International Journal of Molecular Sciences

19 pages, 3228 KB

Open AccessArticle

Towards Designing Green-Inspired Nano- and Microemulsions Alongside Novel Solvatochromic Probes as an Effective Tool in Delivery Issues

by Aleksandra Szarwaryn, Wojciech Bartkowiak, Tomasz K. Olszewski and Urszula Bazylińska

Int. J. Mol. Sci. 2025, 26(18), 9259; https://doi.org/10.3390/ijms26189259 - 22 Sep 2025

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Abstract

The extensive use of submicron emulsion systems, particularly those stabilized by nonionic surfactants, with their proven effectiveness and safety profile, provides a reassuring foundation for our research. Consequently, we designed and engineered new submicron emulsion formulations stabilized with a biocompatible surfactant polyoxyethylated cocoamine, [...] Read more.

The extensive use of submicron emulsion systems, particularly those stabilized by nonionic surfactants, with their proven effectiveness and safety profile, provides a reassuring foundation for our research. Consequently, we designed and engineered new submicron emulsion formulations stabilized with a biocompatible surfactant polyoxyethylated cocoamine, whose nonionic character is due to a high degree of polyoxyethylation. We chose oleic acid as the oil phase, a fatty acid known for its beneficial properties. This led to novel biocompatible nanoemulsions with high stability and cosurfactant-free microemulsions. The dynamic light scattering studies confirmed that both formulations have a nanometric size and low polydispersity index values. Moreover, transmission electron microscopy verified the nanodroplets’ morphological homogeneity and spherical shape. The resulting nanoplatforms can be applied to carry bioactive agents in the pharmaceutical and cosmetic fields. For this reason, we solubilized newly synthesized 5-dimethylamino-5′-nitro-2,2′-bithiophene as a model hydrophobic cargo for delivering poorly water-soluble compounds. This dye was chosen due to its strong solvatochromic behavior and suitability for micropolarity analysis via UV–Vis spectroscopy. We also present a simple method for rapid micropolarity screening to assess the type of nanodispersion via solvatochromic shift as an alternative procedure for evaluating of the oils used to fabricate nanoformulations for pharmaceutical and cosmetic purposes. Full article

(This article belongs to the Special Issue Surfactants: Design, Synthesis and Application)

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13 pages, 1630 KB

Open AccessArticle

Nodal Spread Prediction in Human Oral Tongue Squamous Cell Carcinoma Using a Cancer-Testis Antigen Genes Signature

by Yoav Smith, Amit Cohen, Tzahi Neuman, Yoram Fleissig and Nir Hirshoren

Int. J. Mol. Sci. 2025, 26(18), 9258; https://doi.org/10.3390/ijms26189258 - 22 Sep 2025

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Abstract

Cervical lymph node metastasis is the strongest prognostic factor in oral tongue carcinoma, yet current clinical guidelines rely primarily on depth of invasion to guide elective neck dissection. This approach results in unnecessary surgery in up to 70% of patients. Cancer-testis antigens (CTAs) [...] Read more.

Cervical lymph node metastasis is the strongest prognostic factor in oral tongue carcinoma, yet current clinical guidelines rely primarily on depth of invasion to guide elective neck dissection. This approach results in unnecessary surgery in up to 70% of patients. Cancer-testis antigens (CTAs) are a family of genes associated with tumor aggressiveness and may serve as predictive biomarkers for nodal spread. A multi-step analysis integrating large-scale public datasets, including microarray (GSE78060), bulk RNA-seq emerging from the cancer genome atlas (TCGA), and single-cell RNA-seq (GSE103322), was employed to identify CTA genes active in oral tongue cancer. Selected genes were validated using NanoString nCounter RNA profiling of 16 patients undergoing curative glossectomy with elective neck dissection. Machine learning algorithms, including decision trees, t-distributed stochastic neighbor embedding (t-SNE), and convolutional neural networks (CNN), were applied to assess predictive power for nodal metastasis. Computational analysis initially identified 40 cancer-active CTA genes, of which four genes (LY6K, MAGEA3, CEP55, and ATAD2) were most indicative of nodal spread. In our patient cohort, NanoString nCounter profiling combined with machine learning confirmed these four genes as highly predictive. We present a proof-of-concept CTA-based genetic diagnostic tool capable of discriminating nodal involvement in oral tongue cancer. This approach may reduce unnecessary neck dissections, minimizing surgical morbidity. Full article

(This article belongs to the Special Issue The Role of Genome in Cancer Therapy)

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30 pages, 1114 KB

Open AccessReview

Tumor Innervation: From Bystander to Emerging Therapeutic Target for Cancer

by Zoey Zeyuan Ji, Max Kam-Kwan Chan, Philip Chiu-Tsun Tang, Calvin Sze-Hang Ng, Chunjie Li, Dongmei Zhang, David J. Nikolic-Paterson, Ka-Fai To, Xiaohua Jiang and Patrick Ming-Kuen Tang

Int. J. Mol. Sci. 2025, 26(18), 9257; https://doi.org/10.3390/ijms26189257 - 22 Sep 2025

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Abstract

Innervation is ubiquitous in diseased tissues, including cancer. Increasing evidence suggests that innervation not only plays a direct role in cancer pain, but is also closely related to disease progression, including cancer growth, metastasis, and drug resistance. At the molecular level, tumor-associated nerves [...] Read more.

Innervation is ubiquitous in diseased tissues, including cancer. Increasing evidence suggests that innervation not only plays a direct role in cancer pain, but is also closely related to disease progression, including cancer growth, metastasis, and drug resistance. At the molecular level, tumor-associated nerves can interact with cancer cells and the tumor microenvironment through neurotrophic factors, thereby promoting tumor occurrence and development, and represent a potential intervention for solid tumors with nerve enrichment. By dissecting the transcriptome dynamics of cancer-associated neurons with single cell resolution, numbers of novel therapeutic targets for tumor denervation have been uncovered, including a novel phenomenon—Macrophage to Neuron-like cell Transition (MNT). This review systematically summarizes the latest research findings of tumor denervation, from molecular mechanisms to the innovative denervation strategies, paving the way for novel, safe, and effective cancer treatments in the clinic. Full article

(This article belongs to the Special Issue Neuroimmune Axis in Cancer and Inflammatory Diseases)

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18 pages, 10778 KB

Open AccessArticle

Investigating the Development of Colorectal Cancer Based on Spatial Transcriptomics

by Zhaoyao Qi, Guoqing Gu, Huanwei Huang, Beile Lyu, Yibo Liu, Wei Wang, Xu Zha and Xicheng Liu

Int. J. Mol. Sci. 2025, 26(18), 9256; https://doi.org/10.3390/ijms26189256 - 22 Sep 2025

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Abstract

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. However, the spatial and temporal dynamics underlying its development remain poorly characterized. This study employs spatial transcriptomics (ST) to investigate the progression of intestinal tumors in APC ^Min/+ mice across multiple time [...] Read more.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide. However, the spatial and temporal dynamics underlying its development remain poorly characterized. This study employs spatial transcriptomics (ST) to investigate the progression of intestinal tumors in APC ^Min/+ mice across multiple time points. We identified distinct transcriptional profiles between tumor and normal tissues, resolving six major cell types through integrated dimensionality reduction and pathological annotation. Pseudo-time trajectory analysis revealed increased expression of MMP11 and MYL9 in later stages of tumor progression. Analysis of human CRC cohorts from the TCGA database further confirmed that high expression of these genes is associated with advanced clinical stages and promotes tumor proliferation and invasion. Temporal gene expression dynamics indicated enrichment of cancer-related pathways concurrent with suppression of lipid and amino acid metabolism. Notably, genes in the DEFA family were significantly upregulated in normal tissues compared to tumor tissues. Functional validation showed that DEFA3 inhibits colon cancer cell migration and proliferation in vitro. These demonstrate the value of ST in resolving spatiotemporal heterogeneity in CRC and identify both MMP11/MYL9 and DEFA3 as potential biomarkers and therapeutic targets. Full article

(This article belongs to the Section Molecular Oncology)

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27 pages, 5495 KB

Open AccessArticle

Mesoporous Silicas of Well-Organized Structure: Synthesis, Characterization, and Investigation of Physical Processes Occurring in Confined Pore Spaces

by Magdalena Blachnio, Malgorzata Zienkiewicz-Strzalka and Anna Derylo-Marczewska

Int. J. Mol. Sci. 2025, 26(18), 9255; https://doi.org/10.3390/ijms26189255 - 22 Sep 2025

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Abstract

Mesoporous silica materials with well-organized architectures were synthesized using a series of Pluronic PE-type triblock copolymers (PE6800, PE9200, PE9400, PE10500) as structure-directing agents under acidic conditions. The study aimed to elucidate the impact of synthesis parameters—copolymer type, presence of a swelling agent, 1,3,5-trimethylbenzene, [...] Read more.

Mesoporous silica materials with well-organized architectures were synthesized using a series of Pluronic PE-type triblock copolymers (PE6800, PE9200, PE9400, PE10500) as structure-directing agents under acidic conditions. The study aimed to elucidate the impact of synthesis parameters—copolymer type, presence of a swelling agent, 1,3,5-trimethylbenzene, aging temperature, and silica precursor—on the structural, textural, and functional properties of the resulting mesocellular foam materials. Characterization by Nitrogen Adsorption/Desorption, Transmission Electron Microscopy, X-ray Diffraction, and Small-angle X-ray Scattering revealed that structural ordering and pore morphology are significantly influenced by the EO/PO ratio of the copolymers and the use of the expander. Materials synthesized with PE9400 and PE10500 in the presence of a swelling agent exhibited highly uniform bottle-shaped mesopores with increased surface area and pore volume. Thermal behavior studied via Differential Scanning Calorimetry indicated a correlation between pore size and melting point depression of confined water, consistent with the Gibbs–Thomson effect. Adsorption capacity and kinetics for methylene blue varied significantly with pore structure, with materials possessing narrow mesopores showing superior dye uptake, and materials with larger mesopores and open-pore architecture exhibiting faster adsorption rates. This work demonstrates the tunability of mesoporous silica structure through precise control of synthesis conditions and highlights its potential in applications involving adsorption and phase phenomena in confined pore systems. Full article

(This article belongs to the Section Materials Science)

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29 pages, 23285 KB

Open AccessArticle

Methodological Comparison of Short-Read and Long-Read Sequencing Methods on Colorectal Cancer Samples

by Nikolett Szakállas, Alexandra Kalmár, Kristóf Róbert Rada, Marianna Kucarov, Tamás Richárd Linkner, Barbara Kinga Barták, István Takács and Béla Molnár

Int. J. Mol. Sci. 2025, 26(18), 9254; https://doi.org/10.3390/ijms26189254 - 22 Sep 2025

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Abstract

Colorectal cancer (CRC) is driven by a complex spectrum of somatic mutations and structural variants that contribute to tumor heterogeneity and therapy resistance. In this study, we performed a comparative analysis of short-read Illumina and long-read Nanopore sequencing technologies across multiple CRC sample [...] Read more.

Colorectal cancer (CRC) is driven by a complex spectrum of somatic mutations and structural variants that contribute to tumor heterogeneity and therapy resistance. In this study, we performed a comparative analysis of short-read Illumina and long-read Nanopore sequencing technologies across multiple CRC sample groups, encompassing diverse tissue morphologies. Our evaluation included general base-level metrics—such as nucleotide ratios, sequence match rates, and coverage—as well as variant calling performance, including variant allele frequency (VAF) distributions and pathogenic mutation detection rates. Focusing on clinically relevant genes (KRAS, BRAF, TP53, APC, PIK3CA, and others), we characterized platform-specific detection profiles and completed the ground truth validation of somatic KRAS and BRAF mutations. Structural variant (SV) analysis revealed Nanopore’s enhanced ability to resolve large and complex rearrangements, with consistently high precision across SV types, though recall varied by variant class and size. To enable direct comparison with the Illumina exome panel, we applied an exonic position reference file. To assess the impact of depth and PCR amplification, we completed an additional high-coverage Nanopore sequencing run. This analysis confirmed that PCR-free protocols preserve methylation signals more accurately, reinforcing Nanopore’s utility for integrated genomic and epigenomic profiling. Together, these findings underscore the complementary strengths of short- and long-read sequencing platforms in high-resolution cancer genomics, and we highlight the importance of coverage normalization, epigenetic fidelity, and rigorous benchmarking in variant discovery. Full article

(This article belongs to the Section Molecular Oncology)

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20 pages, 875 KB

Open AccessReview

Epigallocatechin-Gallate (EGCG): An Essential Molecule for Human Health and Well-Being

by Emanuele Rovaldi, Violante Di Donato, Giovanni Paolino, Marzia Bruno, Alessia Medei, Steven Paul Nisticò, Giovanni Pellacani, Norbert Kiss, Giulia Azzella, Andras Banvolgyi and Carmen Cantisani

Int. J. Mol. Sci. 2025, 26(18), 9253; https://doi.org/10.3390/ijms26189253 - 22 Sep 2025

Viewed by 267

Abstract

Green tea, long consumed across Southeast Asia, is highly esteemed for its medicinal properties and is often favored over conventional treatments in Eastern cultures. Its health benefits are largely attributed to its minimal processing, which preserves pharmacologically active compounds, particularly catechins, a key [...] Read more.

Green tea, long consumed across Southeast Asia, is highly esteemed for its medicinal properties and is often favored over conventional treatments in Eastern cultures. Its health benefits are largely attributed to its minimal processing, which preserves pharmacologically active compounds, particularly catechins, a key class of polyphenols, with epigallocatechin-gallate (EGCG) being the most abundant and bioactive. These compounds exhibit antioxidant, anti-cancer, antimicrobial, and antiangiogenic properties. Beyond systemic health, EGCG has diverse applications in dermatology, including the treatment of viral warts, psoriasis, lichen sclerosus, acne, vaginal dryness, alopecia, and UV-induced skin damage. Emerging research also highlights its promise in aesthetic medicine for mitigating skin oxidative stress, improving skin brightness and neutralizing free radicals, responsible for wrinkles, hyperpigmentation, and loss of elasticity. The aim of this review is to examine the most recent literature on the wide-ranging clinical applications of Epigallocatechin-gallate (EGCG) and to assess its potential use as a daily foundational supplement to enhance both physical and mental well-being, focusing on the dermatological benefits. Full article

(This article belongs to the Special Issue Dietary Supplements: A Delicate Balance Between Benefit and Harm)

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13 pages, 1074 KB

Open AccessArticle

Global and Sex-Stratified Genome-Wide Association Study of Long COVID Based on Patient-Driven Symptom Recall

by Sara Polo-Alonso, Álvaro Hernáez, Irene R. Dégano, Ruth Martí-Lluch, Mel·lina Pinsach-Abuin, Roberto Elosua, Isaac Subirana, Marta Puigmulé, Alexandra Pérez, Raquel Cruz, Silvia Diz-de Almeida, Eulàlia Puigdecant, Elisabet Selga, Xavier Nogues, Joan Ramon Masclans, Roberto Güerri-Fernández, Héctor Cubero-Gallego, Helena Tizon-Marcos, Beatriz Vaquerizo, Ramon Brugada, Rafel Ramos, Anna Camps-Vilaró and Jaume Marrugat Show full author list Hide full author list

Int. J. Mol. Sci. 2025, 26(18), 9252; https://doi.org/10.3390/ijms26189252 - 22 Sep 2025

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Abstract

We aimed to explore the global and sex-specific genetic variants associated with long COVID, as defined by patient-driven symptom recall. A 1-year cohort study of 2411 COVID-19 patients collected long COVID symptoms with an open-ended, non-directed questionnaire, and long COVID incidence was determined [...] Read more.

We aimed to explore the global and sex-specific genetic variants associated with long COVID, as defined by patient-driven symptom recall. A 1-year cohort study of 2411 COVID-19 patients collected long COVID symptoms with an open-ended, non-directed questionnaire, and long COVID incidence was determined according to the World Health Organization definition. Global and sex-stratified genome-wide association analyses were conducted by logistic regression models adjusted for age, sex (in the global analysis), and the first 10 principal components. We assessed sex-variant interactions and performed gene-based analyses, gene mapping, and gene-set enrichment analyses. When comparing the 1392 long COVID cases with the non-cases, we identified 23 lead variants from suggestive signals: 13 from the global analysis, 5 from females, and 5 from males. Five variants showed a significant interaction with sex (two in females, three in males). We mapped 15 protein-coding genes related to diseases of the immune and nervous systems and tumoral processes. Notably, CD5 and VPS37C, linked to immune function, were significantly associated with long COVID in men. Our results suggest that persistent immune dysregulation may be involved in the development of precisely defined long COVID. Full article

(This article belongs to the Special Issue Molecular Research and Insights into COVID-19: Third Edition)

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17 pages, 6419 KB

Open AccessArticle

Lactiplantibacillus plantarum HY7715 Alleviates Restraint Stress-Induced Anxiety-like Behaviors by Modulating Oxidative Stress, Apoptosis, and Mitochondrial Function

by Kippuem Lee, Daehyeop Lee, Haeryn Jeong, Joo Yun Kim, Jae Jung Shim and Jae Hwan Lee

Int. J. Mol. Sci. 2025, 26(18), 9251; https://doi.org/10.3390/ijms26189251 - 22 Sep 2025

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Abstract

Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast [...] Read more.

Anxiety disorders are closely associated with oxidative stress-mediated neuronal damage, mitochondrial dysfunction, and apoptosis. In this study, we investigated the neuroprotective effects of Lactiplantibacillus plantarum HY7715 in a mouse model of restraint stress-induced anxiety, and in neuronal cell models (HT-22 mouse hippocampal neuroblast cell and SH-SY5Y human neuroblastoma cells). Oral administration of HY7715 (1 × 10⁹ CFU/kg/day) alleviated anxiety-like behaviors significantly, as shown by increased central exploration in the open field test and prolonged open-arm activity in the elevated plus maze. HY7715 reduced serum norepinephrine levels elevated by stress, and restored hippocampal expression of brain-derived neurotrophic factor, while suppressing pro-inflammatory (NF-κB, IL-6) and pro-apoptotic (BAX, caspase-3) markers. It also increased expression of mitochondrial regulatory genes (SIRT1, mTOR), and decreased that of cytochrome c, in brain tissue. Histological analysis revealed that HY7715 preserved neuronal integrity in the CA1 and CA3 hippocampal regions. In vitro, HY7715 attenuated oxidative stress-induced cytotoxicity, decreased intracellular ROS accumulation, maintained mitochondrial activity, and inhibited apoptosis of both neuronal cell types, showing greater efficacy than the strain type L. plantarum KCTC3108. These findings suggest that HY7715 exerts neuroprotective effects by modulating oxidative stress/apoptosis/mitochondrial pathways, and highlight its potential as a psychobiotic for stress-related neuropsychiatric disorders. Full article

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

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36 pages, 1527 KB

Open AccessReview

The Role of Prenatal Microglial Activation and Its Sex Differences in the Development of Neuropsychiatric Disorders and Neurodegenerative Diseases

by Alexander Sergeevich Lyamtsev, Alexandra Vladislavovna Sentyabreva and Anna Mikhailovna Kosyreva

Int. J. Mol. Sci. 2025, 26(18), 9250; https://doi.org/10.3390/ijms26189250 - 22 Sep 2025

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Abstract

Maternal Immune Activation (MIA) is a phenomenon of pathophysiological stimulation of the maternal immune system during gestation which potentially leads to functional and structural disturbances of fetal neurogenesis. It occurs due to the alteration of paracrine signals between the maternal organism and the [...] Read more.

Maternal Immune Activation (MIA) is a phenomenon of pathophysiological stimulation of the maternal immune system during gestation which potentially leads to functional and structural disturbances of fetal neurogenesis. It occurs due to the alteration of paracrine signals between the maternal organism and the developing nervous system of the fetus. Any disturbances in the brain at embryonic and early postnatal stages might compromise its natural developmental trajectory, which could potentially increase the risk of developing neuropsychiatric disorders, such as schizophrenia, autistic spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), major depressive and bipolar disorders, etc. Presumably, all these conditions could initiate the development of age-related cognitive impairment in late ontogenesis, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. As the main immune cell population in the CNS, microglia both mediate its proper development and receive pathological stimuli from the maternal organism. This could lead to microglia premature activation and could become a part of the mechanisms of the fetal CNS development alterations. In this review, we discuss the role of prenatal activation of microglia in neuropsychiatric disorders and neurodegenerative disease development. We highlight approaches to modeling MIA, as well as sex differences in the morphological and functional state of microglia in the context of physiological conditions. There is a hypothesis discussed regarding the contribution of these distinctions to neuropsychiatric disorders and neurodegenerative disease incidence, prevalence, and progression in males and females. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Alzheimer’s Disease)

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17 pages, 2852 KB

Open AccessArticle

Rotavirus Genotype Dynamics and the Emergence of G3P[8] in Thailand Following Nationwide Vaccine Implementation

by Nutthawadee Jampanil, Kattareeya Kumthip, Thitapa Longum, Zhenfeng Xie, Arpaporn Yodmeeklin, Sirinart Sirilert, Nuthapong Ukarapol, Naphatrapee Sansaard, Channat Promping, Shoko Okitsu, Takeshi Kobayashi, Hiroshi Ushijima, Niwat Maneekarn and Pattara Khamrin

Int. J. Mol. Sci. 2025, 26(18), 9249; https://doi.org/10.3390/ijms26189249 - 22 Sep 2025

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Abstract

Rotavirus A is a leading cause of acute gastroenteritis in infants and young children under the age of five worldwide. The introduction of two live-attenuated oral vaccines, Rotarix and RotaTeq, has significantly decreased illness and death associated with rotavirus in countries where they [...] Read more.

Rotavirus A is a leading cause of acute gastroenteritis in infants and young children under the age of five worldwide. The introduction of two live-attenuated oral vaccines, Rotarix and RotaTeq, has significantly decreased illness and death associated with rotavirus in countries where they are included in childhood immunization schedules. In Thailand, these two vaccines have been part of the national childhood immunization program since 2020. To monitor the changing patterns of rotavirus genotype distribution in the post-vaccination era, a molecular epidemiological study of rotavirus A was conducted in pediatric patients with acute diarrhea in Chiang Mai from 2020 to 2023, which was the period after the rotavirus vaccine was implemented in Thailand. A total of 1192 stool specimens collected from children with acute gastroenteritis were screened for rotavirus A by real-time PCR. The G- and P-genotypes were determined by using semi-nested PCR and nucleotide sequencing. A total of 60 out of 1192 (5.0%) samples were positive for rotavirus A. Among these, G3P[8] (55.0%) was identified as the most prevalent genotype, followed by G8P[8] (15.0%), G1P[8] (13.2%), G9P[8] (3.3%), G2P[4] (3.3%), G1P[6] (1.7%), G9P[4] (1.7%), and G8P[X] (1.7%). Additionally, the unusual rotavirus strains G3P[9] (1.7%), G3P[23] (1.7%), and G5P[23] (1.7%) were detected in this study. Phylogenetic analysis of the VP7 and VP4 genes revealed that the G3P[9] strain was closely related to those of feline rotaviruses, while the G3P[23] and G5P[23] strains showed high similarity to those of the porcine rotavirus strains detected previously in Thailand. This study demonstrated a significant decline in the prevalence of rotavirus A infection in pediatric patients in Chiang Mai, Thailand, during the post-vaccination period. The findings from this study contribute to a better understanding of rotavirus epidemiology in Thailand following the implementation of the rotavirus vaccines. Full article

(This article belongs to the Section Molecular Microbiology)

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12 pages, 1245 KB

Open AccessArticle

Reduced Expression of m⁶A Demethylases FTO and ALKBH5 in Monocytes from the Site of Inflammation in Patients with Juvenile Idiopathic Arthritis

by Hisham I. Abu-Tawil, Lucas W. Picavet, Ellen C. N. van Vroonhoven, Alejandra Bodelón, Rianne C. Scholman, Nienke ter Haar, Arjan Boltjes, Sebastiaan J. Vastert and Jorg van Loosdregt

Int. J. Mol. Sci. 2025, 26(18), 9248; https://doi.org/10.3390/ijms26189248 - 22 Sep 2025

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Abstract

N⁶-methyladenosine (m⁶A) has recently emerged as a post-transcriptional modulator governing cell-specific gene expression in innate immune cells, particularly in monocytes. Disruptions in m⁶A homeostasis, manifested as the altered expression of m⁶A-related proteins and m⁶ [...] Read more.

N⁶-methyladenosine (m⁶A) has recently emerged as a post-transcriptional modulator governing cell-specific gene expression in innate immune cells, particularly in monocytes. Disruptions in m⁶A homeostasis, manifested as the altered expression of m⁶A-related proteins and m⁶A levels, have been implicated in autoimmune disorders. Perturbations in m⁶A dynamics within total Peripheral blood mononuclear cells (PBMCs) have shown strong correlations with disease severity in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). It remains unclear in which specific cell type(s) m⁶A homeostasis is disturbed, and also whether other rheumatic diseases such as juvenile idiopathic arthritis (JIA) show similar features. Here, we assess the involvement of m⁶A and m⁶A-regulatory proteins in JIA monocytes. Notably, the diminished expression of m⁶A-eraser proteins FTO and ALKBH5 was observed in JIA monocytes extracted from the inflamed joint. This resulted in increased m⁶A-methylated transcripts in monocytes from these patients. Correspondingly, we observed that culturing monocytes in the presence of synovial fluid from JIA inflamed joints reduced the expression of both FTO and ALKBH5. The knock-out of FTO in human monocytes of healthy controls increased monocyte activation, indicating the relevance of FTO and m⁶A in the context of JIA. These findings underscore the potential of ALKBH5 and FTO expression as a biomarker in JIA and identify the m⁶A machinery as a potential therapeutic target for the treatment of JIA and possibly other autoimmune diseases in the future. Full article

(This article belongs to the Special Issue New Insights in Biomarkers of Autoimmune and Autoinflammatory Diseases: 2nd Edition)

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16 pages, 832 KB

Open AccessReview

Copper Dysregulation in Major Depression: A Systematic Review and Meta-Analytic Evidence for a Putative Trait Marker

by Rosanna Squitti, Mariacarla Ventriglia, Ilaria Simonelli, Cristian Bonvicini, Daniela Crescenti, Barbara Borroni, Mauro Rongioletti and Roberta Ghidoni

Int. J. Mol. Sci. 2025, 26(18), 9247; https://doi.org/10.3390/ijms26189247 - 22 Sep 2025

Viewed by 144

Abstract

Major depressive disorder (MDD) is a leading contributor to global disability. Despite advances in neurobiological research, no reliable peripheral biomarkers are currently available for diagnosis or monitoring. Copper (Cu), an essential trace element involved in redox balance and monoamine metabolism, has been repeatedly [...] Read more.

Major depressive disorder (MDD) is a leading contributor to global disability. Despite advances in neurobiological research, no reliable peripheral biomarkers are currently available for diagnosis or monitoring. Copper (Cu), an essential trace element involved in redox balance and monoamine metabolism, has been repeatedly associated with MDD, though evidence remains inconsistent. To systematically evaluate and quantify differences in serum Cu concentrations between individuals with MDD and healthy controls, and to explore potential moderators, including sex, age, and analytical methodology. We conducted a systematic review and meta-analysis of observational studies reporting serum Cu levels in MDD patients versus controls. Data were extracted regarding diagnostic criteria, measurement methods, sample characteristics, and study quality. Subgroup and sensitivity analyses were performed based on demographic and methodological variables. Twenty-four studies, including 8617 participants (2736 MDD, 5881 controls), were analyzed. The pooled analysis revealed significantly higher Cu levels in MDD patients (Mean Difference (MD) = 2.22 µmol/L; 95% CI: 0.97–3.48; p = 0.001), although heterogeneity was high (I² = 98.6%). Sub-analysis in females confirmed the association (MD = 1.39 µmol/L; 95% CI: 0.65–2.12; p = 0.009). Results remained robust in sensitivity analyses. Begg’s test did not indicate possible publication bias. Our findings support an association between altered Cu homeostasis and MDD. Elevated Cu levels were observed in most studies, including among females and in subclinical cases, suggesting a potential role as a trait biomarker. Standardization in measurement and longitudinal designs is needed to confirm Cu’s clinical utility. Full article

(This article belongs to the Special Issue New Therapeutic Targets for Neuroinflammation and Neurodegeneration)

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2 pages, 162 KB

Open AccessEditorial

Special Issue “A Commemorative Issue in Honor of József Szejtli: Advances in Cyclodextrin Chemistry and Its Applications”

by Lajos Szente and Éva Fenyvesi

Int. J. Mol. Sci. 2025, 26(18), 9246; https://doi.org/10.3390/ijms26189246 - 22 Sep 2025

Viewed by 116

Abstract

This Special Issue is dedicated to the memory of the late Dr [...] Full article

(This article belongs to the Special Issue A Commemorative Issue in Honor of József Szejtli: Advances in Cyclodextrin Chemistry and Its Applications)

29 pages, 1604 KB

Open AccessReview

Pathological Calcium Signaling in Traumatic Brain Injury and Alzheimer’s Disease: From Acute Neuronal Injury to Chronic Neurodegeneration

by Stephan Neuschmid, Carla Schallerer, Barbara E. Ehrlich and Declan McGuone

Int. J. Mol. Sci. 2025, 26(18), 9245; https://doi.org/10.3390/ijms26189245 - 22 Sep 2025

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Abstract

Loss of calcium homeostasis, a shared feature of Alzheimer’s Disease (AD) and Traumatic Brain Injury (TBI), activates enzyme-dependent cascades that promote protein misfolding, degrade synaptic architecture, impair axonal transport, and lead to neuronal death. Epidemiological studies identify TBI as a major risk factor [...] Read more.

Loss of calcium homeostasis, a shared feature of Alzheimer’s Disease (AD) and Traumatic Brain Injury (TBI), activates enzyme-dependent cascades that promote protein misfolding, degrade synaptic architecture, impair axonal transport, and lead to neuronal death. Epidemiological studies identify TBI as a major risk factor for AD, yet the mechanistic basis for this association remains incompletely understood. Evidence from human and experimental studies implicate calcium dysregulation as a central link, triggering interconnected kinase, phosphatase, and protease networks that drive AD hallmark pathology, including amyloid-β (Aβ) accumulation and tau hyperphosphorylation. The calcium-dependent protease calpain is a key node in this network, regulating downstream enzyme activity, and cleaving essential scaffolding and signaling proteins. Selective vulnerability of the hippocampus and white matter to calcium-mediated damage may underlie cognitive deficits common to both conditions. In preclinical TBI and AD models, pharmacological inhibition of calcium-dependent enzymes confers neuroprotection. Recognizing disrupted calcium signaling as an upstream driver of post-traumatic neurodegeneration may enable early interventions to reduce AD risk among TBI survivors. Full article

(This article belongs to the Special Issue Traumatic Brain Injury/Chronic Traumatic Encephalopathy as Cause of Alzheimer’s Disease: Physics and Molecular Biology in the Genesis of Neurodegeneration?)

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16 pages, 1587 KB

Open AccessReview

Unraveling Resistance in Lung Cancer Immunotherapy: Clinical Milestones, Mechanistic Insights, and Future Strategies

by Maria Vitale, Raffaella Pagliaro, Giuseppe Viscardi, Lucio Pastore, Giuseppe Castaldo, Fabio Perrotta, Susan F. Campbell, Andrea Bianco and Filippo Scialò

Int. J. Mol. Sci. 2025, 26(18), 9244; https://doi.org/10.3390/ijms26189244 - 22 Sep 2025

Viewed by 275

Abstract

Over the last decade, immunotherapy has revolutionized lung cancer treatments, particularly in non-small cell lung cancer, where immune checkpoint inhibitors have achieved significant clinical success. However, high percentages of patients do not respond initially or eventually develop a resistance to these therapies. This [...] Read more.

Over the last decade, immunotherapy has revolutionized lung cancer treatments, particularly in non-small cell lung cancer, where immune checkpoint inhibitors have achieved significant clinical success. However, high percentages of patients do not respond initially or eventually develop a resistance to these therapies. This review explores the evolution and challenges of immunotherapy in lung cancer, highlighting its clinical milestones and intrinsic and extrinsic resistance mechanisms. We investigate tumor-intrinsic resistance factors, including alterations in antigen presentation, the loss of Beta-2 microglobulin function, impaired interferon signaling, immune editing, epigenetic modifications, and tumor-extrinsic resistance, such as an immunosuppressive lung tumor microenvironment, dysregulated cytokine profiles, and the upregulation of immune checkpoints. Then, we focus on the emerging role of resistance biomarkers and the development of personalized treatment strategies to overcome these challenges. The complex interplay between tumor biology and immune modulation in lung cancer paves the way for novel approaches for improving the effectiveness of immunotherapeutic treatments. Full article

(This article belongs to the Collection Feature Papers in Molecular Pathology, Diagnostics, and Therapeutics)

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28 pages, 1074 KB

Open AccessReview

Monoterpenes in Vascular Function: A Review of Bioactivity and Mechanisms of Action

by Tays Gonçalves, Arthur Almeida, Larisse Pontes, Julio Oliveira, Mathania Feitosa, Javanyr Júnior, Robson Veras and Isac Medeiros

Int. J. Mol. Sci. 2025, 26(18), 9243; https://doi.org/10.3390/ijms26189243 - 22 Sep 2025

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Abstract

Cardiovascular diseases are the primary cause of morbidity and mortality worldwide. The function and structure of blood vessels play a crucial role in the development and aggravation of these diseases. Natural products, such as aromatic plants, present a wide variety of terpenes content. [...] Read more.

Cardiovascular diseases are the primary cause of morbidity and mortality worldwide. The function and structure of blood vessels play a crucial role in the development and aggravation of these diseases. Natural products, such as aromatic plants, present a wide variety of terpenes content. Monoterpenes, a selected group of terpenes, have two building blocks of five-carbon isoprene (C₅H₈) unit. Moreover, different monoterpenes have shown pharmacological activity in the cardiovascular system, particularly in vascular function, which is mediated, at least in part, by modulating the nitric oxide pathway, oxidative stress, inflammation, and calcium signaling. Therefore, this review addresses the role of monoterpenes as pharmacological tools in the vascular system, providing mechanisms of action and their biological effects. Full article

(This article belongs to the Special Issue New Insights in Natural Bioactive Compounds: 3rd Edition)

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11 pages, 243 KB

Open AccessArticle

The Significance of Serum Immunoglobulin Concentrations in Children with Autism Spectrum Disorders: In Search of Potential Blood Biomarkers

by Joanna Wawer, Agnieszka Chojęta, Genowefa Anna Wawer, Marcin Gładki, Aneta Klotzka, Bartłomiej Kociński, Tomasz Urbanowicz, Janusz Kocki and Ewelina Grywalska

Int. J. Mol. Sci. 2025, 26(18), 9242; https://doi.org/10.3390/ijms26189242 - 22 Sep 2025

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Abstract

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by a number of dysfunctions in communication, social interactions and repetitive rigid patterns of behavior, interests, and activities. Despite much research, the causes of ASD remain elusive. In addition to genetic [...] Read more.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by a number of dysfunctions in communication, social interactions and repetitive rigid patterns of behavior, interests, and activities. Despite much research, the causes of ASD remain elusive. In addition to genetic and epigenetic etiology, scientists have indicated inflammation, deregulation of cytokines, anti-brain autoantibodies, gut microbiota, and deregulated immunity as mechanisms possibly involved in the development of ASD phenotype. The aim of the study was to analyze the levels of IgA, IgE, and IgM immunoglobulins in the blood serum in patients with ASD to find out whether certain blood parameters are deregulated in that group of patients. The results suggest altered production of the immune cells in ASD patients which may be considered in the assessment of immune functions. Also, PCT% and LYMPH elevated values in patients with ASD might be of clinical relevance, possibly of predictive value for clinical preliminary diagnosis and therapy. Full article

(This article belongs to the Section Molecular Immunology)

20 pages, 1103 KB

Open AccessArticle

High-Fat Diet Alters Behavior and Hippocampal Gene Expression

by Melissa S. Totten, Ava L. Peterson, Derek M. Pierce and Keith M. Erikson

Int. J. Mol. Sci. 2025, 26(18), 9241; https://doi.org/10.3390/ijms26189241 - 22 Sep 2025

Viewed by 251

Abstract

Consuming a high-fat diet (HFD) has been linked to gene expression alterations and negative behavior changes. The aim of this study was to evaluate the impact of a HFD on behavior and gene expression in the hippocampi of male and female mice from [...] Read more.

Consuming a high-fat diet (HFD) has been linked to gene expression alterations and negative behavior changes. The aim of this study was to evaluate the impact of a HFD on behavior and gene expression in the hippocampi of male and female mice from different strains to evaluate sex and genetic differences. C57BL/6J (B6J) and DBA/2J (D2J) mice were randomly assigned to either a control diet containing 10% kcal fat or a HFD containing 60% kcal fat for 16 weeks. Behavior was measured using the open field test for anxiety, nestlet shredding for general welfare, and novel object recognition for memory. Alpha synuclein (αSYN), amyloid precursor protein (APP), and brain-derived neurotrophic factor (BDNF) mRNA expression was assessed. The HFD led to reduced nestlet shredding for male B6J mice exclusively. There was a significant main effect of sex for fecal boli within the B6J strain and higher levels of fecal boli only for HFD male B6Js. No difference in memory was found in either strain. Significant three-way interactions between diet, sex, and strain for mRNA expression of aSYN and APP were found. However, the simple main effect of diet was only significant in the male B6J strain, revealing a 7-fold upregulation of hippocampal αSYN expression and 10-fold upregulation of APP in the HFD group compared to the control diet group. Although there was a significant strain by sex interaction effect for BDNF expression, there was no effect of diet on either strain. Overall, the HFD treatment impacted male B6J mice the greatest. This study demonstrates that biological sex and genetic factors should be considered when examining the impact of diet on behavior and the brain. Full article

(This article belongs to the Special Issue High Fat Diet Metabolism and Diseases)

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16 pages, 3294 KB

Open AccessArticle

Integration of Repeatome and Cytogenetic Data on Tandem DNAs in a Medicinal Plant Polemonium caeruleum L.

by Olga V. Muravenko, Alexandra V. Amosova, Alexey R. Semenov, Julia V. Kalnyuk, Firdaus M. Khazieva, Irina N. Korotkikh, Irina V. Basalaeva, Ekaterina D. Badaeva, Svyatoslav A. Zoshchuk and Olga Yu. Yurkevich

Int. J. Mol. Sci. 2025, 26(18), 9240; https://doi.org/10.3390/ijms26189240 - 22 Sep 2025

Viewed by 202

Abstract

Polemonium caeruleum L. (Polemoniaceae) is a perennial flowering plant native to Eurasia and North America, which is used as a fodder, medicinal, and ornamental plant. Many issues related to the taxonomy and origin of this valuable species still remain unclear. The intraspecific genetic [...] Read more.

Polemonium caeruleum L. (Polemoniaceae) is a perennial flowering plant native to Eurasia and North America, which is used as a fodder, medicinal, and ornamental plant. Many issues related to the taxonomy and origin of this valuable species still remain unclear. The intraspecific genetic variability of P. caeruleum and chromosomal organization of its genome are insufficiently studied. For the first time, we analyzed NGS genomic data of P. caeruleum using ReapeatExplorer2/TAREAN/DANTE Pipelines. In its repeatome, we identified 66.08% of Class I retrotransposons; 0.57% of Class II transposons; 0.42% of ribosomal DNA; and 0.87% of satellite DNA (six high-confident and three low-confident putative satellite DNAs). FISH chromosome mapping of seven tandem DNAs was carried out in two P. caeruleum varieties and two wild populations. Our results demonstrated the effectiveness of using satDNAs Pol_C 46 and Pol_C 33 in combination with 45S rDNA and 5S rDNA for precise chromosome identification. This approach allowed us to study intraspecific chromosomal variability and detect chromosomal rearrangements in the studied accessions of P. caeruleum, which could be related to the speciation process. These novel molecular markers are important for chromosome studies within Polemonium to clarify its taxonomy and phylogeny, and also, they expand the potential of different breeding programs. Full article

(This article belongs to the Special Issue Repetitive DNA)

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12 pages, 251 KB

Open AccessConference Report

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

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

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

Viewed by 157

Abstract

The 5th International Symposium on Frontiers in Molecular Science was held on 26–29 August 2025 in Kyoto (Japan), with the support of Kyoto Prefectural University and Kyoto Prefectural University of Medicine. It is evident that the event has proven to be significant, showcasing [...] Read more.

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

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

4 pages, 157 KB

Open AccessEditorial

Special Issue “Biopolymers in Drug and Gene Delivery Systems 3.0”

by Yury A. Skorik

Int. J. Mol. Sci. 2025, 26(18), 9238; https://doi.org/10.3390/ijms26189238 - 22 Sep 2025

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Abstract

The evolution of biopolymer-based drug and gene delivery systems is a compelling narrative marked by a continuous transition from fundamental concepts to transformative applications [...] Full article

(This article belongs to the Special Issue Biopolymers in Drug and Gene Delivery Systems 3.0)

13 pages, 3677 KB

Open AccessArticle

Preparation of a Micronutrient-Enriched Apricot Kernel Oil and Assessment of In Vitro Chemopreventive Properties

by Melania Elettra Vaccari, Valeria Cavalloro, Martina Bedeschi, Patrizia Serra, Giorgia Simonetti, Emanuele Casali, Alessio Porta, Alice Fossati, Emanuela Martino, Simona Collina and Anna Tesei

Int. J. Mol. Sci. 2025, 26(18), 9237; https://doi.org/10.3390/ijms26189237 - 22 Sep 2025

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Abstract

Apricot kernels (Prunus armeniaca L.) represent a valuable by-product of stone fruit cultivation, offering diverse applications in food, cosmetic, and pharmaceutical industries. While apricot kernel oil is recognized for its rich composition of unsaturated fatty acids, phenolics, and tocopherols, its therapeutic potential, [...] Read more.

Apricot kernels (Prunus armeniaca L.) represent a valuable by-product of stone fruit cultivation, offering diverse applications in food, cosmetic, and pharmaceutical industries. While apricot kernel oil is recognized for its rich composition of unsaturated fatty acids, phenolics, and tocopherols, its therapeutic potential, particularly in cancer prevention, remains unexplored. This study investigated a purified fraction (FOPF) obtained from Farclo variety kernel oil, cultivated in the Emilia-Romagna region of Italy and selected for its naturally low amygdalin content. In vitro studies demonstrated FOPF’s significant antiproliferative effects against colorectal cancer (LoVo, HT29) and hepatocarcinoma (Hep3B) cell lines, with GI₅₀ values ranging from 0.06 to 0.09 mg/mL. The fraction induced cell cycle arrest and significantly inhibited cancer cell migration, effects mediated through PPAR-γ expression modulation. These findings establish FOPF’s potential as a natural chemopreventive agent and provide a foundation for its development as a nutraceutical ingredient targeting colorectal and hepatic cancers. Full article

(This article belongs to the Special Issue Innovative Approaches to Enhancing Bioavailability and Bioaccessibility of Bioactive Compounds from Plant and Food Extracts)

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15 pages, 3560 KB

Open AccessArticle

Calprotectin Expression in Adventitial Layer of Cattle and Sheep Echinococcus granulosus sensu stricto Cysts

by María Soledad Baquedano, Caroll Stoore, Christian Hidalgo, Ismael Pereira and Rodolfo Paredes

Int. J. Mol. Sci. 2025, 26(18), 9236; https://doi.org/10.3390/ijms26189236 - 22 Sep 2025

Viewed by 175

Abstract

Cystic echinococcosis (CE) is a globally distributed zoonotic disease caused by Echinococcus granulosus sensu lato, forming fluid-filled cysts in humans and livestock. These cysts consist of three layers: an inner germinal layer and a middle laminar layer of parasitic origin, and an outer [...] Read more.

Cystic echinococcosis (CE) is a globally distributed zoonotic disease caused by Echinococcus granulosus sensu lato, forming fluid-filled cysts in humans and livestock. These cysts consist of three layers: an inner germinal layer and a middle laminar layer of parasitic origin, and an outer adventitial layer derived from the host’s immune response. The adventitial layer typically contains immune cells such as T and B lymphocytes, macrophages, and other inflammatory cells. Notably, differences have been reported in the cellular composition of this layer depending on the host species. However, the variation in calprotectin expression—a protein specific to phagocytes—between cattle and sheep CE cysts has not been previously described. This study assessed calprotectin expression using immunohistochemistry with anti-calprotectin antibodies on adventitial tissue sections from cattle and sheep CE cysts. The results showed a significantly higher calprotectin expression in the adventitial layer of cattle cysts compared to sheep. This difference was not associated with the fertility or anatomical location of the cysts. These findings suggest that the host species influences the level of calprotectin expression in the adventitial layer, contributing to our understanding of host-specific immune responses in CE. Full article

(This article belongs to the Special Issue State-of-the-Art Molecular Immunology in Chile, 2nd Edition)

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18 pages, 6268 KB

Open AccessArticle

Bioinformatics Analysis and Expression Profiling Under Abiotic Stress of the DREB Gene Family in Glycyrrhiza uralensis

by Linyuan Cheng, Nana Shi, Xiangrong Du, Teng Huang, Yaxin Zhang, Chenjie Zhao, Kun Zhao, Zirun Lin, Denglin Ma, Qiuling Li, Fei Wang, Hua Yao and Haitao Shen

Int. J. Mol. Sci. 2025, 26(18), 9235; https://doi.org/10.3390/ijms26189235 - 22 Sep 2025

Viewed by 171

Abstract

Glycyrrhiza uralensis is an important medicinal plant exhibiting strong tolerance to abiotic stresses, including drought and salinity. DREB (Dehydration-Responsive Element-Binding) transcription factors, key members of the AP2/ERF family, play crucial roles in plant growth, development, and stress responses. Based on transcriptome data, we [...] Read more.

Glycyrrhiza uralensis is an important medicinal plant exhibiting strong tolerance to abiotic stresses, including drought and salinity. DREB (Dehydration-Responsive Element-Binding) transcription factors, key members of the AP2/ERF family, play crucial roles in plant growth, development, and stress responses. Based on transcriptome data, we identified 18 DREB transcription factors in G. uralensis, designated GuDREB1 to GuDREB18. Bioinformatics analysis revealed genomic sequences ranging from 534 to 2864 bp and coding sequence (CDS) lengths between 525 and 1509 bp. All GuDREB proteins contain a single AP2 domain, including the conserved YRG and RAYD elements, and were predicted to localize to the nucleus. Phylogenetic analysis clustered the G. uralensis DREBs with 61 Arabidopsis thaliana DREBs into five subgroups, indicating evolutionary conservation. Promoter analysis detected seventeen stress-responsive cis-acting elements, encompassing hormone-responsive and abiotic stress-responsive motifs, suggesting diverse biological functions. Tissue-specific expression profiling revealed GuDREB transcription in both aerial and underground parts. Drought stress induced varying degrees of GuDREB expression, confirming their involvement in stress responses. Notably, GuDREB10 expression increased significantly in underground parts, while GuDREB15 showed pronounced upregulation in aerial parts under drought; the GuDREB15 promoter contained the highest number of light-responsive elements (23), potentially explaining its aerial tissue specificity. Drought stress significantly increased abscisic acid (ABA) content. Underground parts exhibited higher initial sensitivity to drought, whereas aerial parts displayed a more sustained response; ABA levels overall showed an initial increase followed by a decline. This study expands the G. uralensis DREB gene database, provides a foundation for selecting stress-resistance genes, and offers insights into DREB functional roles in abiotic stress responses in this key medicinal species. Full article

(This article belongs to the Special Issue Plant Response to Drought, Heat, and Light Stress)

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16 pages, 6280 KB

Open AccessArticle

Stratifying ALS Patients by Mode of Inheritance Reveals Transcriptomic Signatures Specific to sALS and fALS

by Alexandria Awai, Erica L. Johnson, Tiandong Leng, John Patrickson, Michael C. Zody, James W. Lillard, Jr. and on behalf of the NYGC ALS Consortium

Int. J. Mol. Sci. 2025, 26(18), 9234; https://doi.org/10.3390/ijms26189234 - 22 Sep 2025

Viewed by 196

Abstract

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease, marked by considerable clinical and molecular heterogeneity. While several genetic drivers have been linked to familial ALS (fALS), the biology of sporadic ALS (sALS)—which accounts for the majority of ALS cases—remains poorly defined. To [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a terminal neurodegenerative disease, marked by considerable clinical and molecular heterogeneity. While several genetic drivers have been linked to familial ALS (fALS), the biology of sporadic ALS (sALS)—which accounts for the majority of ALS cases—remains poorly defined. To address this gap, we analyzed 247 bulk mRNA-sequenced post-mortem tissue samples from the lumbar spinal cord and motor cortex and compared expression profiles between fALS, sALS, and controls. Variance-stabilized DEGs from DESeq2 analysis were used as inputs for weighted gene co-expression network analysis (WGCNA). Finally, gene ontology was used to identify transcriptomic signatures and biological pathways unique to sALS and fALS. In the spinal cord, sALS samples exhibited specific downregulation of mitochondrial complex I subunits (e.g., NDUFS8 and NDUFB7) and regulatory genes (e.g., AURKAIP1 and ATP5F1D), suggesting compromised metabolic resilience. In the motor cortex, a co-expression module associated with adaptive immune function and leukocyte infiltration was downregulated in sALS yet upregulated in fALS, indicating distinct inflammatory pathways between these two forms of ALS. Together, our findings highlight that while sALS and fALS are largely the same disease, they exhibit distinct transcriptomic signatures. By accounting for mode of inheritance in study designs—particularly sALS, which represents ~90% of ALS cases—researchers may reveal deeper insights into ALS pathology. This perspective could enable more targeted therapeutic strategies, ultimately improving outcomes for all ALS patients. Full article

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

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35 pages, 765 KB

Open AccessReview

Advances in Psoriasis Research: Decoding Immune Circuits and Developing Novel Therapies

by Lanying Wang, Ruiling Liu, Yulu Tang, Yuanfang Ma, Guimei Wang, Qingguo Ruan and Shijun J. Zheng

Int. J. Mol. Sci. 2025, 26(18), 9233; https://doi.org/10.3390/ijms26189233 - 21 Sep 2025

Viewed by 573

Abstract

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by erythematous plaques covered with silvery-white scales, often accompanied by systemic complications such as psoriatic arthritis and cardiovascular diseases. The disease and its systemic complications substantially impair quality of life, compromise socioeconomic status, and [...] Read more.

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by erythematous plaques covered with silvery-white scales, often accompanied by systemic complications such as psoriatic arthritis and cardiovascular diseases. The disease and its systemic complications substantially impair quality of life, compromise socioeconomic status, and threaten patient safety. The occurrence and progression of this disease are related to the IL-23/IL-17 axis and involve the aberrant activation and interactions of multiple immune cells, along with genetic predispositions and environmental triggers. Although current therapeutic approaches, including topical agents, systemic medications, biologic agents targeting key cytokines, and Janus Kinase inhibitors, can control symptoms and delay disease progression, a complete cure has not been achieved. Furthermore, these strategies face challenges relating to the cost, safety, efficacy and precision of targeting. This review summarizes recent advances in mechanistic research, highlighting the interplay among microorganisms, innate and adaptive immunity in psoriasis. We also evaluate a range of emerging therapies, including biologics, small-molecule inhibitors, Chimeric antigen receptor T-cell cell therapy, RNA interference-based strategies, and alternative medicine. Specifically, we focus on their novel mechanisms, efficacy challenges, safety profiles, and targeting accuracy. Finally, we assess their potential in personalized treatment, aiming to achieve long-term remission, and propose the future prospects of precision medicine in psoriasis management. Full article

(This article belongs to the Special Issue Autoimmune Diseases: From Pathogenesis to Treatment and Prognostic Markers)

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21 pages, 8351 KB

Open AccessArticle

Reproducibility Crossroads: Impact of Statistical Choices on Proteomics Functional Enrichment

by Karolina A. Biełło, José V. Die, Francisco Amil, Carlos Fuentes-Almagro, Javier Pérez-Rodríguez and Alfonso Olaya-Abril

Int. J. Mol. Sci. 2025, 26(18), 9232; https://doi.org/10.3390/ijms26189232 - 21 Sep 2025

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Abstract

Quantitative proteomics relies on robust statistical methods for differential expression, critically impacting downstream functional enrichment. This meta-analysis systematically investigated how statistical hypothesis testing approaches and criteria for defining biological relevance influence functional enrichment concordance. We reanalyzed five independent label-free quantitative proteomics datasets using [...] Read more.

Quantitative proteomics relies on robust statistical methods for differential expression, critically impacting downstream functional enrichment. This meta-analysis systematically investigated how statistical hypothesis testing approaches and criteria for defining biological relevance influence functional enrichment concordance. We reanalyzed five independent label-free quantitative proteomics datasets using diverse frequentist (t-test, Limma, DEqMS, MSstats) and Bayesian (rstanarm) approaches. Concordance of Gene Ontology (GO) and KEGG pathways was assessed using Jaccard indices and correlation metrics, grouping comparisons by statistical test and biological relevance consistency. The results demonstrated highly significant differences in similarity distributions among the comparison groups. Comparisons varying only hypothesis testing methods (with constant relevance criteria, FC or Bayesian) showed the highest consistency. Conversely, comparisons with differing biological relevance criteria (or varied methodological choices) yielded significantly lower consistency, highlighting this definition’s critical impact on GO term overlaps. KEGG pathways displayed more uniform, method-insensitive concordance. Sensitivity analysis confirmed the findings’ robustness, underscoring that methodological choices profoundly influence functional enrichment outcomes. This work emphasizes the critical need for transparency and careful consideration of analytical decisions in proteomics research to ensure reproducible and biologically sound interpretations. Full article

(This article belongs to the Special Issue Statistical Approaches to Omics Data: Searching for Biological Truth)

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24 pages, 1208 KB

Open AccessReview

by Meng-Ke Ma and Da-Qiang Li

Int. J. Mol. Sci. 2025, 26(18), 9231; https://doi.org/10.3390/ijms26189231 - 21 Sep 2025

Viewed by 458

Abstract

Triple-negative breast cancer (TNBC) represents the most aggressive and therapeutically recalcitrant breast cancer subtype, exhibiting dismal clinical outcomes due to its intrinsic heterogeneity and lack of molecularly targeted treatment options. Emerging evidence has established the autophagy-related proteins (ARPs) as key regulators of TNBC [...] Read more.

Triple-negative breast cancer (TNBC) represents the most aggressive and therapeutically recalcitrant breast cancer subtype, exhibiting dismal clinical outcomes due to its intrinsic heterogeneity and lack of molecularly targeted treatment options. Emerging evidence has established the autophagy-related proteins (ARPs) as key regulators of TNBC pathogenesis, functioning not only as metabolic gatekeepers but also as multifaceted modulators of malignant transformation, disease progression, and therapeutic responsiveness. These proteins exert diverse functions in TNBC through both canonical autophagy-dependent pathways and non-canonical mechanisms. In this review, we critically examine the pleiotropic functions and molecular mechanisms of ARPs in TNBC progression and therapeutic responsiveness, with special emphasis on their context-dependent roles in both fortifying therapeutic resistance and, paradoxically, creating vulnerabilities for therapeutic exploitation. Full article

(This article belongs to the Special Issue Autophagic Related Proteins in Cancer)

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8 pages, 730 KB

Open AccessCase Report

Neuroinflammation in CTLA-4 Haploinsufficiency: Case Report of a New Variant with Remarkable Response to Targeted Therapy

by Letizia Baldini, Lucia Del Vecchio, Sara Cerasi, Anna Fetta, Mattia Moratti, Alessandra Bezzi, Simona Ferrari, Guido Di Dalmazi, Simone Rossi, Francesco Toni, Duccio Maria Cordelli, Marcello Lanari and Francesca Conti

Int. J. Mol. Sci. 2025, 26(18), 9230; https://doi.org/10.3390/ijms26189230 - 21 Sep 2025

Viewed by 222

Abstract

Inborn errors of immunity (IEI) encompass a diverse group of genetic disorders that often present with complex and multifaceted clinical features, including neuroinflammation. CTLA-4 deficiency (CTLA-4d), caused by monoallelic germline mutations in the CTLA4 gene, manifests with autoimmune phenomena, lymphoproliferation, infections, and neurological [...] Read more.

Inborn errors of immunity (IEI) encompass a diverse group of genetic disorders that often present with complex and multifaceted clinical features, including neuroinflammation. CTLA-4 deficiency (CTLA-4d), caused by monoallelic germline mutations in the CTLA4 gene, manifests with autoimmune phenomena, lymphoproliferation, infections, and neurological involvement in up to 30% of patients, with a broad clinical spectrum, ranging from encephalitis to demyelination and lymphocytic infiltration. Imaging typically shows multifocal contrast-enhancing lesions. Early recognition of CTLA-4d is crucial to guide clinical management. Herein, we report the case of a 15-year-old girl presenting with severe multifocal neuroinflammatory lesions, recurrent infections, and systemic granulomatous disease. After extensive infectious and immunological workup, a heterozygous de novo CTLA4 variant c.394G>A_p.Glu132Lys was identified and its pathogenicity confirmed by transendocytosis functional assays. Based on the genetic diagnosis, the patient was started on abatacept, with brilliant clinical and radiological results after dose adjustment. This report describes a new pathogenic variant of the CTLA4 gene and highlights the importance of considering IEIs, such as CTLA-4d, in patients with unexplained severe neuroinflammation. Also, it highlights the efficacy and tolerability of abatacept as a targeted therapy for neuroinflammation in CTLA4-d. Full article

(This article belongs to the Special Issue Neurological Diseases: From Molecular Basis to Therapy)

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