International Journal of Molecular Sciences

25 pages, 1037 KB

Open AccessReview

Osteoporosis in Patients with Pre-Existing Diabetes Mellitus and in Women with Estrogen Deficiency: A Molecular and Cellular Perspective

by Chin-Yen Pang, Li-Ru Chen and Kuo-Hu Chen

Int. J. Mol. Sci. 2026, 27(3), 1453; https://doi.org/10.3390/ijms27031453 (registering DOI) - 31 Jan 2026

Abstract

Osteoporosis is a prevalent metabolic bone disorder characterized by reduced bone mass, compromised microarchitecture, and increased fracture risk. Its pathogenesis extends beyond simple bone mineral density (BMD) loss and reflects complex disruptions in bone remodeling governed by osteoblast–osteoclast coupling and systemic metabolic factors. [...] Read more.

Osteoporosis is a prevalent metabolic bone disorder characterized by reduced bone mass, compromised microarchitecture, and increased fracture risk. Its pathogenesis extends beyond simple bone mineral density (BMD) loss and reflects complex disruptions in bone remodeling governed by osteoblast–osteoclast coupling and systemic metabolic factors. This review lays particular emphasis on diabetes mellitus-related osteoporosis (DOP) and estrogen deficiency-induced osteoporosis (EDOP), discussing bone remodeling between osteoclastogenesis and osteoblast differentiation regulated by key signaling pathways, including the RANKL/RANK/OPG, Wnt/β-catenin, BMP–Smad, Hedgehog, and inflammatory cytokine networks. This review then explores how chronic hyperglycemia, insulin deficiency or resistance, oxidative stress, ferroptosis, advanced glycation end products, and low-grade inflammation disrupt bone homeostasis in diabetes, resulting in impaired bone quality and elevated fracture risk, particularly in type 2 diabetes. In parallel, we discuss the genomic and non-genomic actions of estrogen in maintaining skeletal integrity and elucidate how estrogen deficiency accelerates bone resorption and suppresses bone formation through altered cytokine signaling, oxidative stress, and impaired mechanotransduction. Advances in diagnostic strategies beyond BMD, including trabecular bone score, high-resolution peripheral quantitative computed tomography, and emerging biomarkers, are reviewed. Finally, this review summarizes current and emerging therapeutic approaches tailored to DOP and EDOP, emphasizing the need for mechanism-based, individualized management. A deeper understanding of these shared and distinct pathways may facilitate improved risk stratification and the development of targeted interventions for osteoporosis. Full article

(This article belongs to the Special Issue Hormone Metabolism and Signaling in Human Health and Disease)

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17 pages, 648 KB

Open AccessReview

Microbiome Signatures in Advanced Gastric Cancer: Emerging Biomarkers for Risk Stratification, Therapy Guidance, and Prognostic Insight

by Kyung-il John Kim, Hannah Zhong, Derek Tai, Pranati Shah, Daniel Park, Vitor Goes, Jianan Li, Claire Jung, Lucas Kim, Sofia Guzman, Gagandeep Brar and Dani Castillo

Int. J. Mol. Sci. 2026, 27(3), 1452; https://doi.org/10.3390/ijms27031452 (registering DOI) - 31 Jan 2026

Abstract

Gastric cancer (GC), often diagnosed at advanced or metastatic stages, remains a significant clinical challenge requiring novel biomarkers for early detection, risk stratification, and effective, personalized treatment optimization. Emerging evidence underscores a strong association between gut microbiome dysbiosis and GC initiation, progression, and [...] Read more.

Gastric cancer (GC), often diagnosed at advanced or metastatic stages, remains a significant clinical challenge requiring novel biomarkers for early detection, risk stratification, and effective, personalized treatment optimization. Emerging evidence underscores a strong association between gut microbiome dysbiosis and GC initiation, progression, and therapeutic outcomes. This review explores the potential of the advanced/metastatic gastric microbiome as a source of diagnostic and targetable biomarkers and its role in modulating responses to immunotherapy. Although Helicobacter pylori (H. pylori) is the most significant risk factor for GC, several other gastrointestinal taxa—including Fusobacterium nucleatum (F. nucleatum)—have been implicated in advanced GC (AGC). At its inception, microbial dysbiosis contributes to chronic inflammation and immune evasion, thereby influencing tumor behavior and treatment efficacy. Integrating microbiome-based biomarkers into risk stratification, GC staging, and targetable treatment frameworks may enhance early detection, inform immunotherapy strategies, and improve patient-specific treatment responses. Bifidobacterium and Lactobacillus rhamnosus GG have the potential to change the immunotherapy framework with their direct influence on dendritic cell (DC) and cytotoxic T cell (CTL) activity. However, clinical translation is impeded by methodological heterogeneity, causality limitations, and a lack of clinical trials. Nonetheless, the integration of microbiome profiling and the development of therapeutic microbiome modulation strategies, such as personalized probiotics regimens and fecal microbiota transplantation, hold substantial potential for improving clinical outcomes and reducing treatment-related toxicity in GC management. Full article

(This article belongs to the Special Issue Molecular Targets in Gastrointestinal Diseases)

17 pages, 407 KB

Open AccessArticle

Twenty-Four-Month rhGH Intervention: Insights into Redox Regulation, Vascular Biomarkers, and Body Composition in Adult GHD Patients

by Maria Kościuszko, Angelika Buczyńska, Justyna Hryniewicka, Agnieszka Adamska, Katarzyna Siewko, Marcin Zaniuk, Adam Jacek Krętowski and Anna Popławska-Kita

Int. J. Mol. Sci. 2026, 27(3), 1451; https://doi.org/10.3390/ijms27031451 (registering DOI) - 31 Jan 2026

Abstract

Adult growth hormone deficiency (GHD) is linked to increased cardiovascular and metabolic risk due to oxidative stress (OS), endothelial dysfunction, and unhealthy body composition. Long-term systemic effects of recombinant human growth hormone (rhGH) therapy remain insufficiently defined. This study assessed the impact of [...] Read more.

Adult growth hormone deficiency (GHD) is linked to increased cardiovascular and metabolic risk due to oxidative stress (OS), endothelial dysfunction, and unhealthy body composition. Long-term systemic effects of recombinant human growth hormone (rhGH) therapy remain insufficiently defined. This study assessed the impact of 24-month rhGH replacement on OS, vascular markers, body composition, and bone mineral density (BMD) in adults with severe GHD. Fifteen adults with confirmed GHD received rhGH for 24 months. Serum insulin-like growth factor 1 (IGF-1), oxidized LDL (Ox-LDL), thioredoxin (Trx), 8-oxoguanine DNA glycosylase 1 (OGG1), E-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) were measured at baseline and 12 and 24 months. Body composition and BMD were evaluated by DXA. IGF-1 increased significantly at 12 and 24 months (p < 0.001). Ox-LDL markedly decreased (p < 0.00001), while Trx and OGG1 increased (p < 0.05). Levels of E-selectin, ICAM-1, and VCAM-1 declined, indicating improved endothelial function. Lean body mass and BMD increased, while body fat parameters showed heterogeneous changes. Lipid profiles were unchanged. Significant correlations were observed between vascular markers and adiposity, and between BMD, triglycerides, and IGF-1. A 24-month course of rhGH therapy improves redox balance, vascular function, and body composition in adults with severe GHD, supporting the use of redox and vascular biomarkers to monitor treatment efficacy. Full article

(This article belongs to the Special Issue Hormone Replacement Therapy)

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16 pages, 1401 KB

Open AccessArticle

Unveiling Specificity, Redundancy, and Promiscuity of Five Saccharomyces cerevisiae Mitochondrial Carriers

by Pawel Lojko, Lyubomir Dimitrov Stanchev, Felicia Cara Schulz, Christoph Crocoll, Carlos G. Acevedo-Rocha and Irina Borodina

Int. J. Mol. Sci. 2026, 27(3), 1450; https://doi.org/10.3390/ijms27031450 (registering DOI) - 31 Jan 2026

Abstract

The transport of metabolites across biological membranes is vital for normal cellular functions, including nutrient uptake, homeostasis, and toxin efflux. In eukaryotes, mitochondrial transporters in the inner mitochondrial membrane (IMM) play a pivotal role in energy production, metabolism, and the biosynthesis of a [...] Read more.

The transport of metabolites across biological membranes is vital for normal cellular functions, including nutrient uptake, homeostasis, and toxin efflux. In eukaryotes, mitochondrial transporters in the inner mitochondrial membrane (IMM) play a pivotal role in energy production, metabolism, and the biosynthesis of a wide range of compounds. While functional assignments exist for over half of the mitochondrial transporters, emerging high-throughput methodologies underscore the need for reassessment and expansion of the current knowledge, particularly as evidence suggesting functional redundancy and substrate promiscuity has emerged. In this study, we investigated the substrate specificity of five yeast mitochondrial transporters—Crc1 (YOR100c), Ctp1 (YBR291c), Oac1 (YKL120w), Pet9 (YBL030c), and Yhm2 (YMR241w)—via heterologous gene expression in Xenopus laevis oocytes and liquid chromatography-mass spectrometry (LC-MS)-based transport assays. We used two substrate mixtures: a 17-compound organic acid mix and a ¹³C-labeled yeast metabolite extract. Our results revealed broader substrate specificities than previously reported, as partially supported by substrate docking simulations. Pet9 transported several organic acids and amino acids, while Yhm2 showed uptake of nine amino acids and fumaric acid. Additional promiscuous transport activity was observed for Crc1, indicating that these proteins may have more extensive metabolic roles than previously known. This study advances the understanding of yeast mitochondrial transporter function, demonstrating redundancy and broad substrate specificity among mitochondrial carriers. It highlights the importance of utilizing in vivo heterologous systems and physiologically relevant substrate mixtures to elucidate transporter functionality. Full article

(This article belongs to the Special Issue Mitochondria: Transport of Metabolites Across Biological Membranes)

20 pages, 6823 KB

Open AccessArticle

Chronic Stress Leads to Time-Dependent Bone Loss Through HPA Axis Dysregulation and GR Nuclear Translocation Disorder

by Yupeng Yan, Jiaxin Li, Zhengmin Lu, Zhiguo Zhang, Gaimei Hao, Yukun Zhao, Haixia Liu, Yanjun Liu, Xiangxin Bao, Mengya Duan and Yubo Li

Int. J. Mol. Sci. 2026, 27(3), 1449; https://doi.org/10.3390/ijms27031449 (registering DOI) - 31 Jan 2026

Abstract

Chronic stress and sustained hypothalamic–pituitary–adrenal (HPA) axis activation are major contributors to metabolic bone diseases, including osteoporosis. However, the precise molecular mechanisms by which chronic stress-induced HPA axis dysregulation drives bone deterioration remain unclear. A Chronic Unpredictable Mild Stress (CUMS) model was established [...] Read more.

Chronic stress and sustained hypothalamic–pituitary–adrenal (HPA) axis activation are major contributors to metabolic bone diseases, including osteoporosis. However, the precise molecular mechanisms by which chronic stress-induced HPA axis dysregulation drives bone deterioration remain unclear. A Chronic Unpredictable Mild Stress (CUMS) model was established in male rats to simulate prolonged stress exposure. Animals were randomly allocated into three groups: control, 10-week CUMS, and 20-week CUMS (n = 10/group). Model validity was confirmed via behavioral assessments. Bone mineral density (BMD) and trabecular microarchitecture were quantified using micro-computed tomography (micro-CT). Serum corticosterone (CORT) levels, HPA axis negative feedback function, and the expression of pro-inflammatory cytokines (IL-1β, TNF-α) in HPA-regulatory brain regions (hippocampus, prefrontal cortex, hypothalamus) were assessed. Critically, glucocorticoid receptor (GR) expression and nuclear translocation in these brain regions and bone tissue were examined by immunofluorescence and Western blot analysis. CUMS exposure induced progressive, time-dependent bone loss, with the 20-week group exhibiting significantly greater reductions in BMD and trabecular quality compared to the 10-week and control groups. While the HPA axis showed initial hyperactivation, the 20-week group displayed adrenal exhaustion (reduced serum CORT) alongside elevated ACTH, indicating feedback failure. Mechanistically, stress significantly impaired GR nuclear translocation in both brain and bone tissues, coinciding with the upregulation of FKBP5 and pro-inflammatory cytokines. Notably, despite low systemic CORT at late stages, skeletal 11β-HSD1 expression was significantly upregulated, creating a local microenvironment of glucocorticoid toxicity that aggravated osteoblast apoptosis. Our findings demonstrate that chronic stress induces progressive, time-dependent bone loss through a cascade of HPA axis dysregulation and impaired GR signaling. The FKBP5-mediated impairment of GR nuclear translocation in both central and peripheral tissues fosters glucocorticoid resistance, perpetuating hypercortisolemia and a pro-inflammatory milieu that directly accelerates osteoblast apoptosis and bone deterioration. These findings identify the HPA-GR axis as a critical pathway linking chronic stress to osteoporosis and suggest that restoring GR signaling offers a potential therapeutic strategy. Full article

(This article belongs to the Special Issue Metabolic Regulators of Bone Health)

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14 pages, 1619 KB

Open AccessArticle

Integrative Analysis of Placental Methylomes Identifies Epigenetically Regulated Genes Implicated in Fetal Growth Restriction

by Magdalena Bednarek-Jędrzejek, Olga Taryma-Leśniak, Małgorzata Poniatowska, Mateusz Cejko, Katarzyna Maksym, Sylwia Dzidek, Małgorzata Blatkiewicz, Ewa Kwiatkowska, Andrzej Torbé and Sebastian Kwiatkowski

Int. J. Mol. Sci. 2026, 27(3), 1448; https://doi.org/10.3390/ijms27031448 (registering DOI) - 31 Jan 2026

Abstract

Fetal growth restriction (FGR) is a major contributor to perinatal morbidity and mortality, most commonly arising from placental dysfunction, with increasing evidence implicating aberrant DNA methylation in its pathogenesis. To identify robust epigenetic alterations associated with FGR, we analyzed placental chorionic villi from [...] Read more.

Fetal growth restriction (FGR) is a major contributor to perinatal morbidity and mortality, most commonly arising from placental dysfunction, with increasing evidence implicating aberrant DNA methylation in its pathogenesis. To identify robust epigenetic alterations associated with FGR, we analyzed placental chorionic villi from an in-house early-onset FGR cohort and compared them with a publicly available dataset (GSE100197). DNA methylation profiling was performed using Illumina EPIC (in-house) and 450K (public) arrays, processed with identical normalization and quality-control pipelines, including adjustment for gestational age and estimation of placental cell-type composition. Differentially methylated positions (DMPs) were identified using linear regression models, revealing 10,427 DMPs in the in-house cohort and 7467 in the public dataset, with 108 shared DMPs showing consistent direction of change across both cohorts. Promoter-associated DMPs were mapped to genes involved in angiogenesis, morphogenesis, immune regulation, and transcriptional control, including EPHA1, ANGPTL6, ITGAX, BCL11B, and CYP19A1, while additional novel candidates such as SLC39A12, YEATS4, and MIR515 family members were also identified. Functional annotation suggests that these methylation changes may influence pathways essential for placental vascular development and structural organization. Overall, this cross-cohort comparison highlights reproducible epigenetic signatures of FGR and underscores the need for standardized approaches to clarify the molecular mechanisms underlying placental insufficiency. Full article

(This article belongs to the Special Issue Molecular Pathology of the Placenta in Pregnancy Complications)

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29 pages, 5846 KB

Open AccessArticle

Chemical Profiling, Ampicillin Interaction Patterns, and Exploratory Molecular Docking of Lauraceae Essential Oils

by Anca Hulea, Florin Imbrea, Doris Floares (Oarga), Iuliana Popescu, Mukhtar Adeiza Suleiman, Calin Hulea, Ilinca Merima Imbrea, Alina-Georgeta Neacșu, Marinel Horablaga, Cosmin Alin Popescu and Diana Obistioiu

Int. J. Mol. Sci. 2026, 27(3), 1447; https://doi.org/10.3390/ijms27031447 (registering DOI) - 31 Jan 2026

Abstract

This study compares the chemical composition, antimicrobial effects, and antibiotic-potentiating capacity of three Lauraceae essential oils (EO): Cryptocarya agathophylla (CAEO), Litsea cubeba (LCEO), and Laurus nobilis (LNEO). Gas chromatography–mass spectrometry (GC–MS) analysis revealed distinct chemotypes: CAEO and LCEO were dominated by oxygenated monoterpenes, [...] Read more.

This study compares the chemical composition, antimicrobial effects, and antibiotic-potentiating capacity of three Lauraceae essential oils (EO): Cryptocarya agathophylla (CAEO), Litsea cubeba (LCEO), and Laurus nobilis (LNEO). Gas chromatography–mass spectrometry (GC–MS) analysis revealed distinct chemotypes: CAEO and LCEO were dominated by oxygenated monoterpenes, while LNEO contained the highest levels of monoterpene hydrocarbons. Antibacterial testing against nine bacterial strains showed strain-dependent growth suppression trends, while true minimum inhibitory concentrations (MICs) were reached only in selected cases. EO–ampicillin interactions were evaluated using MIC-based checkerboard criteria, whereas OD-derived inhibition parameters were used exclusively to describe sub-MIC potentiation trends. In combination assays, LNEO exhibited the most pronounced potentiating effects against Streptococcus pyogenes, Shigella flexneri, and Haemophilus influenzae, while CAEO and LCEO showed moderate or strain-dependent enhancement. Hierarchical clustering highlighted distinct oil- and strain-specific interaction profiles. Overall, although CAEO displayed stronger intrinsic antibacterial effects when tested alone, LNEO emerged as the most effective potentiator of ampicillin activity in a strain-dependent manner. The effects of the major compounds identified in the Lauraceae EO were assessed in silico against protein targets of some microorganisms using the AutoDock software. The docking scores revealed binding affinities of the bioactive compounds towards Dpr protein (4.3–5.8 kcal/mol), DNA gyrase (4.7–7.1 kcal/mol), mono- diacylglycerol lipase (4.4–6.2 kcal/mol), CYP51 (5.8–8.0 kcal/mol), phage-encoded quorum sensing anti-activator (5.8–8.0 kcal/mol) and Chondroitin ABC lyase I (4.8–6.3 kcal/mol). Two (2) hit compounds (α-Citral, β-Citral) were finely defined by strong hydrophobic and hydrophilic interactions with the bacterial and fungal protein targets, respectively. Full article

(This article belongs to the Special Issue Rational Design and Synthesis of Bioactive Molecules, 2nd Edition)

14 pages, 3735 KB

Open AccessArticle

Quantitative Measurement of Hexoses by Betaine Aldehyde Derivatisation

by Paulina Kret-Bułat, Przemysław Mielczarek, Paweł Link-Lenczowski, Giuseppe Grasso, Piotr Suder and Anna Bodzon-Kulakowska

Int. J. Mol. Sci. 2026, 27(3), 1446; https://doi.org/10.3390/ijms27031446 (registering DOI) - 31 Jan 2026

Abstract

Hexoses, particularly glucose, are one of the most essential molecules for sustaining life; therefore, reliable methods for their analysis are very important. In our study, we present a qualitative and quantitative approach for analysing hexoses using MALDI IMS (Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry [...] Read more.

Hexoses, particularly glucose, are one of the most essential molecules for sustaining life; therefore, reliable methods for their analysis are very important. In our study, we present a qualitative and quantitative approach for analysing hexoses using MALDI IMS (Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging) with betaine aldehyde derivatisation and a CHCA (α-Cyano-4-hydroxycinnamic acid) matrix in positive ionisation mode. In this study, we demonstrated betaine aldehyde derivatisation of glucose from dried droplets and explored the analysis of hexoses in brain and liver tissue slices. We assessed whether our method could distinguish between mannose, galactose, glucose, and fructose and optimised the preparation of a biomimetic calibration curve using stable-isotope labelled glucose for hexose analysis. For this purpose, we investigated the number of betaine aldehyde layers required to obtain a proper calibration curve; examined whether changes in the spray nozzle position during CHCA matrix deposition could facilitate analysis and investigated how storage conditions influenced the calibration curve analysis. Finally, we optimised the technique for liver and brain analysis and assessed variations in hexose levels between brain, liver, kidney, and spinal cord tissues from control and morphine-addicted animals. We hope that our biomimetic approach to creating the calibration curve will be helpful for quantitative analysis and aid in developing various quantitative methods for assessing endogenous substances. Full article

(This article belongs to the Section Biochemistry)

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27 pages, 1161 KB

Open AccessArticle

Essential Role of LapD in the Absence of Cardiolipins

by Satish Raina, Akshay Maniyeri, Aravind Ayyolath and Gracjana Klein

Int. J. Mol. Sci. 2026, 27(3), 1445; https://doi.org/10.3390/ijms27031445 (registering DOI) - 31 Jan 2026

Abstract

To maintain the integrity of the outer membrane of Gram-negative bacteria, such as Escherichia coli, the levels of two essential components, phospholipids (PL) and lipopolysaccharide (LPS), are tightly regulated, although the underlying molecular mechanisms are unclear. E. coli synthesizes three main [...] Read more.

To maintain the integrity of the outer membrane of Gram-negative bacteria, such as Escherichia coli, the levels of two essential components, phospholipids (PL) and lipopolysaccharide (LPS), are tightly regulated, although the underlying molecular mechanisms are unclear. E. coli synthesizes three main PLs, including essential phosphatidylethanolamine and phosphatidylglycerol and nonessential cardiolipin (CL). We showed that CL synthesis is conditionally essential in ΔlapD bacteria. Using this synthetic lethal phenotype, we isolated suppressors that rescued growth at elevated temperatures. We showed that loss-of-function mutations in cdsA encoding CDP-diglyceride synthetase, and pgsA, which encodes phosphatidylglycerophosphate synthase, bypass this lethality. Such mutations reduce the relative abundance of acidic phospholipids, which are otherwise elevated in Δ(lapD clsA) bacteria, and increase the amounts of cis-vaccenic acid without altering amounts of LpxC mediating the first committed step in LPS biosynthesis. Interestingly, overexpression of genes, including accC and glnB, whose products can inhibit fatty acid/PL synthesis, overcame the lethality of Δ(lapD clsA) bacteria. We demonstrated that PgsA co-purifies with LapB, which regulates LpxC stability and acts as a hub for proteins involved in PL and LPS biosynthesis, including LapD. Overall, our results reveal that LapD is positioned at the regulatory nexus between LPS assembly and fatty acid/PL synthesis. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in Molecular Microbiology)

16 pages, 2856 KB

Open AccessArticle

Morphology-Driven Enhancement of Alkaline OER Performance in Spinel NiCo₂O₄ Nanosheet Electrodes

by Abu Talha Aqueel Ahmed, Abu Saad Ansari, Sangeun Cho and Atanu Jana

Int. J. Mol. Sci. 2026, 27(3), 1444; https://doi.org/10.3390/ijms27031444 (registering DOI) - 31 Jan 2026

Abstract

The oxygen evolution reaction (OER) is a critical anodic process in alkaline water electrolysis, and its catalytic performance can be effectively regulated through rational morphology engineering that governs active-site exposure, mass transport, and charge-transfer kinetics. Herein, we report a precursor-controlled synthesis of spinel [...] Read more.

The oxygen evolution reaction (OER) is a critical anodic process in alkaline water electrolysis, and its catalytic performance can be effectively regulated through rational morphology engineering that governs active-site exposure, mass transport, and charge-transfer kinetics. Herein, we report a precursor-controlled synthesis of spinel NiCo₂O₄ (NCO) catalysts with tunable two-dimensional architectures for efficient alkaline OER. By employing hexamethylenetetramine (H) and urea (U) as precipitating agents, the NiCo₂O₄ catalysts with distinctly different nanosheet morphologies were directly grown on nickel foam. The NCO-H catalyst exhibits substantially enhanced OER activity by achieving lower overpotential of 259 mV, a smaller Tafel slope of 84 mV dec^–1, and higher turnover frequency compared to NCO-U catalyst. The superior OER performance is attributed to an ultrathin, highly interconnected nanosheet network that provides abundant accessible active sites, shortened ion-diffusion pathways, and accelerated interfacial charge transfer. Moreover, the optimized electrode demonstrates excellent durability (50 h) with negligible potential degradation after the partial surface transformation into an oxyhydroxide-rich active phase, while post-stability polarization and impedance analyses confirm the preservation of catalytic integrity. These findings highlight precursor-regulated morphology engineering as an effective strategy for optimizing the electrocatalytic performance of spinel oxides and establish NiCo₂O₄ as a robust, earth-abundant OER catalyst for alkaline water-splitting applications. Full article

(This article belongs to the Special Issue Molecularly Engineered Nanomaterials for Energy Conversion, Storage, and AI-Driven Materials Discovery)

26 pages, 5584 KB

Open AccessReview

Molecular Mechanisms of NF-Y Transcription Factors in Horticultural Plant Development and Stress Responses: Recent Advances

by Mengxia Zhang, Dan Chen and Chunjuan Dong

Int. J. Mol. Sci. 2026, 27(3), 1443; https://doi.org/10.3390/ijms27031443 (registering DOI) - 31 Jan 2026

Abstract

Nuclear Factor Y (NF-Y) transcription factors are evolutionarily conserved regulators that bind the CCAAT box, playing central roles in horticultural plant growth and adaptation. This review summarizes recent progress on NF-Ys in horticultural plants, focusing on their molecular mechanisms in development and stress [...] Read more.

Nuclear Factor Y (NF-Y) transcription factors are evolutionarily conserved regulators that bind the CCAAT box, playing central roles in horticultural plant growth and adaptation. This review summarizes recent progress on NF-Ys in horticultural plants, focusing on their molecular mechanisms in development and stress responses. For development, NF-Ys mediate phase transition, flowering regulation, embryogenesis, and organ development by integrating endogenous signals (gibberellic acid, GA; abscisic acid, ABA) and regulating downstream genes. For stress responses, they enhance tolerance to abiotic stresses (drought, salt, extreme temperatures) via regulating reactive oxygen species (ROS) scavenging, ABA biosynthesis, and stress networks, and mediate biotic stress resistance (e.g., pathogen infection) by activating defense pathways. This review also briefly covers species-specific genomic features (e.g., duplication-driven expansion) and structural traits (conserved core domains, variable termini) underpinning NF-Y specialization. Finally, it highlights key knowledge gaps (e.g., incomplete regulatory networks, limited translational application) and proposes future directions: deciphering NF-Y crosstalk, exploring combined stress responses, accelerating functional validation of uncharacterized NF-Y genes, and translating research into horticultural breeding. This work provides a holistic reference for understanding NF-Y function and improving horticultural plant yield, quality, and stress resilience. Full article

(This article belongs to the Special Issue Transcriptional Regulation in Plant Development: 3rd Edition)

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13 pages, 842 KB

Open AccessArticle

A Transcriptome Study on Seed Germination of Nitraria roborowskii Kom

by Shangfu Ren and Guanghui Lv

Int. J. Mol. Sci. 2026, 27(3), 1442; https://doi.org/10.3390/ijms27031442 (registering DOI) - 31 Jan 2026

Abstract

Nitraria roborowskii Kom. seeds possess pronounced deep dormancy traits. Analyzing changes in gene expression before and after dormancy release is of great significance for elucidating the mechanisms underlying seed dormancy. In this study, transcriptome sequencing and bioinformatics analysis were conducted on N. roborowskii [...] Read more.

Nitraria roborowskii Kom. seeds possess pronounced deep dormancy traits. Analyzing changes in gene expression before and after dormancy release is of great significance for elucidating the mechanisms underlying seed dormancy. In this study, transcriptome sequencing and bioinformatics analysis were conducted on N. roborowskii seeds both before and after dormancy release using high-throughput Illumina NovaSeq 6000 sequencing technology. The key findings are as follows: (1) A total of 215,303 transcripts and 84,450 unigenes were obtained through de novo assembly. (2) Comparative analysis revealed 16,130 significantly differentially expressed unigenes during germination, with 10,776 upregulated and 5354 downregulated. Gene Ontology (GO) enrichment analysis indicated that these differentially expressed genes (DEGs) were primarily associated with biological processes and molecular functions, mainly involved in metabolic processes and catalytic activities. (3) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that the DEGs were predominantly enriched in pathways such as plant hormone signal transduction and starch and sucrose metabolism. Specifically, among the downregulated genes, 126 were linked to plant hormone signal transduction, 110 to phenylpropanoid biosynthesis, 108 to starch and sucrose metabolism, 27 to flavonoid biosynthesis, 20 to plant hormone signal transduction, 6 to phenylpropanoid metabolism, 14 to starch and sucrose metabolism, and none to flavonoid biosynthesis. Full article

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

17 pages, 2590 KB

Open AccessArticle

Serum Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Differential Biomarkers of Response to Dimethyl Fumarate and Ocrelizumab in Multiple Sclerosis

by Alessandra Mingione, Andrea Corona, Corinne Monzani, Alen Zollo, Carola Cirocco, Tiziana Zaccone, Mariangela Scavone, Gian Marco Podda, Paola Signorelli, Monica Miozzo, Alberto Priori and Filippo Martinelli-Boneschi

Int. J. Mol. Sci. 2026, 27(3), 1441; https://doi.org/10.3390/ijms27031441 (registering DOI) - 31 Jan 2026

Abstract

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Quantifying neuronal damage is a critical step for patient care. Neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are the most promising serum biomarkers reflecting neuronal damage and astroglial activation, respectively. [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Quantifying neuronal damage is a critical step for patient care. Neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are the most promising serum biomarkers reflecting neuronal damage and astroglial activation, respectively. This study analyzed sNfL and sGFAP in 177 MS patients and 71 healthy controls (HCs) using SIMOA technology, classifying patients as responders (Rs) or non-responders (NRs) based on “No Evidence of Disease Activity 3” (NEDA-3) status during two years of treatment. Longitudinal analyses were performed for Dimethyl fumarate (DMF) and Ocrelizumab (OCRE) treatment. Biomarker–age correlation analysis in HCs confirmed correlation between both NfL and GFAP, with age and cut-off values specific for age decades being calculated. Both biomarkers were higher in MS patients compared to HCs. sNfL showed a significant increase in NR patients overall. In contrast, sGFAP was elevated in the low-to-moderate-efficacy treatment agents (LETAs) NR group and also in the DMF NR subgroup, suggesting that it monitors persistent astrogliosis. Longitudinal analysis showed that both biomarkers decreased during DMF treatment after one year. During OCRE treatment, sNfL rapidly reduced to HC levels within one year, while sGFAP decreased only after two years. This highlights that OCRE acts differently on the pathological processes linked to the two biomarkers. Full article

(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)

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23 pages, 2487 KB

Open AccessArticle

Transplantation of Soluble Epoxide Hydrolase Inhibitor-Treated Human Brown Adipocytes Promotes Adipose Tissue Activation in High-Fat-Diet-Fed Nude Mice

by Haoying Wu, Xinyun Xu, Jiangang Chen, Christophe Morisseau, Bruce D. Hammock, Yu-Hua Tseng and Ling Zhao

Int. J. Mol. Sci. 2026, 27(3), 1440; https://doi.org/10.3390/ijms27031440 (registering DOI) - 31 Jan 2026

Abstract

Brown adipose tissue (BAT) plays a key role in non-shivering thermogenesis and is a promising target for enhancing energy expenditure to combat obesity. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that catalyzes the conversion of epoxy fatty acids into less active diols. [...] Read more.

Brown adipose tissue (BAT) plays a key role in non-shivering thermogenesis and is a promising target for enhancing energy expenditure to combat obesity. Soluble epoxide hydrolase (sEH) is a cytosolic enzyme that catalyzes the conversion of epoxy fatty acids into less active diols. We have reported that local administration of the sEH inhibitor, t-TUCB, to the endogenous interscapular BAT (iBAT) of diet-induced obese mice decreased serum triglycerides and enhanced the expression of essential genes associated with lipid metabolism. Here, the effects of sEH inhibition by t-AUCB were assessed on human brown adipocyte (HuBr) differentiation and in nude mice transplanted with t-AUCB-treated HuBr. HuBr cells were differentiated with t-AUCB (1–10 µM) or the vehicle (0.1% DMSO). HuBr differentiated with t-AUCB at 5 μM (AUCB 5) or DMSO was mixed with matrix gel and transplanted into the nude mice. The mice were then fed a high-fat diet for eight weeks. The mice receiving AUCB 5-treated HuBr exhibited markedly reduced lipid accumulation in the iBAT compared with DMSO or matrix-only controls, along with increased protein expression of thermogenic PGC1α and UCP1, fatty acid transporter CD36, and CPT1A in the iBAT, while the NFκB inflammatory pathways were suppressed in both the AUCB 5 and DMSO groups. Moreover, the PGC1α and CPT1A protein levels were elevated, and the adipocyte sizes were decreased in the epididymal white adipose tissue of the AUCB 5 group. Our findings indicate that the transplantation of HuBr treated with AUCB 5 may stimulate thermogenesis, enhance lipid metabolism, and reduce inflammation in iBAT. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Advances in Molecular Endocrinology and Metabolism)

18 pages, 1241 KB

Open AccessReview

Pathways of Resistance: Modern Multiple Myeloma Therapies and Overcoming Reliance on Genomic Integrity

by Iulianna Taritsa and Eric Fossel

Int. J. Mol. Sci. 2026, 27(3), 1439; https://doi.org/10.3390/ijms27031439 (registering DOI) - 31 Jan 2026

Abstract

Multiple myeloma (MM) is the second most common hematological malignancy in the US and Europe—comprising approximately 10% of all hematologic cancer cases—and its incidence has increased over the last three decades by approximately 120% due to an aging world population. It remains an [...] Read more.

Multiple myeloma (MM) is the second most common hematological malignancy in the US and Europe—comprising approximately 10% of all hematologic cancer cases—and its incidence has increased over the last three decades by approximately 120% due to an aging world population. It remains an incurable cancer among diseases in modern medicine. This review outlines the relevant cancer biology of MM, with a special emphasis on the role of tumor protein p53. We provide the most up-to-date summary of the current drugs in clinical or pre-clinical trials targeting weaknesses in the MM apoptotic mechanism. In addition, we highlight the potential for new routes to strike and kill myeloma cells, possibly creating a vaccine-like effect that prevents relapse, using the principles of immunogenic cell death (ICD). Full article

(This article belongs to the Special Issue Hematologic Malignancies: From Molecular Pathology to Novel Therapeutics)

21 pages, 3191 KB

Open AccessArticle

Human Fecal Transplantation Modifies the Gut Microbiota but Not Metabolites in Colon Cancer Patient-Derived Xenografts

by Katarzyna Unrug-Bielawska, Zuzanna Sandowska-Markiewicz, Ewelina Kaniuga, Magdalena Cybulska-Lubak, Monika Borowa-Chmielak, Paweł Czarnowski, Magdalena Piątkowska, Aneta Bałabas, Krzysztof Goryca, Natalia Zeber-Lubecka, Maria Kulecka, Michalina Dąbrowska, Piotr Surynt, Małgorzata Statkiewicz, Izabela Rumieńczyk, Michał Mikula and Jerzy Ostrowski

Int. J. Mol. Sci. 2026, 27(3), 1438; https://doi.org/10.3390/ijms27031438 (registering DOI) - 31 Jan 2026

Abstract

Gut microbiota influences colorectal cancer (CRC) development, tumor progression, and response to therapy. Fecal microbiota transplantation (FMT) has been proposed as a strategy to restore microbial balance and modulate treatment outcomes. We evaluated the effects of human fecal transplantation on gut microbiota composition, [...] Read more.

Gut microbiota influences colorectal cancer (CRC) development, tumor progression, and response to therapy. Fecal microbiota transplantation (FMT) has been proposed as a strategy to restore microbial balance and modulate treatment outcomes. We evaluated the effects of human fecal transplantation on gut microbiota composition, metabolites, tumor growth, and the efficacy of folinic acid, fluorouracil and oxaliplatin (FOLFOX) chemotherapy in four CRC patient-derived xenograft (CRC PDX) models in NSG mice. Gut microbiota was profiled by 16S rRNA sequencing; short-chain fatty acids (SCFAs) and amino acids (AAs) were analyzed by mass spectrometry. Prolonged FMT significantly altered gut microbiota structure, increasing α-diversity and modifying β-diversity, and induced distinct changes in bacterial genera. FMT alone did not affect tumor growth. FOLFOX inhibited tumor progression in all CRC PDXs, with FMT enhancing therapeutic efficacy in two models. Despite substantial microbiota shifts, FMT exerted minimal or no effect on fecal SCFAs and AAs. FMT induced robust microbiota remodeling but did not modify selected stool metabolites or intrinsic tumor growth. However, FMT enhanced FOLFOX responsiveness in selected CRC PDXs, supporting a microbiota-mediated modulation of chemotherapy outcomes. Full article

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

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24 pages, 3358 KB

Open AccessArticle

Immunomodulatory Effects of Phallus indusiatus Extract on Cytokine Responses in PBMCs: Implications for Feline Infectious Peritonitis

by Chularat Hlaoperm, Wassamon Moyadee, Emwalee Wongsaengnoi, Lueacha Tabtimmai, Amonpun Rattanasrisomporn, Atchara Paemanee, Kiattawee Choowongkomon, Christopher Gerner, Oumaporn Rungsuriyawiboon and Jatuporn Rattanasrisomporn

Int. J. Mol. Sci. 2026, 27(3), 1437; https://doi.org/10.3390/ijms27031437 (registering DOI) - 31 Jan 2026

Abstract

Feline infectious peritonitis (FIP) is a fatal disease driven by feline coronavirus induced immune dysregulation and excessive inflammatory cytokine production. Immunomodulatory agents capable of rebalancing this response are therefore of increasing interest. Phallus indusiatus (P. indusiatus), an edible mushroom containing diverse [...] Read more.

Feline infectious peritonitis (FIP) is a fatal disease driven by feline coronavirus induced immune dysregulation and excessive inflammatory cytokine production. Immunomodulatory agents capable of rebalancing this response are therefore of increasing interest. Phallus indusiatus (P. indusiatus), an edible mushroom containing diverse bioactive compounds, has previously demonstrated antiviral and anti-inflammatory potential. This study investigated the immunomodulatory effects of P. indusiatus extract on peripheral blood mononuclear cells (PBMCs) from healthy cats and FIP cats and characterized its chemical constituents using liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). PBMCs were isolated from whole blood and FIP fluid. Cytotoxicity screening identified 19 µg/mL as a non-toxic concentration for subsequent assays. Cytokine responses (IL-1β, IFN-γ, and IL-10) were evaluated following LPS stimulation in PBMCs from whole blood and under basal conditions in PBMCs from FIP fluid after treatment with P. indusiatus extract and dexamethasone. LC–MS/MS profiling combined with STITCH analysis was used to identify bioactive metabolites and their predicted molecular targets. PBMCs derived from FIP fluid exhibited markedly elevated IL-1β and IFN-γ, indicating strong baseline immune activation. P. indusiatus significantly reduced IL-1β and IFN-γ in PBMCs from FIP fluid and suppressed LPS-induced IL-1β and IL-10 in whole-blood PBMCs, demonstrating immunomodulatory patterns comparable to dexamethasone. LC–MS/MS analysis identified compounds including adenosine, phenylalanine, tyrosine, cystathionine, arginine, and sialic acid, which were linked to inflammatory signaling. Overall, the extract exhibited context-dependent modulation of pro- and anti-inflammatory cytokines, suggesting that P. indusiatus may serve as a promising natural adjunctive candidate for managing immune imbalance in cats with FIP. Full article

(This article belongs to the Special Issue 25th Anniversary of IJMS: Updates and Advances in “Molecular Immunology”)

33 pages, 2777 KB

Open AccessReview

Carbon Dots Meet MRI: Metal Doping for a Smart Contrast Agent Design

by Oana Elena Carp, Cristina Mariana Uritu, Adina Coroaba, Silviu-Iulian Filipiuc, Conchi O. Ania, Narcisa Laura Marangoci and Mariana Pinteala

Int. J. Mol. Sci. 2026, 27(3), 1436; https://doi.org/10.3390/ijms27031436 (registering DOI) - 31 Jan 2026

Abstract

In clinical and preclinical magnetic resonance imaging (MRI), image quality is often limited by intrinsic tissue contrast, so paramagnetic agents are used to amplify relaxation differences and improve lesion detectability. Widely used gadolinium-based contrast agents present recognized drawbacks, stimulating interest in nanoscale platforms [...] Read more.

In clinical and preclinical magnetic resonance imaging (MRI), image quality is often limited by intrinsic tissue contrast, so paramagnetic agents are used to amplify relaxation differences and improve lesion detectability. Widely used gadolinium-based contrast agents present recognized drawbacks, stimulating interest in nanoscale platforms with tuneable magnetic and biological properties. This review provides a critical analysis on the use of metal-doped carbon nanodots (C-dots) as MRI contrast candidates. We briefly revisit MRI signal formation, spin–lattice (

T_{1}

) and spin–spin (

T_{2}

) relaxation, and relaxometric parameters

r_{1}

and

r_{2}

and outline how pulse-sequence choice favours

T_{1}

- or

T_{2}

-dominant agents. We compare approved small-molecule agents with nanostructured systems, highlighting unmet needs in safety, field-strength dependence, multimodality, and organ-specific imaging. A central focus is how nano- and molecular architectures of metal-doped carbon dots govern

r_{1}

and

r_{2}

: the metal species and oxidation state, its location within the carbon matrix, surface chemistry and hydration, and the accessibility for proton and water exchange can shift performance toward

T_{1}

or

T_{2}

. Engineered C-dots with controlled composition and metal dopants have proven to pair improved relaxivity with fluorescence, targeting ligands, or therapeutic payloads. Overall, metal-doped C-dots represent a flexible and potentially safer alternative to classical contrast agents; however, successful clinical translation and market uptake will still require standardized relaxometry at clinical field strengths, scalable and reproducible synthesis, and comprehensive in vivo safety and efficacy validation. Full article

(This article belongs to the Special Issue Properties and Applications of Nanoparticles and Nanomaterials: 3rd Edition)

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30 pages, 14292 KB

Open AccessArticle

Differences in the Effect of Dopamine on the Phototransduction Between Lampreys and Jawed Vertebrates

by Darya A. Nikolaeva, Alexander Yu. Rotov, Irina Yu. Morina, Michael L. Firsov, Irina V. Romanova and Luba A. Astakhova

Int. J. Mol. Sci. 2026, 27(3), 1435; https://doi.org/10.3390/ijms27031435 (registering DOI) - 31 Jan 2026

Abstract

Dopamine is one of the most important neurotransmitters for regulating retinal function and adjusting vision to the diurnal cycle. It exerts its regulatory effects, in part, through the cAMP pathway. Previous studies have demonstrated that dopamine affects phototransduction in amphibian rods, and that [...] Read more.

Dopamine is one of the most important neurotransmitters for regulating retinal function and adjusting vision to the diurnal cycle. It exerts its regulatory effects, in part, through the cAMP pathway. Previous studies have demonstrated that dopamine affects phototransduction in amphibian rods, and that elevated intracellular levels of cAMP modulate the function of vertebrate rods and cones. Lamprey, the most primitive vertebrate, could be valuable for studying the evolution of dopamine regulatory loops in the retina. We examined whether the photoresponse properties of long (cone-like) and short (rod-like) photoreceptors in the river lamprey could be regulated by dopamine via the cAMP pathway. Using suction pipette recording, we demonstrated that forskolin-induced elevation of cAMP has no effect on long or short photoreceptors. At the same time, dopamine modifies the photoresponse properties of long, but not short, photoreceptors at high, potentially non-physiological concentrations. Immunohistochemical analysis of the lamprey retina revealed the expression of both D1 and D2 dopamine receptors in lamprey photoreceptors; however, their distribution differs from jawed vertebrates. Taken together, our results suggest that, in lampreys, dopamine does not regulate photoreceptor sensitivity to light in the circadian rhythm, but, rather, adjusts other retinal functions based on widespread distribution of its receptors. Full article

(This article belongs to the Special Issue Research on Intracellular Signal Transduction Systems)

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