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Int. J. Mol. Sci., Volume 27, Issue 1 (January-1 2026) – 555 articles

Cover Story (view full-size image): The identification of caveolin-1 (CAV1) as a pathophysiological factor and target for treating various cutaneous conditions and the recognition of its role in the protection of cells from genotoxic stress have opened new avenues for protecting patients against radiation-induced skin injuries, common complications in radiation therapy. A rapid increase in CAV1 content in irradiated cells is coupled with the internalization of epidermal growth factor receptors involved in repairing double-strand breaks. It is proposed that an enhancement in the expression and translocation of CAV1 through local application of thermo-mechanical stress, with parameters inducing the reinforcement of the actin cytoskeleton in treated cells, can additionally protect patients from these severe side effects. View this paper
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28 pages, 942 KB  
Review
The Role of Vitamin D in Autoimmune Diseases
by Federica Vincenzi, Carlo Smirne, Stelvio Tonello and Pier Paolo Sainaghi
Int. J. Mol. Sci. 2026, 27(1), 555; https://doi.org/10.3390/ijms27010555 - 5 Jan 2026
Viewed by 344
Abstract
Vitamin D is a steroid hormone whose relevant immunomodulatory role has been widely described. Therefore, its contribution to the pathogenesis of immune-mediated diseases is an important and ongoing matter of research. Specifically, the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, through the [...] Read more.
Vitamin D is a steroid hormone whose relevant immunomodulatory role has been widely described. Therefore, its contribution to the pathogenesis of immune-mediated diseases is an important and ongoing matter of research. Specifically, the active form of vitamin D, i.e., 1,25-dihydroxyvitamin D, through the interaction with its receptor, exerts different activities on the innate and adaptive immune system, among which are suppression of inflammation and promotion of tolerogenic responses. Indeed, vitamin D insufficiency/deficiency has been related to the pathogenesis and/or disease activity of several autoimmune diseases, including, amongst others, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus. Based on these premises, in this review, we will describe the main molecular mechanisms modulated by vitamin D in the regulation of immune responses, including the induction of immune tolerance. Moreover, we will focus on the current knowledge regarding the contribution of vitamin D depletion to the aforementioned autoimmune diseases, seeking to provide evidence as to why its supplementation in the context of these immune-mediated disorders may potentially ameliorate disease activity and its related clinical manifestations. Full article
(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)
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22 pages, 2753 KB  
Article
Spectroscopic Analysis of the TiO2 Nanoparticles Influence on the Interaction of 5,10,15,20-(Tetra-4-carboxyphenyl)porphyrin with Human Serum Albumin
by Andra Dinache, Ana Maria Udrea, Mihai Boni, Adriana Smarandache and Angela Staicu
Int. J. Mol. Sci. 2026, 27(1), 554; https://doi.org/10.3390/ijms27010554 - 5 Jan 2026
Viewed by 167
Abstract
Photodynamic therapy is a cancer treatment that relies on a photosensitizer (PS) to generate reactive oxygen species upon light activation, thereby destroying cancer cells. The photophysical properties of porphyrins make them effective PSs, while nanoparticles (NPs) enhance their delivery and stability. The bioavailability [...] Read more.
Photodynamic therapy is a cancer treatment that relies on a photosensitizer (PS) to generate reactive oxygen species upon light activation, thereby destroying cancer cells. The photophysical properties of porphyrins make them effective PSs, while nanoparticles (NPs) enhance their delivery and stability. The bioavailability and targeting efficiency of NPs-PS complexes may be improved through transport via human serum albumin (HSA). This study investigates the HSA binding affinity with 5,10,15,20-(Tetra-4-carboxyphenyl)porphyrin (TCPP) and with TiO2-TCPP complexes. The interactions were analyzed using UV-Vis absorption, laser-induced fluorescence (LIF), and FTIR spectroscopy. Molecular docking was performed and provided consistent binding constant values for the TCPP–HSA complex with UV-Vis absorption measurements. LIF data revealed a slightly lower affinity when compare free porphyrin with TiO2-TCPP, possibly due to competitive binding between TiO2 and HSA. Docking simulations indicated that TCPP favorably interacts with amino acid residues located in subdomains IB and IIIA of HSA, supporting a preferential binding near Sudlow site I. FTIR measurements revealed conformational changes in HSA for both its interactions with TCPP and TiO2-TCPP, including alterations in α-helical content and reorganization of the hydrogen bonding network within the polypeptide backbone. Full article
(This article belongs to the Special Issue Spectroscopic Techniques in Molecular Sciences)
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18 pages, 465 KB  
Review
Cerebrospinal Fluid Biomarkers in Creutzfeldt–Jakob Disease: Diagnostic Value, Limitations, and Future Multi-Omics Strategies
by Rui Xu, Cao Chen, Qi Shi and Xiao-Ping Dong
Int. J. Mol. Sci. 2026, 27(1), 553; https://doi.org/10.3390/ijms27010553 - 5 Jan 2026
Viewed by 238
Abstract
Creutzfeldt–Jakob disease (CJD) is a rare but devastating neurodegenerative disorder characterized by the pathological misfolding of the cellular prion protein (PrPC) into the pathogenic isoform-scrapie prion protein (PrPSc), ultimately leading to fatal outcomes. Cerebrospinal fluid (CSF) biomarkers play a [...] Read more.
Creutzfeldt–Jakob disease (CJD) is a rare but devastating neurodegenerative disorder characterized by the pathological misfolding of the cellular prion protein (PrPC) into the pathogenic isoform-scrapie prion protein (PrPSc), ultimately leading to fatal outcomes. Cerebrospinal fluid (CSF) biomarkers play a pivotal role in early diagnosis, longitudinal monitoring, and prognostic assessment, thereby enhancing the clinical management of this challenging disease. This review summarizes the established CSF biomarkers, 14-3-3 protein, tau protein (total tau), phosphorylated tau isoforms, α-synuclein, neurofilament light chain (Nfl), S100B, neuron-specific enolase (NSE), and phosphorylated neurofilament heavy chain (pNFH), highlighting typical sensitivity ranges (14-3-3 ~70–85%; RT-QuIC > 90%) and subtype-dependent performance variation. We further dissect limitations related to assay variability, inter-laboratory cut-off inconsistencies, and reduced specificity in non-prion dementias. Looking ahead, we discuss emerging multi-omics discovery, integration of CSF with blood-based biomarkers and imaging signatures, and AI-enabled diagnostic modeling. We propose a three-tier biomarker framework combining Real-Time Quaking-Induced Conversion (RT-QuIC) as a confirmatory assay, tau/NfL/pNFH as injury-severity indicators, and multi-omics-derived signatures for early detection and prognosis stratification. Full article
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13 pages, 2202 KB  
Article
Differential Glycosylation Patterns in Parkinson’s Disease: Emphasis on Male-Specific Changes Identified via HILIC-LC-MS
by Béla Demeter, Adriána Kutás, Béla Viskolcz, Csaba Oláh, Edina Petercsák, Attila Garami and Csaba Váradi
Int. J. Mol. Sci. 2026, 27(1), 552; https://doi.org/10.3390/ijms27010552 - 5 Jan 2026
Viewed by 171
Abstract
Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons, leading to significant motor and non-motor symptoms. This study investigates glycosylation patterns with a significant emphasis on male Parkinson’s Disease (PD) patients, revealing unique alterations distinguishing PD [...] Read more.
Parkinson’s disease (PD) is a progressive neurodegenerative disorder primarily characterized by the degeneration of dopaminergic neurons, leading to significant motor and non-motor symptoms. This study investigates glycosylation patterns with a significant emphasis on male Parkinson’s Disease (PD) patients, revealing unique alterations distinguishing PD from healthy states, utilizing high-performance liquid chromatography coupled with mass spectrometry (HILIC-LC-MS). Findings reveal significantly altered serum N-glycosylation profiles between male and female patients, with increased levels of high-mannose glycans and reduced mono-sialylated glycans in male patients. ROC curve analysis indicates that these glycan changes are the most important features for distinguishing PD from healthy states, with AUC values of 0.71 for M5 and 0.85 for M6. This study underscores the critical role of glycosylation in the pathophysiology of Parkinson’s disease and highlights its potential in early detection and monitoring of disease progression. Full article
(This article belongs to the Special Issue Mass Spectrometry Approaches as Clinical Diagnostic/Prognostic Tools)
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16 pages, 3732 KB  
Article
Development of a Sensitive and Specific RPA-CRISPR/Cas12a Assay for Intrahepatic Quantification of HBV cccDNA
by Pattida Kongsomboonchoke, Chaiyaboot Ariyachet, Pornchai Kaewsapsak, Pongserath Sirichindakul and Pisit Tangkijvanich
Int. J. Mol. Sci. 2026, 27(1), 551; https://doi.org/10.3390/ijms27010551 - 5 Jan 2026
Viewed by 159
Abstract
Hepatitis B virus (HBV) persists in infected hepatocytes through covalently closed circular DNA (cccDNA), a stable episomal form that serves as the transcriptional template for viral replication. Accurate and sensitive quantification of intrahepatic cccDNA is crucial for evaluating antiviral therapies, particularly those targeting [...] Read more.
Hepatitis B virus (HBV) persists in infected hepatocytes through covalently closed circular DNA (cccDNA), a stable episomal form that serves as the transcriptional template for viral replication. Accurate and sensitive quantification of intrahepatic cccDNA is crucial for evaluating antiviral therapies, particularly those targeting a functional cure. Here, we report the development of a novel, cccDNA-specific detection system combining recombinase polymerase amplification (RPA) with CRISPR/Cas12a-based fluorescence detection. We designed and validated CRISPR RNAs (crRNAs) targeting HBV cccDNA-specific regions conserved across genotypes A–D. Reaction conditions for both RPA and Cas12a detection were optimized to enhance sensitivity, specificity, and accuracy. The system reliably detected as few as 10 copies of cccDNA-containing plasmid per reaction and showed no cross-reactivity with non-cccDNA forms in serum or plasma, indicating assay specificity. When applied to liver tissue samples from 10 HBV-infected and 6 non-HBV patients, the RPA-CRISPR/Cas12a assay exhibited a high sensitivity (90%) and a strong correlation with qPCR results (R2 = 0.9155), confirming its accuracy. In the conclusion, the RPA-CRISPR/Cas12a system provides a robust, cost-effective, and scalable platform for sensitive and specific quantification of intrahepatic HBV cccDNA. This method holds promises for research and high-throughput therapeutic screening applications targeting cccDNA clearance. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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21 pages, 2641 KB  
Article
Plasma Short-Chain Fatty Acids and Cytokine Profiles in Chronic Kidney Disease: A Potential Pathophysiological Link
by Anna V. Sokolova, Dmitrii O. Dragunov and Grigory P. Arutyunov
Int. J. Mol. Sci. 2026, 27(1), 550; https://doi.org/10.3390/ijms27010550 - 5 Jan 2026
Viewed by 158
Abstract
Sarcopenia is highly prevalent among patients with chronic kidney disease (CKD) and chronic heart failure (CHF), yet the underlying immunometabolic mechanisms remain insufficiently understood. Short-chain fatty acids (SCFAs), inflammatory cytokines, and body-composition alterations may jointly contribute to the development of muscle dysfunction in [...] Read more.
Sarcopenia is highly prevalent among patients with chronic kidney disease (CKD) and chronic heart failure (CHF), yet the underlying immunometabolic mechanisms remain insufficiently understood. Short-chain fatty acids (SCFAs), inflammatory cytokines, and body-composition alterations may jointly contribute to the development of muscle dysfunction in this population. In this cross-sectional study, 80 patients with CKD and CHF underwent comprehensive clinical, biochemical, bioimpedance, inflammatory, and SCFA profiling. Sarcopenia was diagnosed according to EWGSOP2 criteria. Multivariable logistic regression, LASSO feature selection, correlation analysis, PCA, and Random Forest modeling were used to identify key determinants of sarcopenia. Sarcopenia was present in 39 (49%) participants. Patients with sarcopenia exhibited significantly lower body fat percentage, reduced ASM, and slower gait speed. Hexanoic acid (C6) showed an independent positive association with sarcopenia (OR = 2.24, 95% CI: 1.08–5.37), while IL-8 showed an inverse association with sarcopenia (OR = 0.38, 95% CI: 0.13–0.94), indicating that lower IL-8 levels were more frequently observed in individuals with sarcopenia. Correlation heatmaps revealed distinct SCFA–cytokine coupling patterns depending on sarcopenia status, with stronger pro-inflammatory clustering in C6-associated networks. The final multivariable model integrating SCFAs, cytokines, and body-composition metrics achieved excellent discrimination (AUC = 0.911) and good calibration. Sarcopenia in CKD–CHF patients represents a systemic immunometabolic disorder characterized by altered body composition, chronic inflammation, and dysregulated SCFA signaling. Hexanoic acid (C6) and IL-8 may serve as informative biomarkers of muscle decline. These findings support the use of multidimensional assessment and highlight potential targets for personalized nutritional, microbiota-modulating, and rehabilitative interventions. Full article
(This article belongs to the Section Molecular Immunology)
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15 pages, 4868 KB  
Article
Phylostratigraphic Analysis Reveals the Evolutionary Origins and Potential Role of New Genes in the Adaptive Evolution of Spodoptera frugiperda
by Yi Yang, Bo Zhang, Yaobin Lu and Xinyang Zhang
Int. J. Mol. Sci. 2026, 27(1), 549; https://doi.org/10.3390/ijms27010549 - 5 Jan 2026
Viewed by 169
Abstract
The fall armyworm, Spodoptera frugiperda, has become one of the most damaging agricultural pests worldwide, yet the genetic basis of its extraordinary adaptability remains elusive. Recent studies have highlighted the pivotal role of newly evolved genes in adaptive evolution, and phylostratigraphy has [...] Read more.
The fall armyworm, Spodoptera frugiperda, has become one of the most damaging agricultural pests worldwide, yet the genetic basis of its extraordinary adaptability remains elusive. Recent studies have highlighted the pivotal role of newly evolved genes in adaptive evolution, and phylostratigraphy has emerged as a powerful conceptual framework to trace their origins. Here, we adopt this framework to investigate how new genes have contributed to the rapid adaptive evolution of S. frugiperda. Using high-quality genomic data, we inferred gene ages across evolutionary phylostrata and identified 277 newly evolved genes that originated after the divergence of Spodoptera. These new genes exhibit hallmark genomic signatures of recent origin, including shorter coding regions, simplified structures, and relaxed evolutionary constraints. Interestingly, transcriptomic analyses revealed strong tissue specificity, with pronounced enrichment in the antenna and brain, indicating possible involvement in chemosensory and neural functions essential for environmental and behavioral adaptation. Under diverse environmental challenges such as pesticide and parasitoid wasp exposure, and virus infection, we found many of the new genes acted as hubs in the regulatory networks associated with pesticide response. Together, our findings suggest that the emergence of new genes has played a critical role in shaping the rapid adaptive evolution of S. frugiperda and provide broader insights into how newly evolved genes contribute to species adaptation. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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28 pages, 888 KB  
Review
From Structure to Function of Promoters and 5′UTRs in Maize
by Nikita V. Sytov, Vladimir V. Choob, Sileshi Nemomissa, Alexander S. Mishin and Maxim M. Perfilov
Int. J. Mol. Sci. 2026, 27(1), 548; https://doi.org/10.3390/ijms27010548 - 5 Jan 2026
Viewed by 211
Abstract
As a cornerstone of global agriculture, maize (Zea mays) is a crucial component of sustainable food systems and industrial uses. However, global agricultural production faces pressures from climate change, resource scarcity, and rising nutritional demands. To adapt to changes in their [...] Read more.
As a cornerstone of global agriculture, maize (Zea mays) is a crucial component of sustainable food systems and industrial uses. However, global agricultural production faces pressures from climate change, resource scarcity, and rising nutritional demands. To adapt to changes in their environment, plants evolved precise and sophisticated gene expression regulatory mechanisms. A majority of gene expression regulatory elements are located in promoters and untranslated regions of mRNA. This review aims to elucidate how promoters and 5′ untranslated regions function in complex synergy to regulate gene expression in maize. We discuss the structural organization of these regulatory elements, from their basic components to their integrated roles in shaping plant gene expression. Particular emphasis is placed on their significant impact on maize biotechnology, including strategies for controlling, fine-tuning, and enhancing gene expression for crop improvement. With this review we wish to guide future biotechnological innovations and food security. Full article
(This article belongs to the Topic Genetic Engineering in Agriculture, 2nd Edition)
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15 pages, 541 KB  
Article
Haplotype GWAS in Colorectal Cancer Patients with a Family History of Gastric or Prostate Cancer
by David Kudrén, Linda Waage, Johanna Samola Winnberg, Mats Lindblad, Chunde Li, Annika Lindblom and Litika Vermani
Int. J. Mol. Sci. 2026, 27(1), 547; https://doi.org/10.3390/ijms27010547 - 5 Jan 2026
Viewed by 145
Abstract
Previous haplotype Genome Wide Association Studies (GWASs) have suggested several rare loci with a shared increased risk of colorectal, gastric, and prostate cancer. This study aimed to find out more about markers specifically addressing the shared risk of colorectal and gastric cancer, as [...] Read more.
Previous haplotype Genome Wide Association Studies (GWASs) have suggested several rare loci with a shared increased risk of colorectal, gastric, and prostate cancer. This study aimed to find out more about markers specifically addressing the shared risk of colorectal and gastric cancer, as well as the shared risk of colorectal and prostate cancer. One analysis used 426 colorectal cancer cases with gastric cancer, with no prostate cancer cases in their families, and another analysis used 324 colorectal cancer cases with prostate cancer but no gastric cancer among relatives. The computational program PLINK v1.07 was used for the analysis and for the calculation of corresponding ORs, standard errors, and 95% confidence intervals (CI). The study found support for the loci from previous studies and many new loci with a shared risk of colorectal cancer and gastric cancer. There were no significant loci from the second analysis for a shared risk of colorectal and prostate cancer. Altogether, more than 100 new loci with a shared risk of colorectal cancer and gastric cancer were suggested. A shared risk of colorectal and prostate cancer at some loci could not be ruled out. Haplotype GWAS has again demonstrated its ability to find rare risk loci mostly associated with coding genes. Full article
(This article belongs to the Special Issue Genetic and Epigenetic Analyses in Cancer)
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24 pages, 1338 KB  
Review
Cognition, Cytokines, Blood–Brain Barrier, and Beyond in COVID-19: A Narrative Review
by Ana Barajas, Gemma Riquelme-Alacid, América Vera-Montecinos and Belén Ramos
Int. J. Mol. Sci. 2026, 27(1), 546; https://doi.org/10.3390/ijms27010546 - 5 Jan 2026
Viewed by 250
Abstract
Numerous studies report cognitive impairment in COVID-19 patients from the acute to post-acute phases, linked to blood inflammation affecting blood–brain barrier (BBB) permeability and causing leakage of glial and neuronal proteins. However, a clear classification of these cognitive deficits and molecular blood events [...] Read more.
Numerous studies report cognitive impairment in COVID-19 patients from the acute to post-acute phases, linked to blood inflammation affecting blood–brain barrier (BBB) permeability and causing leakage of glial and neuronal proteins. However, a clear classification of these cognitive deficits and molecular blood events over time is still lacking. This narrative review summarizes the neuropsychological consequences of COVID-19 and evidence of altered cytokines and BBB disruption as potential mediators of cognitive impairment across post-infection phases. Post-COVID-19 cognitive dysfunction appears to follow a temporal course, evolving from acute focal deficits in attention, working memory, and executive function to more persistent multidomain impairments. We reviewed key cytokines released into the blood during COVID-19 infection, including antiviral (IFNγ, CXCL1, CXCL10), inflammatory (IL-1β, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, GM-CSF, TNFα), and monocyte chemoattractants (MCP1/CCL2, MCP3/CCL7, MIP-1α/CCL3, GM-CSF, G-CSF). This analysis shows that several inflammatory and viral cytokines remain elevated beyond the acute phase and are associated with cognitive deficits, including IL-6, IL-13, IL-8, IL-1β, TNFα, and MCP1 in long-term post-COVID-19 patients. In addition, we examined studies analyzing changes over time in neurovascular unit proteins as biomarkers of BBB disruption, including extracellular matrix proteins (PPIA, MMP-9), astrocytes (S100β, GFAP), and neurons (NFL). These proteins are elevated in acute COVID-19 but generally return to control levels within six months, suggesting BBB restoration. However, in patients followed for over a year, BBB disruption persists only in those with cognitive impairment and is associated with systemic inflammation, with TGFβ as a related biomarker. Although cognitive sequelae can persist for over 12 months after SARS-CoV-2 infection, further studies are needed to investigate long-term neurocognitive outcomes and their link to sustained proinflammatory cytokine elevation and brain impact. Full article
(This article belongs to the Section Molecular Neurobiology)
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11 pages, 1368 KB  
Article
Genetic Diversity Analysis of Cotton Cultivars Using a 40K Liquid Chip in Northern Xinjiang
by Zhihong Zheng, Ningshan Wang, Shangkun Jin, Kewei Ning, Guoli Feng, Haiqiang Gao, Zhanfeng Si, Tianzhen Zhang and Nijiang Ai
Int. J. Mol. Sci. 2026, 27(1), 545; https://doi.org/10.3390/ijms27010545 - 5 Jan 2026
Viewed by 150
Abstract
Genetic diversity and kinship information of cotton germplasm resources are fundamental to breeding, providing a theoretical basis for the rational selection of hybrid parents and further breeding of new varieties with high yield, high quality, and multi-resistance. This study utilized cotton varieties that [...] Read more.
Genetic diversity and kinship information of cotton germplasm resources are fundamental to breeding, providing a theoretical basis for the rational selection of hybrid parents and further breeding of new varieties with high yield, high quality, and multi-resistance. This study utilized cotton varieties that have been used for variety improvement or are widely planted in the Northern Xinjiang cotton region as materials. Genotyping was performed using the ZJU CottonSNP40K chip to analyze genetic diversity and kinship relationships. A total of 26,852 high-quality SNP markers were obtained, including 15,222 SNPs in subgenome A and 11,630 SNPs in subgenome D. The number of SNPs per chromosome ranged from 547 (A04) to 2168 (A08). Based on phylogenetic tree and principal component analysis, the 83 materials were clustered into 3 major subgroups. Group I contained varieties introduced from the former Soviet Union and the United States, which have become important parents for cotton breeding in Northern Xinjiang. Among them, as many as 27 varieties were derived and selected from the introduced US variety ‘Beiersinuo’ as a parent. While playing an important role in cotton breeding in Northern Xinjiang, this has also led to the current situation where the genetic base of Northern Xinjiang varieties is relatively narrow (average kinship coefficient 0.72). It clarifies the significant role of introduced American variety ‘Beiersinuo’ in the breeding of Northern Xinjiang cultivars and provides theoretical guidance for broadening the genetic base of Northern Xinjiang cotton varieties. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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25 pages, 2151 KB  
Review
Cardio-Vascular Extracellular Matrix: The Unmet Enigma
by Ioannis Paraskevaidis, Elias Tsougos and Christos Kourek
Int. J. Mol. Sci. 2026, 27(1), 544; https://doi.org/10.3390/ijms27010544 - 5 Jan 2026
Viewed by 227
Abstract
The cardiac extracellular matrix (ECM) is a dynamic, tissue-specific scaffold essential for cardiovascular development, homeostasis, and disease. Once considered a passive structural framework, the ECM is now recognized as an active regulator of mechanical, electrical, and biochemical signaling in the heart. Its composition [...] Read more.
The cardiac extracellular matrix (ECM) is a dynamic, tissue-specific scaffold essential for cardiovascular development, homeostasis, and disease. Once considered a passive structural framework, the ECM is now recognized as an active regulator of mechanical, electrical, and biochemical signaling in the heart. Its composition evolves from embryogenesis through adulthood, coordinating cardiomyocyte maturation, chamber formation, and postnatal remodeling. In pathological states, diverse stimuli—including ischemia, pressure or volume overload, metabolic dysfunction, and aging—disrupt ECM homeostasis, triggering fibroblast activation, myofibroblast transformation, and maladaptive collagen deposition. These processes underpin myocardial fibrosis, a key driver of impaired contractility, diastolic dysfunction, arrhythmogenesis, and heart failure across ischemic and non-ischemic cardiac diseases. ECM alterations also exhibit age- and sex-specific patterns that influence susceptibility to cardiovascular pathology. Advances in imaging and circulating biomarkers have improved fibrosis assessment, though limitations persist. Therapeutic strategies targeting ECM remodeling, including modulation of profibrotic signaling pathways, non-coding RNAs, cellular therapies, and nano-delivery systems, show promise but remain largely experimental. Collectively, expanding knowledge of ECM biology highlights its central role in cardiovascular physiology and pathology and underscores the need for targeted diagnostic and therapeutic innovations. Full article
(This article belongs to the Special Issue Current Research for Heart Disease Biology and Therapeutics (Third Edition))
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22 pages, 924 KB  
Article
Identifying a Common Autoimmune Gene Core as a Tool for Verifying Biological Significance and Applicability of Polygenic Risk Scores
by Victoria Sergeevna Shchekina, Nikita Aleksandrovich Batashkov, Anna Arkadievna Maznina, Julia Aleksandrovna Krupinova, Viktor Pavlovich Bogdanov, Anna Vasilievna Korobeinikova, Dmitry Igorevich Tychinin, Olga Valentinovna Glushkova, Ekaterina Sergeevna Petriaikina, Dmitry Vladimirovich Svetlichnyy, Mary Woroncow, Vladimir Sergeevich Yudin, Anton Arturovich Keskinov, Sergey Mikhailovich Yudin, Veronika Igorevna Skvortsova, Dmitry Vyacheslavovich Tabakov, Andrei Andreevich Deviatkin and Pavel Yu. Volchkov
Int. J. Mol. Sci. 2026, 27(1), 543; https://doi.org/10.3390/ijms27010543 - 5 Jan 2026
Viewed by 179
Abstract
Polygenic autoimmune diseases (ADs) have several common features that are caused by a complex interplay of genetic and environmental factors. Common pathophysiological mechanisms include dysregulation of the immune system, chronic inflammation, and epigenetic changes influenced by external factors. For the prediction of the [...] Read more.
Polygenic autoimmune diseases (ADs) have several common features that are caused by a complex interplay of genetic and environmental factors. Common pathophysiological mechanisms include dysregulation of the immune system, chronic inflammation, and epigenetic changes influenced by external factors. For the prediction of the genetic predisposition of AD manifestation, polygenic risk scale (PRS), or polygenic scores (PGSs), are used. Use of PRSs faces several challenges such as applicability on a specific population, performance comparison, and estimation of biological relevance based on SNP number. We compared PRS with different numbers of SNPs and tried to find the common genetic core of ADs. Our analysis revealed a list of the most common altered genes, which we annotated and interpreted. Clustering of PRS based on used genes showed that clusters of ADs remained consistent across all chosen PRS sizes. We concluded that PRS size does not have an impact on biological relevance. Full article
(This article belongs to the Special Issue Genetics and Omics in Autoimmune Diseases)
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23 pages, 1265 KB  
Review
MMPs at Work: Deciphering Their Role in the Cellular Mechanisms of Orthodontic Tooth Movement
by Mariana Ramos Patrão, Pedro Mariano Pereira, Jorge Caldeira and Madalena Salema-Oom
Int. J. Mol. Sci. 2026, 27(1), 542; https://doi.org/10.3390/ijms27010542 - 5 Jan 2026
Viewed by 185
Abstract
Matrix metallopeptidases (MMPs) are enzymes that, in balance with their inhibitors, play a vital role in extracellular matrix remodelling, particularly during orthodontic tooth movement (OTM). Despite growing interest, significant research is still required to fully comprehend the mechanisms and signalling pathways involved in [...] Read more.
Matrix metallopeptidases (MMPs) are enzymes that, in balance with their inhibitors, play a vital role in extracellular matrix remodelling, particularly during orthodontic tooth movement (OTM). Despite growing interest, significant research is still required to fully comprehend the mechanisms and signalling pathways involved in periodontal ligament remodelling and OTM, particularly those mediated by MMPs. This review explores recent in vitro and in vivo evidence on how specific MMPs—namely, MMP-1, -2, -3, -8, -9, -12, -13, and -14—respond to compressive and tensile forces, regulate collagen degradation, and influence periodontal ligament fibroblast and osteoblast behaviour, ultimately shaping tissue resorption and formation. We also summarize the roles of periodontal ligament cells, hypoxia, the neurovascular and immune systems, and well-known molecules—including receptor activator of nuclear factor kappa β, receptor activator of nuclear factor kappa β ligand, osteoprotegerin, macrophage colony-stimulating factor, tumour necrosis factor α, transforming growth factor, and interleukins—in orchestrating these responses. Finally, we address the clinical relevance of these pathways, highlighting the potential for therapeutic strategies targeting MMPs activity. Overall, this review underscores the pivotal contribution of MMPs to extracellular matrix turnover and tissue adaptation during OTM and suggests that modulating the MMPs/tissue inhibitors of matrix metallopeptidase (TIMPs) balance may enhance orthodontic outcomes. Full article
(This article belongs to the Special Issue From Biology to Biomechanics: Molecular Advances in Orthodontic Remodeling and Acceleration)
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13 pages, 878 KB  
Article
Binding of Tetrachloroaurate(III) to Bovine or Human γ-Globulins
by Daniil N. Yarullin, Olga I. Logacheva, Maksim N. Zavalishin and George A. Gamov
Int. J. Mol. Sci. 2026, 27(1), 541; https://doi.org/10.3390/ijms27010541 - 5 Jan 2026
Viewed by 137
Abstract
The interaction of metals with serum γ-globulins is of particular interest, as it can modulate immune system function and lead to unforeseen consequences following the intake of metal ions or their complexes, which are often considered (pro)drugs. This paper focuses on the interactions [...] Read more.
The interaction of metals with serum γ-globulins is of particular interest, as it can modulate immune system function and lead to unforeseen consequences following the intake of metal ions or their complexes, which are often considered (pro)drugs. This paper focuses on the interactions between gold(III) species and bovine or human serum γ-globulins in aqueous solutions. Using UV-Vis, fluorescence, and CD (circular dichroism) spectroscopy in diluted or 0.1 M NaCl aqueous solutions, we determined the most probable stoichiometry of the gold(III)-protein associates and their conditional binding constants. On average, 13 to 19 gold atoms bind per protein molecule, depending on the medium and protein origin, with apparent binding constants ranging from 3.6 to 4.6 (log K values; hydroxyl-containing complexes exhibit lower binding affinity). CD spectra revealed no changes in protein secondary structure induced by the increase in electrolyte concentration. However, the addition of gold(III) species resulted in a decrease in β-sheet content and a corresponding increase in turns or disordered fragments. Full article
(This article belongs to the Topic Metal Ions in Health and Diseases: Current Progress and Future Challenges)
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18 pages, 729 KB  
Article
Endothelin-2 and Its Association with Uric Acid Levels and Systemic Inflammation: Relevance to Chronic Kidney Disease Progression
by Alexander Bozhidarov Blazhev, Krasimir Kostov, Borislav Ivanov Ignatov, Tsvetelina Eftimova, Tatyana Nedkova Simeonova and Svetla Ognyanova Blazheva
Int. J. Mol. Sci. 2026, 27(1), 540; https://doi.org/10.3390/ijms27010540 - 5 Jan 2026
Viewed by 172
Abstract
Chronic kidney disease (CKD) is associated with chronic inflammation and metabolic dysregulation. While endothelin-1 (ET-1) has been extensively studied, the role of endothelin-2 (ET-2) in CKD remains poorly understood. This cross-sectional study included 76 participants, 12 healthy controls and 64 CKD patients, stratified [...] Read more.
Chronic kidney disease (CKD) is associated with chronic inflammation and metabolic dysregulation. While endothelin-1 (ET-1) has been extensively studied, the role of endothelin-2 (ET-2) in CKD remains poorly understood. This cross-sectional study included 76 participants, 12 healthy controls and 64 CKD patients, stratified into three groups based on estimated glomerular filtration rate (eGFR): Group 1 (eGFR ≥ 90 mL/min/1.73 m2), Group 2 (eGFR 45–89 mL/min/1.73 m2), and Group 3 (eGFR 15–44 mL/min/1.73 m2). Serum concentrations of ET-1, ET-2, ET-3, uric acid (UA), and inflammatory markers (hsCRP and IL-6) were measured. ET-2 levels were significantly higher in the advanced CKD group (median 24.49 pg/mL) compared to controls (median 19.32 pg/mL; p = 0.030). No significant differences were observed for ET-1 or ET-3 across groups. ET-2 levels positively correlated with UA (rho = 0.243, p = 0.036), hsCRP (rho = 0.241, p = 0.039), and IL-6 (rho = 0.244, p = 0.038). These findings suggest that ET-2 may represent a potential biomarker reflecting metabolic and inflammatory dysregulation in CKD and highlight its possible relevance in disease severity assessment. Full article
(This article belongs to the Special Issue Molecular Insights and Novel Therapeutics in Chronic Kidney Disease)
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18 pages, 12725 KB  
Article
Dicer Deletion in the Ear Can Cut Most Neurons and Their Innervation of Hair Cells to Project to the Ear and the Brainstem
by Ebenezer N. Yamoah, Gabriela Pavlinkova, Jeong Han Lee, Jennifer Kersigo, Marsha L. Pierce and Bernd Fritzsch
Int. J. Mol. Sci. 2026, 27(1), 539; https://doi.org/10.3390/ijms27010539 - 5 Jan 2026
Viewed by 239
Abstract
Dicer is crucial for the generation of microRNAs (miRNAs), which are essential for regulating gene expression and keeping neuronal health. Dicer’s conditional deletion cuts all spiral ganglion neurons but spares a small fraction of vestibular ganglion neurons, innervating the utricle and part of [...] Read more.
Dicer is crucial for the generation of microRNAs (miRNAs), which are essential for regulating gene expression and keeping neuronal health. Dicer’s conditional deletion cuts all spiral ganglion neurons but spares a small fraction of vestibular ganglion neurons, innervating the utricle and part of the saccule. Hair cells develop in the utricle, saccule, posterior crista, and the cochlea in Pax2Cre; Dicerf/f. Cochlear hair cells develop at the base and expand the OHC and IHC in the middle, or split into a base/middle and the apex. In contrast, Foxg1Cre; Dicerf/f cuts all canal cristae and cochlea hair cells, leaving a reduced utricle and an exceedingly small saccule. Likewise, Foxg1Cre; Gata3f/f shows no cochlear hair cells and is absent in the horizontal and reduced in the posterior crista. In contrast, the utricle, saccule, and anterior crista are nearly normal, underscoring the intricate regulatory networks involved in hair cell and neuronal development. The central projections have been described as the topology of various null deletions. Still, without spiral ganglion neurons, fibers from Dicer null mice navigate to the cochlear nuclei and expand into the vestibular nuclei to innervate the caudal brainstem. Beyond a ramification around the CN, no fibers expand to reach the cerebellum, likely due to Pax2 and Foxg1 that cut these neurons. Genetic alterations, such as Dicer deletion, can lead to hearing loss and impairments in auditory signal processing, illustrating the critical role of microRNAs in the development and function of auditory and vestibular neurons. Further studies on this topic could help in understanding potential therapeutic targets for hearing loss associated with neuronal degradation of miRNA. Full article
(This article belongs to the Section Molecular Biology)
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22 pages, 5813 KB  
Article
Gel Microparticles Based on Polymeric Sulfonates: Synthesis and Prospects for Biomedical Applications
by Olga D. Iakobson, Elena M. Ivan’kova, Yuliya Nashchekina and Natalia N. Shevchenko
Int. J. Mol. Sci. 2026, 27(1), 538; https://doi.org/10.3390/ijms27010538 - 5 Jan 2026
Viewed by 123
Abstract
Polyelectrolyte microspheres based on a polymer containing sulfonate groups are considered promising drug delivery systems for encapsulating drugs and ensuring their prolonged release. In this study, gel microparticles based on various sulfonate-containing polymers were formed, and their potential as drug delivery systems was [...] Read more.
Polyelectrolyte microspheres based on a polymer containing sulfonate groups are considered promising drug delivery systems for encapsulating drugs and ensuring their prolonged release. In this study, gel microparticles based on various sulfonate-containing polymers were formed, and their potential as drug delivery systems was evaluated, particularly for the controlled administration of the cytotoxic anthracycline antibiotic doxorubicin and the antifungal drug fuchsine. An undeniable advantage of such gel microspheres is the presence in their structure of sulfonate groups localized both in the surface layer and in the volume. The main monomers used were styrene-4-sulfonic acid sodium salt and 3-sulfopropyl methacrylate potassium salt; spherical, porous microparticles were obtained via free-radical reverse suspension polymerization. Microsphere properties (size, porosity, pore structure, electrical surface properties, and swelling) were tailored by changing the nature of the sulfonate, using a comonomer (vinyl acetate or ethyl acrylate), adding a co-solvent, or modulating the crosslinker composition, which influenced drug loading efficiency (doxorubicin, fuchsine). The gel-like structure of the microspheres was confirmed, and the sulfonate groups were found to be distributed throughout both the surface layer and the internal volume of the microspheres. A comparison was also made with non-porous polymer particles containing sulfonate groups. The sorption capacity of the gel microspheres for doxorubicin was 2.2 mmol/g, significantly higher than the 0.4 mmol/g observed for the non-porous reference particles. The obtained values of doxorubicin sorption on gel microspheres are over 60 times higher than the values reported in the literature. Full article
(This article belongs to the Collection State-of-the-Art Macromolecules in Russia)
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23 pages, 2464 KB  
Article
Biosynthesis of UV-Absorbing Mycosporine-like Amino Acids and Transcriptomic Profiling of Differential Gene Expression in Green Microalga Under Abiotic Stresses
by Georgia Tsintzou, Evmorfia Bataka, Georgia Tagkalaki, Sofoklis Keisaris, Nikolaos Tsiropoulos, Nikolaos Labrou and Panagiotis Madesis
Int. J. Mol. Sci. 2026, 27(1), 537; https://doi.org/10.3390/ijms27010537 - 5 Jan 2026
Viewed by 151
Abstract
Microalgae display remarkable resilience to harsh environments, partly through the biosynthesis of diverse secondary metabolites. Cyanobacteria and red algae are well known to produce mycosporine-like amino acids (MAAs)—low-molecular-weight, water-soluble UV-absorbing compounds with anti-inflammatory, anticancer, and antimicrobial activities. By contrast, green microalgae typically lack [...] Read more.
Microalgae display remarkable resilience to harsh environments, partly through the biosynthesis of diverse secondary metabolites. Cyanobacteria and red algae are well known to produce mycosporine-like amino acids (MAAs)—low-molecular-weight, water-soluble UV-absorbing compounds with anti-inflammatory, anticancer, and antimicrobial activities. By contrast, green microalgae typically lack detectable MAAs under standard conditions, and their responses under abiotic stress remain poorly characterized. Here, we investigated the freshwater green microalga Jaagichlorella luteoviridis grown under three stressors (salinity, heat, and UV) and assessed MAA induction. High-performance liquid chromatography (HPLC) revealed that stressed cultures accumulated multiple MAAs, whereas untreated controls showed no such accumulation. All stress treatments (UV, salinity, and heat) produced a substantial increase in peak intensity at 323–350 nm, whereas the control samples showed significantly lower absorption in this region. We also optimized an MAA extraction protocol suitable for “green” downstream applications in the pharmaceutical, nutraceutical, and cosmeceutical sectors and formulated an emulsion showing preliminary positive results and exhibiting an increased SPF index from 3.60 (control) to 3.78 when 0.2% MAA extract was added. Transcriptomic profiling against a reference genome revealed stress-specific differential gene expression and overexpression of specific genes of the MAA pathway, like ArioC and AroM/Aro1 SAM methyltransferases, thus identifying candidate targets for engineering enhanced MAA production. Given market demand for environmentally friendly and safe bioactives, microalgae represent a promising source of these valuable molecules. Full article
(This article belongs to the Special Issue Recent Research of Natural Products from Microalgae and Cyanobacteria)
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2 pages, 567 KB  
Correction
Correction: Mano et al. Fluidity of Poly (ε-Caprolactone)-Based Material Induces Epithelial-to-Mesenchymal Transition. Int. J. Mol. Sci. 2020, 21, 1757
by Sharmy Saimon Mano, Koichiro Uto and Mitsuhiro Ebara
Int. J. Mol. Sci. 2026, 27(1), 536; https://doi.org/10.3390/ijms27010536 - 5 Jan 2026
Viewed by 86
Abstract
In the original publication [...] Full article
(This article belongs to the Section Biochemistry)
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29 pages, 1598 KB  
Review
Inflammation and Resolution in Obesity-Related Cardiovascular Disease
by Paschalis Karakasis, Panagiotis Stachteas, Panagiotis Iliakis, Georgios Sidiropoulos, Konstantinos Grigoriou, Dimitrios Patoulias, Antonios P. Antoniadis and Nikolaos Fragakis
Int. J. Mol. Sci. 2026, 27(1), 535; https://doi.org/10.3390/ijms27010535 - 5 Jan 2026
Viewed by 745
Abstract
Obesity-associated inflammation underlies much of cardiometabolic pathology, reflecting the convergence of chronic, low-grade systemic immune activation with region-specific maladaptation of adipose depots. Among these, epicardial adipose tissue (EAT)—a visceral fat layer contiguous with the myocardium and sharing its microvasculature—functions as a cardio-proximal immunometabolic [...] Read more.
Obesity-associated inflammation underlies much of cardiometabolic pathology, reflecting the convergence of chronic, low-grade systemic immune activation with region-specific maladaptation of adipose depots. Among these, epicardial adipose tissue (EAT)—a visceral fat layer contiguous with the myocardium and sharing its microvasculature—functions as a cardio-proximal immunometabolic interface that influences atrial fibrillation, heart failure with preserved ejection fraction, and coronary atherogenesis through paracrine crosstalk. These relationships extend beyond crude measures of adiposity, emphasizing the primacy of local inflammatory signaling, adipokine flux, and fibro-inflammatory remodeling at the EAT–myocardium interface. Of importance, substantial weight reduction only partially reverses obesity-imprinted transcriptional and epigenetic programs across subcutaneous, visceral, and epicardial depots, supporting the concept of an enduring adipose memory that sustains cardiovascular (CV) risk despite metabolic improvement. Accordingly, therapeutic strategies should move beyond weight-centric management toward mechanism-guided interventions. Resolution pharmacology—leveraging specialized pro-resolving mediators and their cognate G-protein-coupled receptors—offers a biologically plausible means to terminate inflammation and reprogram immune–stromal interactions within adipose and CV tissues. Although preclinical studies report favorable effects on vascular remodeling, myocardial injury, and arrhythmic vulnerability, clinical translation is constrained by pharmacokinetic liabilities of native mediators and by incomplete validation of biomarkers for target engagement. This review integrates mechanistic, depot-resolved, and therapeutic evidence to inform the design of next-generation anti-inflammatory strategies for obesity-related CV disease. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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27 pages, 1924 KB  
Article
Male Stress Is Associated with Ovarian and Endometrial Responses in ICSI Cycles: Is Seminal Plasma the Linchpin?
by Marina Nikolaeva, Alla Arefieva, Alina Babayan, Andrey Romanov, Nataliya Makarova, Liubov Krechetova, Elena Kalinina and Gennady Sukhikh
Int. J. Mol. Sci. 2026, 27(1), 534; https://doi.org/10.3390/ijms27010534 - 5 Jan 2026
Viewed by 161
Abstract
Evidence indicates that seminal plasma (SP) has pregnancy-favorable biological effects, but there is no definitive proof that exposure to SP increases pregnancy rates in assisted reproductive techniques. We previously showed that this discrepancy may be due to male stress altering SP composition. This [...] Read more.
Evidence indicates that seminal plasma (SP) has pregnancy-favorable biological effects, but there is no definitive proof that exposure to SP increases pregnancy rates in assisted reproductive techniques. We previously showed that this discrepancy may be due to male stress altering SP composition. This study investigated the association between male stress biomarkers in saliva, serum and SP and key determinants of female fertility in women exposed to their partner’s SP during the intracytoplasmic sperm injection (ICSI) cycle. The prospective pilot study included couples with tubal infertility who had unprotected intercourse during the ICSI cycle, supplemented by intravaginal SP injection on the oocyte retrieval day. Salivary cortisol and seminal noradrenaline were quantified by enzyme-linked immunosorbent assay to assess the activity of the hypothalamic–pituitary–adrenal axis and sympathetic nervous systems. Seminal interleukin-18 was measured using LegendPlex™ technology. Cluster analysis of male stress biomarkers identified two neuroendocrine-immune (NEI) phenotypes, characterized by signs of acute (phenotype-1) and chronic (phenotype-2) stress. Women with NEI phenotype-2 partners had fewer collected, mature, and fertilized oocytes, thinner endometrium, and significantly lower pregnancy rates (18.2%) compared to those with NEI phenotype-1 partners (84.6%). These data may suggest a dual role for SP in female fertility, depending on the type of male stress. Full article
(This article belongs to the Special Issue Endocrine–Immune Crosstalk in Human Reproductive Health and Pathology)
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12 pages, 755 KB  
Case Report
Novel SIM1 Variants Expanding the Spectrum of SIM1-Related Obesity
by Idris Mohammed, Wesam S. Ahmed, Tara Al-Barazenji, Hajar Dauleh, Donald R. Love and Khalid Hussain
Int. J. Mol. Sci. 2026, 27(1), 533; https://doi.org/10.3390/ijms27010533 - 5 Jan 2026
Viewed by 118
Abstract
Monogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader–Willi-like syndrome, characterized by hyperphagia, [...] Read more.
Monogenic forms of severe early-onset obesity often involve genetic disruptions in the hypothalamic leptin-melanocortin pathway. Pathogenic variants in the SIM1 gene, a key transcription factor required for the development of the paraventricular nucleus, are a known cause of Prader–Willi-like syndrome, characterized by hyperphagia, severe obesity, and developmental delay. We performed targeted next-generation sequencing of 52 obesity-associated genes on a cohort of pediatric patients with severe early-onset obesity. Identified variants were analyzed for population frequency and predicted pathogenicity using in silico tools. The structural impact of the novel missense variants was assessed using protein domain modeling with AlphaFold3. We identified five rare SIM1 variants in eleven patients. Four were heterozygous nonsynonymous variants: one frameshift in the bHLH domain (p.Ser18Ter), one frameshift in the Per-ARNT-Sim domain (p.His143Ter), and two missense variants, p.Pro30Ala and p.Ser663Leu. Structural modeling suggested that the missense variants are likely to disrupt critical protein–protein interactions. The fifth variant was a synonymous change, c.1173G>A, p.(Ser391Ser), which was detected in five unrelated patients. Bioinformatic analysis predicted that this variant could alter splicing. Structural modeling suggested that the missense variants interfere with SIM1 function. This study expands the mutational spectrum of SIM1-linked monogenic obesity, reporting novel likely pathogenic frameshift variants, a missense variant, and a recurrent synonymous variant with a potential splice-site effect. The majority of the variants are predicted to affect the SIM1 protein. Our findings strengthen the critical role of the SIM1 gene in hypothalamic development and energy homeostasis. The results underscore the importance of including the SIM1 gene in genetic testing panels for children with severe obesity and hyperphagia, enabling precise diagnosis and potential future personalized management. Functional in vitro or in vivo validation of these variants is required to confirm their pathogenicity. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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11 pages, 1276 KB  
Article
Genetic Evolution of Melanoma: Comparative Analysis of Candidate Gene Mutations in Healthy Skin, Nevi, and Tumors from the Same Patients
by Marta Gil-Barrachina, Barbara Hernando, Gemma Perez-Pastor, Victor Alegre-de-Miquel, Cristian Valenzuela-Oñate, Sandra Minguez-Lujan, Pablo Monfort-Lanzas, Elena Tomas-Bort, Maria Angeles Marques-Torrejon and Conrado Martinez-Cadenas
Int. J. Mol. Sci. 2026, 27(1), 532; https://doi.org/10.3390/ijms27010532 - 5 Jan 2026
Viewed by 142
Abstract
Melanocytic tumorigenesis is thought to occur through stepwise genomic evolution from normal skin to nevi and, ultimately, melanoma. To investigate this progression, we performed targeted deep sequencing of a 46-gene panel in matched healthy skin, nevus, and melanoma samples from 15 patients, including [...] Read more.
Melanocytic tumorigenesis is thought to occur through stepwise genomic evolution from normal skin to nevi and, ultimately, melanoma. To investigate this progression, we performed targeted deep sequencing of a 46-gene panel in matched healthy skin, nevus, and melanoma samples from 15 patients, including 14 complete tissue trios. Mutation burden increased progressively across tissues, with median mutation counts rising from benign skin to nevi and showing the highest levels in melanoma, consistent with cumulative somatic alterations. Canonical MAPK pathway mutations were common: BRAF V600E and NRAS Q61 variants were detected in many nevi and melanomas and were shared between lesions in 8 of 15 patients, providing direct evidence of clonal continuity. Variant allele frequencies for driver and nonsynonymous mutations were higher than those of passenger and synonymous mutations, reflecting selective expansion of functionally relevant clones. UV-signature substitutions were abundant, particularly among synonymous variants, suggesting background mutagenesis without clonal advantage. Melanoma-private mutations in genes such as ARID1A, ARID2, PIK3CA, and CDKN2A indicated additional late events contributing to malignant progression. Overall, this study supports a model in which many melanomas evolve from pre-existing nevi through sequential acquisition and clonal amplification of somatic mutations, while also revealing heterogeneous evolutionary trajectories. Full article
(This article belongs to the Section Biochemistry)
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15 pages, 3028 KB  
Article
Evaluating the Immunological Impact of Hepatitis B Vaccination in Patients with Inflammatory Bowel Disease
by Irene Soleto, Alicia C. Marin, Montse Baldan-Martin, David Bernardo, María Chaparro and Javier P. Gisbert
Int. J. Mol. Sci. 2026, 27(1), 531; https://doi.org/10.3390/ijms27010531 - 5 Jan 2026
Viewed by 173
Abstract
Patients with inflammatory bowel disease (IBD) frequently fail to achieve protective immunity after hepatitis B vaccination, even with intensified vaccination schedules. In this observational real-world study, 18 patients with IBD who were seronegative for hepatitis B virus (HBV) received three standard doses of [...] Read more.
Patients with inflammatory bowel disease (IBD) frequently fail to achieve protective immunity after hepatitis B vaccination, even with intensified vaccination schedules. In this observational real-world study, 18 patients with IBD who were seronegative for hepatitis B virus (HBV) received three standard doses of the Engerix-B® vaccine (at 0, 1, and 6 months). After immunisation, patients were classified into responders and non-responders according to their serological response. Blood samples were collected before the first dose and after completion of the vaccination schedule. Responders activated pathways that supported durable protection, including conventional dendritic cells type 1 mobilisation, expansion of IgG plasmablasts, and preservation of B- and T-cell memory. In contrast, non-responders displayed a more inflammatory innate profile, characterised by enrichment of CCR2+ monocytes. They also showed higher baseline Treg frequencies, which may suppress effective effector responses, together with impaired natural killer (NK) activation and progressive loss of memory potential. This study shows that hepatitis B vaccine failure in inflammatory bowel disease reflects a convergence of excessive immune regulation, inflammatory activation, and loss of memory potential, underscoring that no single pathway can explain the impaired response. Full article
(This article belongs to the Special Issue Advances in Vaccine Immunology)
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22 pages, 1898 KB  
Article
Dormancy Versus Germination: 3D Protein Modeling and Evolutionary Analyses Define the Roles of Genetic Variants in the Barley MKK3 Enzyme
by Maria Hrmova, Christoph Dockter, Flavia Krsticevic, Morten Egevang Jørgensen, Birgitte Skadhauge and Geoffrey B. Fincher
Int. J. Mol. Sci. 2026, 27(1), 530; https://doi.org/10.3390/ijms27010530 - 5 Jan 2026
Viewed by 214
Abstract
Dormancy is a characteristic of plant seeds that has evolved to avoid exposing the young seedling to adverse weather conditions. The mitogen-activated protein kinase MKK3 from barley is known to mediate the duration of dormancy and subsequent germination of the grain. Here, we [...] Read more.
Dormancy is a characteristic of plant seeds that has evolved to avoid exposing the young seedling to adverse weather conditions. The mitogen-activated protein kinase MKK3 from barley is known to mediate the duration of dormancy and subsequent germination of the grain. Here, we used computational and phylogenetic approaches to define the structural model of the monomeric MKK3 domain in complex with the downstream MAPK protein kinase that it phosphorylates. We utilized key genetic variants of the barley MKK3 and generated the structural MKK3/MAPK enzyme-substrate complex, supported by evolutionary analyses, to rationalize the effects of the MKK3 variants occurring at the ATP binding site and in the loops that can be phosphorylated. We propose the likely mechanism of ATP hydrolysis and the effects of common genetic variants on MKK3 activity, thereby influencing the duration of dormancy. The data will facilitate future manipulations of dormancy length in different environments. Full article
(This article belongs to the Collection Feature Papers in Molecular Plant Sciences)
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29 pages, 17558 KB  
Article
Subtype-Specific m6A circRNA Methylation Patterns Identify Epigenetic Biomarker Candidates of Potential Diagnostic and Prognostic Significance in Breast Cancer
by Amal Qattan, Wafa Alkhayal, Kausar Suleman, Taher Al-Tweigeri and Asma Tulbah
Int. J. Mol. Sci. 2026, 27(1), 529; https://doi.org/10.3390/ijms27010529 - 4 Jan 2026
Viewed by 245
Abstract
Breast cancer subtypes are known to have important pathobiological and clinical features. For example, triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant breast cancer subtypes, lacking hormone and HER2 targets. Increasing evidence suggests that circular RNAs (circRNAs) and their [...] Read more.
Breast cancer subtypes are known to have important pathobiological and clinical features. For example, triple-negative breast cancer (TNBC) remains one of the most aggressive and treatment-resistant breast cancer subtypes, lacking hormone and HER2 targets. Increasing evidence suggests that circular RNAs (circRNAs) and their N6-methyladenosine (m6A) modifications play critical roles in cancer biology through the regulation of gene expression, stability, and signaling networks. This study aimed to identify m6A methylation patterns in circRNAs among breast cancer subtypes, explore their potential biological functions, and assess their diagnostic and prognostic relevance compared with luminal breast cancer subtypes. Genome-wide profiling of m6A-modified circRNAs was conducted in TNBC and luminal breast tumor samples using methylated RNA immunoprecipitation followed by microarray analysis. Differential methylation and expression analyses were integrated with pathway enrichment, survival correlation, and receiver operating characteristic (ROC) curve assessments to identify subtype-specific and clinically relevant circRNA candidates. Distinct m6A circRNA methylation signatures were identified across breast cancer subtypes, with TNBC showing enrichment in pathways related to Wnt/β-catenin, CDC42 GTPase signaling, and cytoskeletal remodeling. Several circRNAs, including those derived from ZBTB16, DOCK1, METTL8, and VAV3, exhibited significant hypermethylation and high diagnostic accuracy (AUC > 0.80). Survival analyses revealed associations between circRNAs from key host genes and overall or relapse-free survival, suggesting prognostic potential. These findings uncover subtype-specific m6A circRNA methylation landscapes that may contribute to tumor aggressiveness and heterogeneity. Identified circRNAs represent candidates for investigation as biomarkers for subtype classification and prognosis and may inform future research into epigenetic and post-transcriptional therapeutic targets in breast cancer. Full article
(This article belongs to the Special Issue The Role of RNAs in Cancers: Recent Advances)
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28 pages, 6222 KB  
Review
Specific Recognition of Glycoproteins: Design Strategies and Application Prospects of Molecularly Imprinted Polymers
by Ping Xie, Zi-Ying Chen, Chun-Fang Xie and Jie-Ping Fan
Int. J. Mol. Sci. 2026, 27(1), 528; https://doi.org/10.3390/ijms27010528 - 4 Jan 2026
Viewed by 308
Abstract
Glycoproteins pose significant challenges for specific recognition due to their structural complexity and microheterogeneity. Molecularly imprinted polymers (MIPs) have emerged as promising synthetic receptors, offering high stability and tailorable recognition sites. This review specifically highlights and systematically evaluates several cutting-edge design strategies tailored [...] Read more.
Glycoproteins pose significant challenges for specific recognition due to their structural complexity and microheterogeneity. Molecularly imprinted polymers (MIPs) have emerged as promising synthetic receptors, offering high stability and tailorable recognition sites. This review specifically highlights and systematically evaluates several cutting-edge design strategies tailored for glycoproteins, including oriented surface imprinting for site-accessible recognition, epitope imprinting for enhanced specificity, and post-imprinting modification for tailored functionality. The fundamental principles, technical advantages, and applications in glycoprotein detection and separation are thoroughly discussed, with a particular emphasis on a comparative analysis to guide strategy selection and how they collectively address the persistent challenges of traditional imprinting. Future perspectives highlight stimuli-responsive systems, multimodal recognition, and computational design to advance MIPs as indispensable tools in proteomics and personalized medicine. The synergistic integration of these advanced strategies within sustainable and standardized MIP systems is particularly promising for fabricating next-generation synthetic receptors with enhanced recognition capabilities. Full article
(This article belongs to the Section Macromolecules)
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32 pages, 5015 KB  
Review
Evidence Synthesis and Mechanism Analysis of Quercetin Treatment for Atherosclerosis: A Preclinical Systematic Review and Meta-Analysis
by Daiqian Chen, Jiawei Wang, Zhiguo Lei, Liping Qu and Wenjun Zou
Int. J. Mol. Sci. 2026, 27(1), 527; https://doi.org/10.3390/ijms27010527 - 4 Jan 2026
Viewed by 180
Abstract
Atherosclerosis seriously endangers human health. Quercetin has drawn attention for its potential anti-atherosclerotic pharmacological effects. This study aimed to comprehensively assess quercetin’s effect and potential mechanism in treating atherosclerosis through a systematic review and meta-analysis. Preclinical studies published before 20 January 2025 were [...] Read more.
Atherosclerosis seriously endangers human health. Quercetin has drawn attention for its potential anti-atherosclerotic pharmacological effects. This study aimed to comprehensively assess quercetin’s effect and potential mechanism in treating atherosclerosis through a systematic review and meta-analysis. Preclinical studies published before 20 January 2025 were searched for in databases including PubMed, Embase, Web of Science, CNKI, Wanfang, and VIP. The CAMARADES list was used to assess the quality of the included studies. Stata 12 was applied for overall effect, sensitivity, subgroup, and publication bias analyses. Time–dose interval analyses were conducted to explore how quercetin dose and dosing cycle affect intervention effects. Finally, trial sequential analyses were performed using TSA 0.9 software. A total of 22 studies involving 421 animals were included, with a mean methodological quality score of 7.73/10. Meta-analysis showed that relative to the control group, quercetin reduced aortic plaque area, adjusted lipids (lowered TC, TG, and LDL-C and raised HDL-C), downregulated adhesion factors (e.g., VCAM-1) and pro-inflammatory factors (e.g., IL-1β and IL-6), upregulated anti-inflammatory factor IL-10 and antioxidant enzymes (SOD, CAT) while decreasing MDA content, and regulated atherosclerosis-related targets (e.g., LXRα, SIRT1, and mTOR). Subgroup analyses found model establishment time and quercetin administration time affected aortic lesion areas, TC, and TG. Time–dose analysis indicated quercetin had better ameliorative effects on atherosclerosis at 25–100 mg/kg with an 8–10-week intervention. Quercetin significantly improves atherosclerosis and inhibits its occurrence and progression through multiple pathways, such as regulating lipid metabolism, anti-inflammatory effects, and counteracting oxidative stress. Based on current evidence, quercetin is a potential therapeutic agent for treating atherosclerosis. Full article
(This article belongs to the Section Molecular Pharmacology)
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15 pages, 3976 KB  
Article
Antioxidant N-Acetylcysteine Facilitates Breast Cancer Metas-Tasis via Immunosuppressive Reprogramming of Neutrophils
by Jiawen Zhang, Di Wang, Huige Wang, Qiuyu Wu, Menghao Liu, Qing Li and Zheng Gong
Int. J. Mol. Sci. 2026, 27(1), 526; https://doi.org/10.3390/ijms27010526 - 4 Jan 2026
Viewed by 296
Abstract
N-acetylcysteine (NAC) is a widely used antioxidant. It has also attracted significant research interest with regard to its role in cancer progression, although the mechanisms involved remain controversial and poorly understood. Here, using murine models of breast cancer metastasis, we found that systemic [...] Read more.
N-acetylcysteine (NAC) is a widely used antioxidant. It has also attracted significant research interest with regard to its role in cancer progression, although the mechanisms involved remain controversial and poorly understood. Here, using murine models of breast cancer metastasis, we found that systemic NAC administration significantly enhanced pulmonary metastasis without altering primary tumor growth in immunocompetent mice, whereas this metastasis-promoting property of NAC was abrogated in T cell-deficient mice. This phenomenon was not due to the direct effects of NAC on T cells or tumor cells, since in vitro studies indicated that NAC exhibited no impact on the effector functions of T cells or the malignant behavior of breast cancer cells. Mechanistically, we demonstrated that NAC endows neutrophils with an immunosuppressive phenotype, which is characterized by the upregulation of immunosuppressive genes, and these NAC-educated neutrophils potently suppress the activation and effector functions of T cells. Collectively, our study reveals a previously unrecognized role played by NAC in regulating breast cancer lung metastasis by orchestrating the myeloid-dependent suppression of anti-tumor T cell immunity and suggests a need to consider immune-mediated mechanisms when evaluating the systemic impact of antioxidant agents in cancer patients. Full article
(This article belongs to the Section Molecular Oncology)
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