clades, and variations in gene structure and conserved motifs suggested potential functional divergence. Promoter cis-acting element analysis revealed widespread enrichment of motifs responsive to light, phytohormones, and abiotic stresses. Transcriptomic sequencing and qRT-PCR validation revealed distinct tissue-specific and seed development stage-specific expression patterns of JmGELP members, as well as their differential responses to various stress and hormone treatments. Gene Ontology (GO) annotation and protein–protein interaction (PPI) network analyses further supported their involvement in lipid metabolism. In silico analyses of transcription factor binding sites, miRNA targets, and molecular docking predicted that JmGELP-3, -38, and -41 have distinct transcriptional and post-transcriptional regulatory networks and potentially divergent substrate preferences. This study provides the first comprehensive characterization of the GELP family in J. mandshurica, identifying candidate genes that may inform future germplasm improvement and stress-resistance breeding in Juglans species. Full article

(This article belongs to the Special Issue Plant Molecular Ecology and Genomic Perspectives)

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19 pages, 3014 KB

Open AccessArticle

Structural Remodeling of TCR–HLA-DQ8 Recognition by a β-Cell Stress-Associated C19S Insulin Neoepitope in Type 1 Diabetes

by Rahul Mittal, Farhad Alipour, Prem Chapagain and Khemraj Hirani

Int. J. Mol. Sci. 2026, 27(15), 6556; https://doi.org/10.3390/ijms27156556 (registering DOI) - 23 Jul 2026

Abstract

Inflammatory and oxidative stress within the pancreatic islet microenvironment can alter insulin-derived peptides and generate neoepitopes that may reshape autoreactive T cell recognition in type 1 diabetes (T1D). One such modification, C19S, represents a cysteine-to-serine substitution at position 19 of the insulin B-chain [...] Read more.

Inflammatory and oxidative stress within the pancreatic islet microenvironment can alter insulin-derived peptides and generate neoepitopes that may reshape autoreactive T cell recognition in type 1 diabetes (T1D). One such modification, C19S, represents a cysteine-to-serine substitution at position 19 of the insulin B-chain and has recently been identified among human leukocyte antigen class II (HLA-II)-associated insulin neoepitopes recognized by autoreactive CD4+ T cells. Although the biological relevance of C19S has been determined, the molecular features that may distinguish C19S-specific T cell receptor (TCR) engagement from native insulin recognition remain incompletely defined. Here, we used comparative protein–protein docking, molecular dynamics (MD) simulations, interface-contact analysis, conformational landscape analysis, and binding-energy calculations to examine TCR engagement of human leukocyte antigen DQ8 (HLA-DQ8) presenting either native insulin peptide or the corresponding C19S insulin peptide. Initial modeling indicated that both peptide-HLA-DQ8 complexes were compatible with TCR-bound ternary complex formation. However, the C19S-containing complex was predicted to exhibit altered peptide-centered dynamics, changes in peptide backbone presentation, and reorganization of both TCR-peptide and TCR-HLA-DQ8 contacts. Comparative molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) and molecular mechanics generalized Born surface area (MM/GBSA) analyses further suggested a distinct calculated energetic profile under the applied modeling conditions for the C19S-containing complex, with residue-level decomposition localizing energetic differences to selected interface hotspots. Together, these findings provide a molecular framework for generating hypotheses about how C19S may reshape the HLA-DQ8-presented insulin recognition surface, with implications for future experimental studies of autoreactive CD4+ T cell recognition and antigen-specific tolerogenic strategies in T1D. Full article

(This article belongs to the Section Biochemistry)

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23 pages, 1318 KB

Open AccessArticle

Docking Analysis of Drugs Used in the Treatment of Alzheimer’s Disease, Using Cell Membrane Receptors and Enzymes of the Kynurenine Pathway: A Pilot Study

by Abdulla A. B. Badawy, Shazia Dawood, Felix I. L. Clanchy, Richard O. Williams and Trevor W. Stone

Int. J. Mol. Sci. 2026, 27(15), 6555; https://doi.org/10.3390/ijms27156555 (registering DOI) - 23 Jul 2026

Abstract

Molecular docking in silico techniques were used to assess the interactions between several drugs used in the treatment of Alzheimer’s disease (AlzD) with neuronal receptors and with tryptophan and glycolytic pathway enzymes. AlzD drugs believed to act by inhibiting acetylcholinesterase (AChE) docked to [...] Read more.

Molecular docking in silico techniques were used to assess the interactions between several drugs used in the treatment of Alzheimer’s disease (AlzD) with neuronal receptors and with tryptophan and glycolytic pathway enzymes. AlzD drugs believed to act by inhibiting acetylcholinesterase (AChE) docked to that enzyme, whereas other drugs did not. No docking was observed to the nicotinic acetylcholine receptor (α-7-nAChR). All the drugs tested docked to the kainic acid receptor for glutamate, whereas donepezil, galantamine, tropisetron and N-acetylcysteine docked to the glutamate-NMDA receptor, but none docked to the glutamate-AMPA receptor. Two compounds docked to GABA receptors. Since the kynurenine pathway of tryptophan metabolism has been linked to AlzD, docking was examined with its various enzymes. Docking to tryptophan-2,3-dioxygenase (TDO2), indoleamine-2,3-dioxygenase-1 (IDO1) and 2-amino-3-carboxymuconic acid-6-semialdehyde decarboxylase was seen with most of the AlzD drugs. Donepezil docked to kynurenine monooxygenase, while rivastigmine, memantine and tropisetron docked to kynurenine aminotransferase-2. There was limited docking to the aryl hydrocarbon receptor and glycolytic enzymes, whereas most drugs docked to phosphoenolpyruvate carboxykinase (PEPCK). Despite their strong docking ability to IDO1 and TDO, none of the compounds tested inhibited their enzyme activity in an assay of kynurenine production. This pilot study highlights the varied pharmacological profile of drugs used in AlzD and suggests that a detailed examination of their functional effects should be considered to assist understanding of their different profiles at on- and off- target sites in human treatment. Full article

(This article belongs to the Section Molecular Neurobiology)

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36 pages, 8606 KB

Open AccessReview

Metainflammation, Mitochondrial Dysfunction, and Organokine Crosstalk: A Central Axis Linking Metabolic Syndrome to Cardiovascular Diseases

by Ana Flávia Pontes Sodré, Lucca Gonsales Rodrigues, Kátia P. Sloan, Lance A. Sloan, Masaru Tanaka, Rui Curi, Larissa Naomi Takeda, Ricardo de Alvares Goulart, Ana Luiza Decanini Miranda de Souza, Claudia Rucco Penteado Detregiachi, Antonelly Cassio Alves Carvalho, Ricardo J. Tofano, Elen Landgraf Guiguer, Adriano Cressoni Araújo, Claudio J. Rubira, Anupam Bishayee, Vitor E. Valenti and Sandra Maria Barbalho

Int. J. Mol. Sci. 2026, 27(15), 6554; https://doi.org/10.3390/ijms27156554 (registering DOI) - 23 Jul 2026

Abstract

Metabolic Syndrome (MetS) is a complex and multifactorial condition characterized by insulin resistance, visceral obesity, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which contribute to increased cardiovascular risk. Central to its pathophysiology is metainflammation, a persistent inflammatory state closely linked to oxidative [...] Read more.

Metabolic Syndrome (MetS) is a complex and multifactorial condition characterized by insulin resistance, visceral obesity, dyslipidemia, hypertension, and chronic low-grade inflammation, all of which contribute to increased cardiovascular risk. Central to its pathophysiology is metainflammation, a persistent inflammatory state closely linked to oxidative stress and mitochondrial dysfunction. This review aims to provide an integrated and updated overview of the interplay between metainflammation, oxidative stress, mitochondrial dysfunction, and organokine signaling in the development and progression of MetS and its cardiovascular complications. Current evidence indicates that mitochondrial dysfunction plays a pivotal role by promoting excessive production of reactive oxygen species (ROS), impairing ATP synthesis, and disrupting redox balance, thereby exacerbating insulin resistance and endothelial dysfunction. In parallel, dysregulated secretion of organokines—including adipokines, myokines, hepatokines, cardiokines, osteokines, and renokines—alters interorgan communication and amplifies pro-inflammatory and atherogenic pathways. Additionally, gut microbiota contributes to metabolic homeostasis through the production of short-chain fatty acids, whereas dysbiosis is associated with worsening metabolic parameters. Collectively, these interconnected mechanisms establish a self-perpetuating cycle that drives metabolic dysfunction and cardiovascular disease progression. This review highlights the central role of the metainflammation–mitochondrial dysfunction axis and emphasizes the importance of organokine-mediated crosstalk as a key regulator of systemic metabolism. Targeting these pathways may represent a promising strategy for the prevention and management of MetS and its associated complications. Full article

(This article belongs to the Special Issue Evolving Landscape of Cardiovascular Pathophysiology)

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16 pages, 4735 KB

Open AccessArticle

AI-Predicted Model-Guided Rebuilding of the Experimental Structure of Mouse δ-Aminolevulinic Acid Dehydratase

by Ki Hyun Nam

Int. J. Mol. Sci. 2026, 27(15), 6553; https://doi.org/10.3390/ijms27156553 (registering DOI) - 23 Jul 2026

Abstract

Experimental macromolecular structures are foundational for elucidating molecular mechanisms and guiding drug design and protein engineering. However, inaccurate structural models are occasionally deposited in the Protein Data Bank (PDB), potentially confounding structural analyses and misleading subsequent studies. Although the integration of artificial intelligence [...] Read more.

Experimental macromolecular structures are foundational for elucidating molecular mechanisms and guiding drug design and protein engineering. However, inaccurate structural models are occasionally deposited in the Protein Data Bank (PDB), potentially confounding structural analyses and misleading subsequent studies. Although the integration of artificial intelligence (AI)-predicted models to improve experimentally determined structures has been proposed, the impact of AI-guided rebuilding on functional interpretation remains largely uncharacterized. Here, AI-predicted models of δ-aminolevulinic acid dehydratase (ALAD) were analyzed, and a misinterpreted region in its original crystal structure was rebuilt using an AlphaFold3 (AF3) model as a template. The incorrectly modeled region between Cys122 and Leu142 was corrected utilizing the AF3 main-chain conformation. This rebuilding decreased the R_free value and improved structural geometry compared to the experimental structure. Notably, the initially deposited ALAD structure exhibited an inactive conformation characterized by a disrupted substrate-binding A-site. In contrast, the AI-rebuilt ALAD model restored a biologically relevant active-site conformation, featuring a coordinated zinc-binding pocket, mediated by Cys122, Cys124, and Cys132, and an intact substrate-binding configuration at the A-site. These results demonstrate the feasibility of AI-predicted model-guided rebuilding in the present ALAD case and may provide a basis for future studies evaluating its applicability to other protein systems. Full article

(This article belongs to the Special Issue Interdisciplinary Molecular Design: Catalysis, Therapeutics, and Biomaterials)

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19 pages, 9937 KB

Open AccessReview

Comprehensive Review on Doping Strategies for Two-Dimensional Tungsten Diselenide

by Donghun Lee

Int. J. Mol. Sci. 2026, 27(15), 6552; https://doi.org/10.3390/ijms27156552 - 23 Jul 2026

Abstract

Two-dimensional transition metal dichalcogenides are being studied as channel materials for beyond-silicon electronics because their atomic-scale thickness enables strong electrostatic control. Among these materials, tungsten diselenide (WSe₂) is particularly attractive because it exhibits ambipolar transport. Despite this advantage, practical WSe₂ [...] Read more.

Two-dimensional transition metal dichalcogenides are being studied as channel materials for beyond-silicon electronics because their atomic-scale thickness enables strong electrostatic control. Among these materials, tungsten diselenide (WSe₂) is particularly attractive because it exhibits ambipolar transport. Despite this advantage, practical WSe₂ transistors remain constrained by Fermi-level pinning at metal contacts, contact-dominated carrier injection, and defect-induced variability, making controlled doping a central issue. This review examines doping strategies developed for WSe₂, focusing on methods compatible with atomically thin van der Waals semiconductors. The discussion covers surface charge-transfer doping by molecular adsorbates, Lewis acids, and alkali metals, as well as defect-mediated chemisorption, self-limiting oxide interfacial layers, and in situ vacancy engineering during growth. Particular attention is given to the thermodynamic mechanisms of charge transfer, the distinction between contact-selective and channel-selective doping, and the trade-offs between degenerate and non-degenerate doping. The effects of doping are also discussed, including contact-resistance reduction through Schottky-barrier narrowing, threshold-voltage control, apparent mobility enhancement through impurity screening and defect passivation, and thermal and temporal stability. The review further summarizes how controlled doping has enabled complementary metal-oxide-semiconductor logic circuits and identifies the remaining challenges in air stability, selective-area patterning, scalable synthesis, and low-temperature integration for monolithic three-dimensional electronic devices. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in "Materials Science" Section)

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1 pages, 139 KB

Open AccessCorrection

Correction: Kaniowski et al. EGFR-Targeted Cellular Delivery of Therapeutic Nucleic Acids Mediated by Boron Clusters. Int. J. Mol. Sci. 2022, 23, 14793

by Damian Kaniowski, Justyna Suwara, Katarzyna Ebenryter-Olbińska, Agata Jakóbik-Kolon and Barbara Nawrot

Int. J. Mol. Sci. 2026, 27(15), 6551; https://doi.org/10.3390/ijms27156551 - 23 Jul 2026

Abstract

In the original publication [...] Full article

(This article belongs to the Special Issue Implication of Nanoparticles in Cancer Therapy Research)

27 pages, 1354 KB

Open AccessReview

Neuro-Renal Crosstalk Across the Chronic Kidney Disease Spectrum: Stage-Dependent Molecular Mechanisms of Cognitive Impairment—An Integrative Review

by Piotr Olejnik, Dominika Kurzawa, Jolanta Małyszko and Aleksandra Golenia

Int. J. Mol. Sci. 2026, 27(15), 6550; https://doi.org/10.3390/ijms27156550 - 23 Jul 2026

Abstract

Chronic kidney disease (CKD) is a major public health problem worldwide, affecting over 10% of the global population, and its prevalence continues to increase. In addition to classic comorbidities, including cardiovascular and metabolic disorders, cognitive impairment (CI) has recently been recognized as a [...] Read more.

Chronic kidney disease (CKD) is a major public health problem worldwide, affecting over 10% of the global population, and its prevalence continues to increase. In addition to classic comorbidities, including cardiovascular and metabolic disorders, cognitive impairment (CI) has recently been recognized as a serious complication of CKD. CI can be observed across the entire spectrum of CKD, from G1 to G5 stages, independent of age-related changes. The kidney–brain axis seems to provide a conceptual framework in which microvascular disease, blood–brain barrier disruption, uremic toxins, oxidative stress, systemic inflammation, and consequent neuroinflammation converge to promote CI. This narrative review aims to synthesize the existing evidence on stage-dependent molecular mechanisms of CI in CKD, integrating clinical observations with proposed molecular and pathophysiological mechanisms. Because most studies investigating CI in CKD rely primarily on eGFR-based staging, our analysis was structured around GFR categories, assessing early-to-moderate CKD, defined according to KDIGO as G1–G3 stages, advanced CKD stages, including G4–G5 not yet requiring kidney replacement therapies, and kidney failure treated with different modalities of kidney replacement therapy, such as peritoneal dialysis, hemodialysis, and kidney transplantation. In addition to clinical observations and the burden of CI in CKD, we describe the potential stage-dependent pathomechanisms underlying vascular-executive, uremic-toxic, inflammatory, dialysis-hemodynamic, and post-transplant medication-related profiles as a continuum of cognitive disorders in individuals with CKD. Full article

(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)

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18 pages, 2211 KB

Open AccessCommunication

Primer-Less Species Identification Throughout Fungal (Tuber magnatum), Plant (Corylus avellana) and Animal (Eisenia fetida) Kingdoms by Direct RNA Sequencing

by Tadeusz Malewski, Slavica Matić, Aleksandra Gabriela Bilska, Maria Alexandra Cucu, Laura Miozzi, Antonietta Mello, Andrzej Skwiercz, Tomasz Oszako and Justyna Anna Nowakowska

Int. J. Mol. Sci. 2026, 27(15), 6549; https://doi.org/10.3390/ijms27156549 - 23 Jul 2026

Abstract

Accurate species identification is essential for biodiversity studies, ecological monitoring, and biosecurity, but current molecular approaches rely on PCR amplification, which requires universal primers. Here, we evaluated the possibility of primer-free species identification via direct RNA sequencing (dRNA-seq) by using Oxford Nanopore Technology [...] Read more.

Accurate species identification is essential for biodiversity studies, ecological monitoring, and biosecurity, but current molecular approaches rely on PCR amplification, which requires universal primers. Here, we evaluated the possibility of primer-free species identification via direct RNA sequencing (dRNA-seq) by using Oxford Nanopore Technology (ONT). Total RNA isolated from three major eukaryotic kingdoms—fungal (Tuber magnatum Picco 1788), plant (Corylus avellana L. 1753), and animal (Eisenia fetida Savigny 1826) specimens—was sequenced without reverse transcription and PCR amplification. Taxonomic assignments based on similarity to ribosomal nuclear (fungi and animals) and chloroplast (plant) transcripts enabled reliable host species identification. Ribosomal RNA reads dominated the datasets and supported accurate identification of the target organisms, while additional sequences revealed associated microbiota and co-occurring taxa. Notably, dRNA-seq successfully detected symbiotic bacteria in E. fetida and latent fungal infection in C. avellana, highlighting the method sensitivity. However, the complex organization of nuclear ribosomal gene clusters may complicate taxonomic assignment in plants, underscoring the need for improved analytical pipelines. Overall, our results provide proof of concept that dRNA-seq enables primer-independent species identification while simultaneously providing insights into the host microbiomes. Direct sequencing of naturally present RNA molecules generated sufficient sequence information for species identification across different taxonomic kingdoms, indicating the technical feasibility of the developed technique. Further validation using larger biological datasets and direct comparisons with conventional sequencing methods will determine its wider applicability as an innovative and complementary species identification approach. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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21 pages, 579 KB

Open AccessReview

Quercetin in COPD: A Multi-Target Approach to Modulate Inflammation, Oxidative Stress, and Epithelial Dysfunction

by Priyanka Sarkar and Umadevi Sajjan

Int. J. Mol. Sci. 2026, 27(15), 6548; https://doi.org/10.3390/ijms27156548 - 23 Jul 2026

Abstract

Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder that affects millions of people globally. Although the mechanisms of COPD pathogenesis are not completely known, oxidative stress and lung inflammation caused by chronic exposure to cigarette smoke, environmental or occupational pollutants, gas [...] Read more.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disorder that affects millions of people globally. Although the mechanisms of COPD pathogenesis are not completely known, oxidative stress and lung inflammation caused by chronic exposure to cigarette smoke, environmental or occupational pollutants, gas from burning biomass fuel are thought to contribute to development of COPD. Therefore, therapies aimed at reducing oxidative stress along with inflammation may be important in treating COPD. However, the current pharmacological therapies treat symptoms and reduce acute exacerbations, but do not treat the root cause of COPD. Quercetin is a plant polyphenol present in berries, apples and onions, and has potent antioxidant and anti-inflammatory properties. Quercetin inhibits oxidative stress by scavenging reactive oxidant species and promoting expression of antioxidant enzymes. It reduces inflammation by inhibiting various kinases that participate in the expression of pro-inflammatory cytokines. It also alters gene expression by functioning as an epigenetic modifier. Quercetin also acts as antiviral agent by attenuating viral entry and replication. In preclinical models of COPD, quercetin reduces oxidative stress, lung inflammation, goblet cell metaplasia, expression of matrix metalloprotease MMP-9 and MMP-12, and prevents rhinovirus-induced progression of emphysema. It also promotes normal regeneration of airway epithelium by improving cell polarization, reducing goblet cell hyperplasia and increasing number of ciliated cells. This review compiles the current understanding of the biological properties of quercetin and its potential therapeutic role in COPD. We also summarize its potential benefits over the current therapeutic drugs used to treat COPD. Full article

(This article belongs to the Special Issue Plant-Derived Bioactives: Antioxidant Mechanisms and Preventive Health Strategies)

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19 pages, 1675 KB

Open AccessArticle

Whole Tumor Heterogeneity Topography (WTHT)—A New Approach for Assessment of Intratumor Mutational Heterogeneity in Colorectal Adenomas

by Tereza Halkova, Lucia Hodasova Pauerova, Karolina Blechova, Tereza Benesova, Tomas Grega, Nadija Brodyuk, Eva Traboulsi, Katerina Hejcmanova, Ondrej Ngo, Jan Bures, Stepan Suchanek and Lucie Benesova

Int. J. Mol. Sci. 2026, 27(15), 6547; https://doi.org/10.3390/ijms27156547 - 23 Jul 2026

Abstract

Intratumor heterogeneity (ITH) of premalignant colorectal lesions is an important area of research for understanding the diverse biological behavior of colorectal cancer (CRC). Accurate assessment of ITH depends substantially on the sampling strategy used. We present a novel methodological approach termed whole tumor [...] Read more.

Intratumor heterogeneity (ITH) of premalignant colorectal lesions is an important area of research for understanding the diverse biological behavior of colorectal cancer (CRC). Accurate assessment of ITH depends substantially on the sampling strategy used. We present a novel methodological approach termed whole tumor heterogeneity topography (WTHT) and compare it with three previously described sampling strategies: whole tumor homogenization, macrodissection of selected tumor regions, and multisampling. A cohort of 184 advanced precancerous colorectal lesions was processed into paraffin blocks, and the entire tumor mass was systematically divided into equally sized samples (~10 mm³). DNA was isolated from each sample separately and analyzed for hotspot mutations in APC, KRAS, BRAF, PIK3CA, and TP53. ITH was quantified using mutation variance and a newly introduced Heterogeneity Grade (HG). Results obtained by WTHT were statistically and graphically compared with three other modeled sampling strategies. Significant differences were observed among the analyzed sampling approaches. Macrodissection showed the greatest deviation from WTHT, indicating substantial sampling bias, whereas multisampling produced the closest results. WTHT enabled precise quantification and spatial mapping of mutational clones across the entire lesion. WTHT combined with HG provides a robust and reproducible framework for comprehensive assessment of ITH in colorectal adenomas. Full article

(This article belongs to the Special Issue Gene Mutations in Cancer)

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22 pages, 25236 KB

Open AccessArticle

ROS-Responsive Micelles Loaded with Podophyllotoxin Inhibit Tumor Growth via ROS Self-Amplification and Regulation of Survivin and p21 Expression

by Shuaiheng Song, Qiang Shao, Siyi Liang, Haoyang Du, Qingnan Zhao, Jing Guan, Ping Lin and Feng Lin

Int. J. Mol. Sci. 2026, 27(15), 6546; https://doi.org/10.3390/ijms27156546 - 23 Jul 2026

Abstract

Podophyllotoxin (PPT) inhibits tumors such as lung cancer and breast cancer. However, it has poor water solubility and causes gastrointestinal dysfunction and bone marrow suppression, which severely limit its clinical application. Based on the differential reactive oxygen species (ROS) levels between tumor microenvironments [...] Read more.

Podophyllotoxin (PPT) inhibits tumors such as lung cancer and breast cancer. However, it has poor water solubility and causes gastrointestinal dysfunction and bone marrow suppression, which severely limit its clinical application. Based on the differential reactive oxygen species (ROS) levels between tumor microenvironments and normal tissues, we designed and constructed a ROS-responsive micelle delivery system, successfully fabricating blank micelles (M) and PPT-loaded micelles (M@PPT). Both micelles exhibited good particle size uniformity, colloidal stability, and biosafety. The ROS responsiveness experiment revealed that, after incubating blank micelles (M) with 10 mM H₂O₂, the particle size increased significantly, and the size distribution broadened. High-performance liquid chromatography (HPLC) confirmed the release of cinnamaldehyde from the micelles upon H₂O₂ exposure. Additionally, DCFH-DA assays demonstrated that treatment with blank micelles (M) enhanced intracellular ROS levels. In vitro release studies showed that drug-loaded micelles (M@PPT) achieved 77.76% cumulative PPT release within 24 h in a buffer containing 10 mM H₂O₂, significantly exceeding the release observed in the H₂O₂-free control group. These results collectively validate the ROS-responsive disintegration of micelles and the subsequent release of cinnamaldehyde. The liberated cinnamaldehyde further amplified intracellular ROS levels, establishing a positive feedback loop that accelerated drug release. Cellular assays revealed superior tumor growth inhibition by M@PPT over free PPT, mediated through apoptosis induction, G2/M phase cell cycle arrest, downregulation of the anti-apoptotic protein Survivin, and upregulation of the p21 protein. In vivo studies further confirmed the enhanced antitumor efficacy and improved biosafety of M@PPT compared to free PPT. This ROS-responsive micellar system, by enabling tumor-targeted drug delivery and controlled release, provides a novel strategy to optimize the clinical utility of podophyllotoxin-based chemotherapeutics. Full article

(This article belongs to the Section Molecular Biology)

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1 pages, 129 KB

Open AccessRetraction

RETRACTED: Kim et al. Neuroprotective Effect of Statins in a Rat Model of Chronic Ocular Hypertension. Int. J. Mol. Sci. 2021, 22, 12500

by Mi-Lyang Kim, Kyung Rim Sung, Junki Kwon, Go Woon Choi and Jin-A Shin

Int. J. Mol. Sci. 2026, 27(15), 6545; https://doi.org/10.3390/ijms27156545 - 23 Jul 2026

Abstract

The Journal retracts the article “Neuroprotective Effect of Statins in a Rat Model of Chronic Ocular Hypertension” [...] Full article

(This article belongs to the Section Biochemistry)

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