International Journal of Molecular Sciences

24 pages, 993 KB

Open AccessReview

Cell Death in Orthodontic Tooth Movement: Recent Advances and Emerging Insights

by Fumitoshi Ohori, Hideki Kitaura, Aseel Marahleh, Jinghan Ma, Kohei Narita, Angyi Lin, Ziqiu Fan, Kou Murakami and Hiroyasu Kanetaka

Int. J. Mol. Sci. 2026, 27(2), 1130; https://doi.org/10.3390/ijms27021130 - 22 Jan 2026

Viewed by 451

Abstract

Orthodontic tooth movement (OTM), a complex biological process driven by orchestrated bone remodeling, involves osteoclastic bone resorption and osteoblastic bone formation in response to mechanical force. Traditionally, OTM-related cell death has been discussed in terms of apoptosis and necrosis. However, recent advances in [...] Read more.

Orthodontic tooth movement (OTM), a complex biological process driven by orchestrated bone remodeling, involves osteoclastic bone resorption and osteoblastic bone formation in response to mechanical force. Traditionally, OTM-related cell death has been discussed in terms of apoptosis and necrosis. However, recent advances in cell death research have revealed various forms of regulated cell death (RCD) beyond these conventional categories. This review summarizes the current understanding of the diverse RCD pathways and their roles in various cell populations during OTM. It delineates the involvement of distinct RCD mechanisms, including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis. On the compression side, these RCD pathways in periodontal ligament (PDL) cells, cementoblasts, cementocytes, and bone-related cells actively drive inflammatory responses, promote bone resorption, and contribute to root resorption. Conversely, on the tension side, specific RCD pathways, notably autophagy in the PDL and osteocytes, play crucial roles in promoting osteogenesis and tissue repair. Collectively, cell death is not merely a passive elimination of cells but actively functions as a critical switch for alveolar bone remodeling during OTM. Understanding these multifaceted RCD mechanisms provides novel insights into the biological regulation of tooth movement and identifies potential therapeutic targets for enhancing tooth movement efficiency and mitigating adverse effects. Full article

(This article belongs to the Special Issue From Biology to Biomechanics: Molecular Advances in Orthodontic Remodeling and Acceleration)

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24 pages, 8852 KB

Open AccessArticle

Microenvironment Modulates Tumorigenicity of Breast Cancer Cells Depending on Hormone Receptor Status

by Priscila Pagnotta, Tomás González-Garello, María Luján Crosbie, Natalia Santiso, Anabela Ursino, Celeste Frascarolli, Alicia Amato, Rubén Dreszman, Juan Carlos Calvo and Judith Toneatto

Int. J. Mol. Sci. 2026, 27(2), 1129; https://doi.org/10.3390/ijms27021129 - 22 Jan 2026

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Abstract

Adipose tissue plays a crucial role in breast cancer (BC) progression by actively modulating the tumor microenvironment. We investigated how tumor proximity modifies adipose tissue by analyzing selected adipose-related and prognosis-associated markers in explants from BC patients and healthy donors. Explants were categorized [...] Read more.

Adipose tissue plays a crucial role in breast cancer (BC) progression by actively modulating the tumor microenvironment. We investigated how tumor proximity modifies adipose tissue by analyzing selected adipose-related and prognosis-associated markers in explants from BC patients and healthy donors. Explants were categorized by proximity to the tumor as adjacent (less than 2 cm), distant (over 2 cm), alongside normal explants (controls). FABP4 and vimentin expression was increased in proximity to the tumor, while caveolin-1, CD44, MMP9, and adiponectin showed minimal or no changes. Conditioned media (CM) from adjacent and normal explants were then assessed for their effects on tumorigenic traits in hormone-receptor-positive breast cancer (HR+ BC) and triple-negative breast cancer (TNBC) cell lines. Adjacent-CM enhanced migration, induced cytoskeletal remodeling, reduced adhesion, and promoted an elongated, motile phenotype in T47D cells. Poor-prognosis markers (caveolin-1, vimentin, CD44) were upregulated in at least one HR+ BC model, whereas Nanog and KLF4 showed modest variation. In TNBC cells, both normal- and adjacent-CM partially shifted MDA-MB-231 morphology toward a more epithelial-like state, decreasing caveolin-1 levels, while adjacent-CM increased MMP9 expression. Overall, these results reveal that adipose tissue-derived soluble factors exert significant and subtype-dependent effects on BC tumorigenicity. Full article

(This article belongs to the Special Issue Cell Metabolism: Its Physiology, Dysfunction, and Related Metabolic Complications)

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26 pages, 1615 KB

Open AccessArticle

Discovery and Preliminary Characterization of Lactose-Transforming Enzymes in Ewingella americana L47: A Genomic, Biochemical, and In Silico Approach

by Katherine Rivero, Rodrigo Valenzuela, Inaira Rivero, Pedro General, Nicole Neira, Fernanda Contreras, Jans Alzate-Morales, Claudia Muñoz-Villagrán, Carlos Vera, Mauricio Arenas-Salinas and Felipe Arenas

Int. J. Mol. Sci. 2026, 27(2), 1128; https://doi.org/10.3390/ijms27021128 - 22 Jan 2026

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Abstract

D-tagatose is a high-value, low-calorie sweetener that can be produced from dairy lactose via a two-step enzymatic route: lactose hydrolysis to galactose followed by galactose isomerization to tagatose. Here, we combined genomics, in silico structural analysis, and biochemical assays to evaluate the lactose-to-tagatose [...] Read more.

D-tagatose is a high-value, low-calorie sweetener that can be produced from dairy lactose via a two-step enzymatic route: lactose hydrolysis to galactose followed by galactose isomerization to tagatose. Here, we combined genomics, in silico structural analysis, and biochemical assays to evaluate the lactose-to-tagatose conversion potential of an Antarctic isolate, L47, identified as Ewingella americana (NCBI accession SAMN54554459). Genome mining revealed one L-arabinose isomerase gene (araA) and three β-galactosidase genes (bgaA, bglY, lacZ), an uncommon combination in a single bacterium. Recombinant AraA was produced in Escherichia coli and biochemically characterized, showing Mn²⁺ dependence and measurable D-galactose isomerization, reaching ~18% tagatose from 100 mM galactose after 48 h under the tested conditions. In contrast, the β-galactosidases were predominantly recovered as insoluble aggregates in E. coli; therefore, β-galactosidase activity was assessed using washed inclusion-body preparations. Under these conditions, BgaA displayed the most consistent o-NPG hydrolyzing activity, whereas BglY and LacZ did not yield reproducible activity. Overall, our results identify BgaA as the most tractable lactose-hydrolyzing candidate from L47 in the current workflow and indicate that AraA performance is the principal bottleneck toward an efficient lactose-to-tagatose process, motivating future optimization at the enzyme and process levels. Full article

(This article belongs to the Special Issue Advanced Research on Enzymes in Biocatalysis)

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20 pages, 3693 KB

Open AccessArticle

Cannabidiol-Loaded Mucoadhesive PLGA Nanosphere-Chitosan Hydrogel Patch for Oral Therapeutic Applications

by Badmaarag-Altai Chuluunbaatar, Jisu Park, Junyoung Song, Subin Mun, Ji-Hyun Kang and Kyung Hyun Min

Int. J. Mol. Sci. 2026, 27(2), 1127; https://doi.org/10.3390/ijms27021127 - 22 Jan 2026

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Abstract

Cannabidiol (CBD), the primary bioactive element of cannabis, has shown promise in alleviating pain and inflammation, although mechanisms in periodontal inflammation are not fully understood. To improve its limited solubility and mucosal permeability, the developed chitosan-based mucoadhesive hydrogel incorporating CBD-loaded PLGA nanospheres (CPN [...] Read more.

Cannabidiol (CBD), the primary bioactive element of cannabis, has shown promise in alleviating pain and inflammation, although mechanisms in periodontal inflammation are not fully understood. To improve its limited solubility and mucosal permeability, the developed chitosan-based mucoadhesive hydrogel incorporating CBD-loaded PLGA nanospheres (CPN hydrogel) was characterized by FT-IR, SEM, particle size, rheological, swelling, and diffusion analyses, followed by biological evaluations, including wound-healing and RT-qPCR-based anti-inflammatory assays. The improved CPN hydrogel had a homogeneous shape, better viscoelastic behavior, and sustained drug release. Over 90% of CBD was released within 96 h, and Franz cell experiments showed improved permeability (124.1 μg/cm² after 72 h). The gellan gum-based mucosal substrate significantly increased adhesion (1137.33 ± 142.25 s) compared to the control groups. Antioxidant studies indicated 73.65% DPPH radical scavenging, whereas antibacterial tests showed more than 99% suppression of Staphylococcus aureus. Furthermore, in vitro studies validated its wound healing and the downregulation of the inflammatory cytokines IL-6 and TNF-α. The results indicate that the CPN-loaded chitosan hydrogel has extended mucosal retention, strong antibacterial activity, and steady release of CBD. This underscores its significant potential as a targeted treatment for inflammatory oral diseases such as gingivitis and periodontitis. Full article

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

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34 pages, 1418 KB

Open AccessArticle

Hybrid Dual-Context Prompted Cross-Attention Framework with Language Model Guidance for Multi-Label Prediction of Human Off-Target Ligand–Protein Interactions

by Abdullah, Zulaikha Fatima, Muhammad Ateeb Ather, Liliana Chanona-Hernandez and José Luis Oropeza Rodríguez

Int. J. Mol. Sci. 2026, 27(2), 1126; https://doi.org/10.3390/ijms27021126 - 22 Jan 2026

Viewed by 247

Abstract

Accurately identifying drug off-targets is essential for reducing toxicity and improving the success rate of pharmaceutical discovery pipelines. However, current deep learning approaches often struggle to fuse chemical structure, protein biology, and multi-target context. Here, we introduce HDPC-LGT (Hybrid Dual-Prompt Cross-Attention Ligand–Protein Graph [...] Read more.

Accurately identifying drug off-targets is essential for reducing toxicity and improving the success rate of pharmaceutical discovery pipelines. However, current deep learning approaches often struggle to fuse chemical structure, protein biology, and multi-target context. Here, we introduce HDPC-LGT (Hybrid Dual-Prompt Cross-Attention Ligand–Protein Graph Transformer), a framework designed to predict ligand binding across sixteen human translation-related proteins clinically associated with antibiotic toxicity. HDPC-LGT combines graph-based chemical reasoning with protein language model embeddings and structural priors to capture biologically meaningful ligand–protein interactions. The model was trained on 216,482 experimentally validated ligand–protein pairs from the Chemical Database of Bioactive Molecules (ChEMBL) and the Protein–Ligand Binding Database (BindingDB) and evaluated using scaffold-level, protein-level, and combined holdout strategies. HDPC-LGT achieves a macro receiver operating characteristic–area under the curve (macro ROC–AUC) of 0.996 and a micro F1-score (micro F1) of 0.989, outperforming Deep Drug–Target Affinity Model (DeepDTA), Graph-based Drug–Target Affinity Model (GraphDTA), Molecule–Protein Interaction Transformer (MolTrans), Cross-Attention Transformer for Drug–Target Interaction (CAT–DTI), and Heterogeneous Graph Transformer for Drug–Target Affinity (HGT–DTA) by 3–7%. External validation using the Papyrus universal bioactivity resource (Papyrus), the Protein Data Bank binding subset (PDBbind), and the benchmark Yamanishi dataset confirms strong generalisation to unseen chemotypes and proteins. HDPC-LGT also provides biologically interpretable outputs: cross-attention maps, Integrated Gradients (IG), and Gradient-weighted Class Activation Mapping (Grad-CAM) highlight catalytic residues in aminoacyl-tRNA synthetases (aaRSs), ribosomal tunnel regions, and pharmacophoric interaction patterns, aligning with known biochemical mechanisms. By integrating multimodal biochemical information with deep learning, HDPC-LGT offers a practical tool for off-target toxicity prediction, structure-based lead optimisation, and polypharmacology research, with potential applications in antibiotic development, safety profiling, and rational compound redesign. Full article

(This article belongs to the Section Molecular Informatics)

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19 pages, 2834 KB

Open AccessArticle

Antiprotozoal Potential of Cultivated Geranium macrorrhizum Against Giardia duodenalis, Trichomonas gallinae and Leishmania infantum

by Sara Marcos-Herraiz, María José Irisarri-Gutiérrez, Javier Carrión, Iris Azami Conesa, Rodrigo Suárez Lombao, Juliana Navarro-Rocha, Jose Francisco Quilez del Moral, Alejandro Fernández Barrero, Eneko Ochoa Larrigan, Azucena González-Coloma, María Teresa Gómez-Muñoz and María Bailén

Int. J. Mol. Sci. 2026, 27(2), 1125; https://doi.org/10.3390/ijms27021125 - 22 Jan 2026

Viewed by 206

Abstract

Plant-derived natural products are an invaluable source of structurally diverse secondary metabolites with ecological and pharmacological significance. Geranium macrorrhizum, a species known for producing essential oils rich in monoterpenoids and sesquiterpenes, has been scarcely explored for its antiparasitic potential. This study represents [...] Read more.

Plant-derived natural products are an invaluable source of structurally diverse secondary metabolites with ecological and pharmacological significance. Geranium macrorrhizum, a species known for producing essential oils rich in monoterpenoids and sesquiterpenes, has been scarcely explored for its antiparasitic potential. This study represents the first comprehensive evaluation of the antiprotozoal activity of G. macrorrhizum obtained from cultivated plants. Plant material was produced under controlled greenhouse cultivation systems, ensuring high-quality and reproducible metabolite profiles. Essential oils were obtained through hydrodistillation and chemically characterized by Gas Chromatography-Mass Spectrometry (GC–MS). In vitro assays were conducted against Giardia duodenalis, Trichomonas gallinae, and Leishmania infantum to assess antiparasitic efficacy and cytotoxicity. The results demonstrated strong activity of essential oils against Trichomonas gallinae, and Leishmania infantum, indicating the relevance of lipophilic compounds—especially germacrone—as key bioactive constituents. Germacrone exhibited strong and selective antiparasitic activity, outperforming its structural analogues. Microscopic analyses revealed distinct parasite-specific morphological alterations, differing from those induced by conventional drugs such as metronidazole and amphotericin B. These findings highlight G. macrorrhizum obtained through biotechnological cultivation as a novel and sustainable source of natural antiprotozoal agents. The study underscores the importance of integrating controlled cultivation with phytochemical and biological evaluation to advance the discovery of innovative bioactive compounds. Full article

(This article belongs to the Section Molecular Pharmacology)

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23 pages, 10643 KB

Open AccessArticle

Genome-Wide Identification Analysis of the MAPKKK Gene Family in Cotton and Its Role in Development and Stress Response

by Yahui Deng, Nan Zhao, Shuo Ning, Yifan Wang, Weiran Wang, Meng Wang, Zixin Zhou, Yaohua Li, Caixia Li, Lingfang Ran, Jiahui Zhu, Zhiqing Liu, Jing Yang, Alifu Aierxi, Jie Kong, Aixing Gu and Jianping Li

Int. J. Mol. Sci. 2026, 27(2), 1124; https://doi.org/10.3390/ijms27021124 - 22 Jan 2026

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Abstract

Mitogen-activated protein kinase kinase kinases (MAPKKKs) are pivotal upstream regulators of MAPK cascades, integrating signals that coordinate plant development and stress responses. However, the specific functions of MAPKKKs, particularly within the MEKK subfamily, in mediating cotton resistance to Verticillium wilt and Fusarium wilt [...] Read more.

Mitogen-activated protein kinase kinase kinases (MAPKKKs) are pivotal upstream regulators of MAPK cascades, integrating signals that coordinate plant development and stress responses. However, the specific functions of MAPKKKs, particularly within the MEKK subfamily, in mediating cotton resistance to Verticillium wilt and Fusarium wilt remain poorly characterized. To address this, we conducted a systematic, cross-species analysis of the MAPKKK family in four key cotton species: Gossypium arboreum, Gossypium barbadense, Gossypium hirsutum, and Gossypium raimondii. Genome-wide identification and phylogenetic analysis revealed 660 MAPKKK genes, classifying them into the MEKK, Raf, and ZIK subfamilies. Evolutionary analysis indicated that Whole-Genome Duplication (WGD) events were the primary driver of family expansion. Promoter cis-element and Gene Ontology (GO) enrichment analyses implicated these genes in hormone signaling and stress adaptation. Expression profiling demonstrated functional modularity, with distinct members responding specifically to cold stress or cooperatively to drought and salt stresses. Upon pathogen infection, members diverged into regulatory modules associated with immune homeostasis, tissue-specific defense, and core signaling potentially governing systemic acquired resistance (SAR). The temporal expression patterns of core candidate genes were validated by qRT-PCR. This study provides, for the first time, a comprehensive evolutionary and functional framework for the MEKK subfamily within the cotton MAPKKK family. It reveals the conserved and divergent roles of this subfamily in stress adaptation and identifies key candidate genes for breeding disease-resistant cotton varieties. Full article

(This article belongs to the Special Issue Functional Genomics and Molecular Mechanisms of Plant Stress Responses)

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59 pages, 1662 KB

Open AccessReview

BCL-2 and BCL-xL in Cancer: Regulation, Function, and Therapeutic Targeting

by João P. N. Silva, Bárbara Pinto, Patrícia M. A. Silva and Hassan Bousbaa

Int. J. Mol. Sci. 2026, 27(2), 1123; https://doi.org/10.3390/ijms27021123 - 22 Jan 2026

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Abstract

The BCL-2 family of proteins plays a central role in the regulation of apoptosis, with BCL-2 and BCL-xL representing two of its most prominent antiapoptotic members. This review explores the molecular regulation of BCL-2 and BCL-xL genes, emphasizing the structural domains that define [...] Read more.

The BCL-2 family of proteins plays a central role in the regulation of apoptosis, with BCL-2 and BCL-xL representing two of its most prominent antiapoptotic members. This review explores the molecular regulation of BCL-2 and BCL-xL genes, emphasizing the structural domains that define the functions of the broader BCL-2 family. Beyond their canonical roles in preventing mitochondrial outer membrane permeabilization, both proteins contribute significantly to cancer development. Their overexpression enhances invasiveness and tumor progression, supports angiogenesis, and critically modulates cellular responses to chemotherapy, often conferring drug resistance. Additional non-apoptotic functions, including roles in metabolism, mitochondrial dynamics, and cellular homeostasis, further expand their biological relevance. Clinical trials exploring strategies to inhibit BCL-2 and BCL-xL, including selective BH3 mimetics and combination regimens, are discussed with emphasis on their potential and limitations in oncology. Overall, this review highlights the multifaceted contributions of BCL-2 and BCL-xL to cancer biology and underscores the importance of continued efforts to refine targeted therapeutic approaches. Full article

(This article belongs to the Special Issue Multidrug Resistance in Cancer: Molecular Mechanisms and Therapeutic Challenges)

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19 pages, 3226 KB

Open AccessArticle

Traditional Medicinal Plant Dahlia pinnata Selectively Suppresses TNF-α Expression Through Modulation of NF-κB and p38 Signaling

by HyeRin Woo, Yeji Lee, Jongmin Ahn, Yongxin Jin, Weihui Wu and Un-Hwan Ha

Int. J. Mol. Sci. 2026, 27(2), 1122; https://doi.org/10.3390/ijms27021122 - 22 Jan 2026

Viewed by 218

Abstract

Tumor necrosis factor-α (TNF-α) is a central mediator of inflammatory pathology; thus, the selective suppression of TNF-α without causing broad immunosuppression remains a critical therapeutic goal. This study investigated the anti-inflammatory potential and underlying mechanisms of Dahlia pinnata (D. pinnata) extract [...] Read more.

Tumor necrosis factor-α (TNF-α) is a central mediator of inflammatory pathology; thus, the selective suppression of TNF-α without causing broad immunosuppression remains a critical therapeutic goal. This study investigated the anti-inflammatory potential and underlying mechanisms of Dahlia pinnata (D. pinnata) extract in human monocytes and epithelial cells. We demonstrate that D. pinnata extract selectively suppresses basal TNF-α expression in THP-1 monocytes and BEAS-2B bronchial epithelial cells, with minimal impact on IL-1β, IL-6, or IL-10 and without inducing cytotoxicity. The extract also potently attenuated TNF-α induction triggered by Pseudomonas aeruginosa infection or lipopolysaccharide (LPS) stimulation. Notably, D. pinnata extract exhibited stronger and broader TNF-α-suppressive effects than dexamethasone, particularly in monocytes where dexamethasone was ineffective under the tested conditions. Mechanistic analyses revealed that the extract suppresses TNF-α expression primarily through the inhibition of NF-κB signaling, accompanied by enhanced p38 MAPK activation. Fractionation of the extract identified two active fractions (06 and 07) that robustly suppressed TNF-α expression under both basal and stimulated conditions while maintaining low cytotoxicity. These fractions recapitulated the signaling profile of the crude extract by inhibiting NF-κB activation and promoting p38 signaling. Collectively, our findings identify D. pinnata as a rich source of bioactive compounds that selectively suppresses TNF-α through the coordinated modulation of NF-κB and p38 pathways, highlighting its potential as a scaffold for developing targeted anti-inflammatory therapeutics. Full article

(This article belongs to the Special Issue Bioactive Natural Products: From Molecular Mechanisms to Biological Function)

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17 pages, 1259 KB

Open AccessReview

Molecular Genetics of β-Cell Compensation in Gestational Diabetes Mellitus: Insights from CDKAL1, SLC30A8 and HHEX

by Justyna Hryniewicka, Angelika Buczyńska-Backiel, Monika Zbucka-Krętowska, Adam Jacek Krętowski and Małgorzata Szelachowska

Int. J. Mol. Sci. 2026, 27(2), 1121; https://doi.org/10.3390/ijms27021121 - 22 Jan 2026

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Abstract

Gestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy associated with significant short- and long-term risks for both mother and offspring. Increasing evidence indicates that genetic susceptibility plays a central role in GDM pathogenesis, particularly through variants affecting insulin secretion and [...] Read more.

Gestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy associated with significant short- and long-term risks for both mother and offspring. Increasing evidence indicates that genetic susceptibility plays a central role in GDM pathogenesis, particularly through variants affecting insulin secretion and pancreatic β-cell function. This narrative review integrates molecular, clinical, and epidemiological perspectives, highlighting population-specific effects and gene–environment interactions. Improved understanding of the genetic risk architecture may support earlier risk stratification and enable the future development of personalized strategies for GDM prevention and management, with particular emphasis on genetic polymorphisms in SLC30A8, CDKAL1, and HHEX genes consistently implicated in glucose homeostasis and β-cell integrity. These genes contribute to distinct but complementary molecular pathways underlying GDM, including impaired insulin biosynthesis, defective zinc transport within insulin granules, and altered paracrine regulation within pancreatic islets. While associations between these variants and GDM have been repeatedly demonstrated, their clinical relevance and mechanistic impact remain incompletely understood. Available evidence suggests that CDKAL1 represents the strongest genetic determinant, followed by SLC30A8, while HHEX appears to play a modulatory role. This review summarizes current findings on the molecular functions and clinical significance of these polymorphisms, highlighting population-specific effects and gene–environment interactions. Improved understanding of genetic risk architecture may support earlier risk stratification and enable future development of personalized strategies for GDM prevention and management. Full article

(This article belongs to the Special Issue Advanced Molecular Research on Pregnancy Complication Mechanisms)

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39 pages, 489 KB

Open AccessReview

A Decade-Old Atlas of TMEM (Transmembrane) Protein Family in Lung Cancer: Lessons Learnt and Future Directions

by Siwei Zhang, Guojie Cao, Xuelin Hu, Chen Chen and Peng Chen

Int. J. Mol. Sci. 2026, 27(2), 1120; https://doi.org/10.3390/ijms27021120 - 22 Jan 2026

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Abstract

A growing body of work has linked the dysregulation of transmembrane (TMEM) proteins to the proliferation, metastasis, drug resistance, and tumor microenvironment remodeling of lung cancer, the leading global cause of cancer mortality. Renamed members such as STING1 (stimulator of interferon response cGAMP [...] Read more.

A growing body of work has linked the dysregulation of transmembrane (TMEM) proteins to the proliferation, metastasis, drug resistance, and tumor microenvironment remodeling of lung cancer, the leading global cause of cancer mortality. Renamed members such as STING1 (stimulator of interferon response cGAMP interactor 1, TMEM173), ANO1 (anoctamin-1, TMEM16A), ORAI1 (ORAI calcium release-activated calcium modulator 1, TMEM142A), ORAI3 (TMEM142C), and NDC1 (NDC1 transmembrane nucleoporin, TMEM48) are among the most extensively studied ones. Mechanisms of TMEM dysregulation in lung cancer span the modulation of Ca²⁺ influx, lysosomal exocytosis, ferroptosis, Wnt and β-catenin signaling, and immune cell infiltration and immune checkpoint rewiring, among others. Epigenetic silencing and targetable fusions (i.e., TMEM106B-ROS1 and TMEM87A-RASGRF1) create DNA-level vulnerabilities, while miRNA sponges offer RNA-level druggability. A subset of studies revealed context-specific expression (endothelial, B cell, and hypoxic EV) that can be exploited to remodel the tumor microenvironment. One study specifically focused on how isoform-specific expression and localization of TMEM88 determine its functional impact on tumor progression. Yet for most TMEMs, only pre-clinical or early-phase data exist, with many supported by a single study lacking independent validation. This review brings together scattered evidence on TMEM proteins in lung cancer, with the aim of guiding future work on their possible use as biomarkers or therapeutic targets. Full article

(This article belongs to the Section Molecular Oncology)

17 pages, 2271 KB

Open AccessArticle

UBE4B Mediates Mitophagy via NIPSNAP1 Ubiquitination and NDP52 Recruitment

by Bo Jin, Junyao Qu, Ke Xu, Yufei Zhang, Peng Xu, Xin Wang, Bo Zhao and Xianting Jiao

Int. J. Mol. Sci. 2026, 27(2), 1119; https://doi.org/10.3390/ijms27021119 - 22 Jan 2026

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Abstract

Mitophagy, as a critical form of selective autophagy, plays a central role in maintaining cellular homeostasis. While the canonical PTEN-Induced Kinase 1 (PINK1)–Parkin pathway is well established, mitophagy can still be effectively induced in Parkin-deficient cells such as HeLa, indicating the existence of [...] Read more.

Mitophagy, as a critical form of selective autophagy, plays a central role in maintaining cellular homeostasis. While the canonical PTEN-Induced Kinase 1 (PINK1)–Parkin pathway is well established, mitophagy can still be effectively induced in Parkin-deficient cells such as HeLa, indicating the existence of Parkin-independent alternative pathways. The mitochondrial matrix proteins 4-Nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) acts as a key effector in such pathways, yet its regulatory mechanisms remain incompletely understood. Here, we identify Ubiquitination Factor E4B (UBE4B) as an E3 ubiquitin ligase for NIPSNAP1 and demonstrate that it catalyzes NIPSNAP1 ubiquitination in both Human Embryonic Kidney 293 cells (HEK293T) and HeLa cells. Under mitochondrial depolarization, UBE4B not only promotes NIPSNAP1 ubiquitination and subsequent lysosome-dependent degradation, but also significantly enhances its interaction with the autophagy adaptors Nuclear Dot Protein 52 kDa (NDP52) and Sequestosome 1 (p62/SQSTM1). Notably, while Parkin does not ubiquitinate NIPSNAP1, UBE4B-mediated ubiquitination facilitates mitophagy in Parkin-null HeLa cells by strengthening the binding between NIPSNAP1 and NDP52. Collectively, this study unveils a novel mitophagy pathway regulated by the UBE4B-NIPSNAP1 axis, offering new insights into mitochondrial quality control. Full article

(This article belongs to the Special Issue Research on the Key Role of Ubiquitination in Signaling and Cancer)

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17 pages, 5007 KB

Open AccessArticle

Evaluation of the Antiviral Activity of a Natural Product, Schisandrin B, Against Rhabdovirus Infection in Chinese Rice Field Eels

by Yisha Liu, Mingyang Xue, Chen Xu, Yong Zhou, Nan Jiang, Yan Meng, Yiqun Li, Zhenyu Huang, Wenzhi Liu and Yuding Fan

Int. J. Mol. Sci. 2026, 27(2), 1118; https://doi.org/10.3390/ijms27021118 - 22 Jan 2026

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Abstract

Chinese rice-field eel rhabdovirus (CrERV), an emerging viral pathogen, causes massive death in rice-field eels (Monopterus albus), thus threatening the industry’s development. There is currently no established treatment strategy for CrERV. This study evaluated the anti-CrERV effects of schisandrin B (Sch [...] Read more.

Chinese rice-field eel rhabdovirus (CrERV), an emerging viral pathogen, causes massive death in rice-field eels (Monopterus albus), thus threatening the industry’s development. There is currently no established treatment strategy for CrERV. This study evaluated the anti-CrERV effects of schisandrin B (Sch B) in vitro and in vivo. The results indicated that Sch B at 20 mg/L could inhibit the expression of the CrERV G protein, with a maximum inhibition rate of 69.5%. Additionally, Sch B mitigated the nuclear damage and mitochondrial membrane potential decline induced by CrERV, thereby preserving cellular morphology. A time-of-addition study suggested that Sch B might exert its antiviral effects during the mid-stage of viral replication. In vivo, Sch B exhibited promising preventive and therapeutic effects against CrERV infection in rice-field eels, enhancing their survival rate by 57% and 51%, when added at 0.075% and 0.025%, respectively. Overall, the natural product Sch B was proven to have excellent anti-CrERV activity, with broad prospects for application in aquaculture. Full article

(This article belongs to the Section Molecular Microbiology)

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11 pages, 513 KB

Open AccessCase Report

Clinical Impact of Macrotroponin on Immunometric Troponin Assays: A Cross-Analytical Case Evaluation

by Michela Salvatici, Chiara Corrado, Rita Passerini, Monica Gaimarri, Delia Francesca Sansico, Ludovica Barile, Francesco Bandera and Lorenzo Drago

Int. J. Mol. Sci. 2026, 27(2), 1117; https://doi.org/10.3390/ijms27021117 - 22 Jan 2026

Viewed by 176

Abstract

High-sensitivity cardiac troponin assays are susceptible to analytical interferences, including macrotroponin, an immunoglobulin-bound complex that may cause persistent, non-dynamic, and assay-dependent elevations. This paper describes the case of a 74-year-old woman with hypertension who presented with intermittent mild chest discomfort and exertional dyspnea [...] Read more.

High-sensitivity cardiac troponin assays are susceptible to analytical interferences, including macrotroponin, an immunoglobulin-bound complex that may cause persistent, non-dynamic, and assay-dependent elevations. This paper describes the case of a 74-year-old woman with hypertension who presented with intermittent mild chest discomfort and exertional dyspnea and exhibited persistently elevated but stable cardiac troponin I concentrations over several months, in the absence of clinical, electrocardiographic, or imaging evidence of myocardial injury. Orthogonal testing revealed discordant results across different assay platforms, and polyethylene-glycol (PEG) precipitation resulted in a substantial signal reduction, confirming macrotroponin as the source of assay-dependent analytical interference. Recognizing this phenomenon is crucial to avoid misdiagnosis, unnecessary diagnostic procedures and inappropriate management in patients with isolated troponin elevation. In conclusion, this report provides evidence-based recommendations on the optimal diagnostic strategies and laboratory approaches to adopt in cases of suspected macrotroponin-mediated interference in high-sensitivity cardiac troponin assays. Full article

(This article belongs to the Section Biochemistry)

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13 pages, 370 KB

Open AccessReview

Beyond the Genome: Can Epigenetics Forecast Therapeutic Success in Graves’ Disease and Thyroid Eye Disease?

by Jacopo Manso, Dario Sardone, Vincenzo Marotta, Antonio Stefano Salcuni, Alessandro Brunetti, Claudia Cipri, Silvia Maria Sciannimanico, Lorenzo Piva, Maria Carpentieri, Alberto Falchetti and Fabio Vescini

Int. J. Mol. Sci. 2026, 27(2), 1116; https://doi.org/10.3390/ijms27021116 - 22 Jan 2026

Viewed by 239

Abstract

Graves’ disease (GD) and Thyroid Eye Disease (TED) are autoimmune disorders characterized by significant heterogeneity in treatment response. Up to 50% of GD patients relapse after antithyroid drug (ATD) withdrawal, and a substantial portion of TED patients (20–50%) are resistant to first-line glucocorticoid [...] Read more.

Graves’ disease (GD) and Thyroid Eye Disease (TED) are autoimmune disorders characterized by significant heterogeneity in treatment response. Up to 50% of GD patients relapse after antithyroid drug (ATD) withdrawal, and a substantial portion of TED patients (20–50%) are resistant to first-line glucocorticoid (GC) therapy. This review evaluates the current evidence on epigenetic modifications as predictive biomarkers to guide personalized treatment. We synthesized recent findings (up to 2025) from PubMed, focusing on DNA methylation and microRNAs (miRNAs). For GD, ATD relapse risk is linked to a persistent “epigenetic memory” in T cells, notably the hypomethylation of Th17-associated genes. Circulating miRNA signatures, including miR-346, miR-23b-5p, and miR-92a-3p, also show promise in predicting remission. For TED, GC sensitivity is strongly correlated with specific circulating miRNAs. High pre-treatment levels of miR-146a predict a positive response (100% positive predictive value), while low levels of miR-224-5p predict non-responsiveness. While DNA methylation is confirmed in TED pathogenesis, its predictive role is unstudied. Major research gaps persist, particularly the near-total absence of data on histone modifications as predictive markers and the lack of epigenetic predictors for new biologics treatments, which currently rely on genetic or pharmacokinetic markers. Epigenetic biomarkers represent a promising frontier for stratifying patients and optimizing therapeutic strategies in Graves’ autoimmunity. Full article

(This article belongs to the Special Issue Gene Regulation in Endocrine Disease, 2nd Edition)

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15 pages, 1216 KB

Open AccessReview

Anti-Chlamydia trachomatis Host Defence Arsenal Within the Cervicovaginal Environment

by Simone Filardo, Giulia Chicarella, Rosa Sessa and Marisa Di Pietro

Int. J. Mol. Sci. 2026, 27(2), 1115; https://doi.org/10.3390/ijms27021115 - 22 Jan 2026

Viewed by 187

Abstract

Chlamydia trachomatis has a significant impact on public health, especially among adolescents and young women; it primarily affects urogenital epithelial cells, leading to cervicitis and urethritis, with >90% of cases showing no symptoms. Consequently, chlamydial infections are commonly misdiagnosed, and, if untreated, they [...] Read more.

Chlamydia trachomatis has a significant impact on public health, especially among adolescents and young women; it primarily affects urogenital epithelial cells, leading to cervicitis and urethritis, with >90% of cases showing no symptoms. Consequently, chlamydial infections are commonly misdiagnosed, and, if untreated, they may result in severe reproductive sequelae including infertility. A better understanding of C. trachomatis cell biology and bacterial–host cell interactions may be helpful to identify strategies able to counter its transmission among the population, as well as its dissemination in reproductive tissues, reducing the risk of developing severe reproductive sequelae. Therefore, the present review aims to summarize the evidence on the interplay between C. trachomatis and the host defence factors within the cervicovaginal environment. The sophisticated strategies employed by this clinically significant pathogen to counteract these mechanisms are also discussed. In the literature, the main defence factors include the microbiota dominated by Lactobacillus crispatus and several molecules like lactoferrin, able to protect the cervicovaginal microenvironment against C. trachomatis through several mechanisms (e.g., EB coaggregation and competitive exclusion, as well as anti-inflammatory activity). However, the major player in clearing chlamydial infections remains the interferon-gamma (IFN-γ) produced by natural killer and T cells, via the depletion of critical nutrients for C. trachomatis such as tryptophan, or via the ubiquitylation and destruction of chlamydial inclusions. Full article

(This article belongs to the Special Issue Chlamydia trachomatis Pathogenicity and Disease (Third Edition))

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27 pages, 1944 KB

Open AccessArticle

The Diverse Effect of HDAC Inhibitors: Sodium Butyrate and Givinostat on Microglia Polarization After Hypoxia-Ischemia In Vitro

by Karolina Ziabska, Paulina Pawelec, Luiza Stanaszek and Malgorzata Ziemka-Nalecz

Int. J. Mol. Sci. 2026, 27(2), 1114; https://doi.org/10.3390/ijms27021114 - 22 Jan 2026

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Abstract

Microglia play a key role in the development of neuroinflammation induced by cerebral ischemia. On the other hand, these cells participate in neurorepair processes. This dual role of microglia stems from the ability to shift their phenotype from pro-inflammatory M1 to protective M2. [...] Read more.

Microglia play a key role in the development of neuroinflammation induced by cerebral ischemia. On the other hand, these cells participate in neurorepair processes. This dual role of microglia stems from the ability to shift their phenotype from pro-inflammatory M1 to protective M2. Histone deacetylase inhibitors (HDACis) are a group of agents that exhibit neuroprotective effects in some models of ischemia, among others, by modulation of signaling pathways that regulate microglial activation. This study aimed to examine the effect of HDACis—sodium butyrate and Givinostat—on polarization of microglia and their potential mechanism of action in a model of ischemia in vitro (oxygen and glucose deprivation, OGD). We examined the expression of pro- and anti-inflammatory markers in the BV2 microglial cell line after OGD and HDACis treatment by qPCR; polarization of microglia by flow cytometry; and the activation/phosphorylation of ERK and AKT in BV2 cells by Western blot and ELISA. Our findings demonstrate a divergent impact of HDACis on the phenotype of microglial cells. Sodium butyrate significantly suppressed the mRNA expression of pro-inflammatory markers (IL-1β, TNF-α, CD86) and increased the level of anti-inflammatory factors in BV2 microglial cells after OGD, whereas Givinostat failed to attenuate these inflammatory responses. Our findings demonstrate that sodium butyrate, but not Givinostat, promotes a shift in microglia toward an anti-inflammatory M2 phenotype under ischemic conditions. This effect is associated with suppression of pro-inflammatory gene expression and activation of the PI3K/AKT signaling pathway. These results identify sodium butyrate as a potential modulator of microglial responses following ischemic injury. Full article

(This article belongs to the Special Issue Molecular and Cellular Mechanism in Neuroinflammation Research)

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13 pages, 2339 KB

Open AccessArticle

Molecular Identification and Pathogenicity of a Chilli Veinal Mottle Virus Isolate from Sichuan, China

by Cheng Chen, Daihua Lu, Xiaotong Lin, Xueping Zhou and Xiuling Yang

Int. J. Mol. Sci. 2026, 27(2), 1113; https://doi.org/10.3390/ijms27021113 - 22 Jan 2026

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Abstract

Chilli veinal mottle virus (ChiVMV) is an important potyvirus that poses a serious threat to crop production. In this study, small RNA sequencing and molecular cloning were used to obtain the complete genome sequence of a ChiVMV isolate identified in pepper plants in [...] Read more.

Chilli veinal mottle virus (ChiVMV) is an important potyvirus that poses a serious threat to crop production. In this study, small RNA sequencing and molecular cloning were used to obtain the complete genome sequence of a ChiVMV isolate identified in pepper plants in Sichuan (SC1 isolate). Molecular evolutionary and phylogenetic analysis of SC1 and 35 ChiVMV isolates revealed four clades of ChiVMV isolates. Recombination analysis found 23 recombinant events and 28 recombinants, with the SC1 isolate arising from the recombination of the PK isolate from Pakistan and the YNpe isolate from Yunnan, China. A full-length infectious cDNA clone of ChiVMV was constructed and demonstrated to be infectious in both Nicotiana benthamiana and pepper plants. Moreover, a Myc-tag was inserted after NIb, and the derived infectious clone of ChiVMV remained infectious, and NIb-Myc was readily expressed in infected host plants. These reverse genetic tools will promote the study of the function of ChiVMV-encoded proteins, especially the NIb protein, and facilitate basic and translational studies of ChiVMV. Full article

(This article belongs to the Section Molecular Microbiology)

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19 pages, 7426 KB

Open AccessArticle

Promoter Methylation–Expression Coupling of Gliogenesis Genes in IDH-Wildtype Glioblastoma: Longitudinal Analysis and Prognostic Value

by Roxana Radu, Ligia Gabriela Tataranu, Anica Dricu and Oana Alexandru

Int. J. Mol. Sci. 2026, 27(2), 1112; https://doi.org/10.3390/ijms27021112 - 22 Jan 2026

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Abstract

Glioblastoma (GBM) shows extensive epigenetic heterogeneity. In IDH-wildtype (IDH-WT) GBM, promoter DNA methylation may regulate lineage programs influencing tumor evolution and prognosis; here, we systematically profiled promoter-level methylation dynamics across longitudinal tumors. Genome-wide DNA methylation data were obtained from the [...] Read more.

Glioblastoma (GBM) shows extensive epigenetic heterogeneity. In IDH-wildtype (IDH-WT) GBM, promoter DNA methylation may regulate lineage programs influencing tumor evolution and prognosis; here, we systematically profiled promoter-level methylation dynamics across longitudinal tumors. Genome-wide DNA methylation data were obtained from the publicly available Gene Expression Omnibus (GEO; GSE279073) dataset, comprising a longitudinal cohort of 226 IDH-wildtype glioblastomas profiled on the Illumina Infinium EPIC 850K array across primary and recurrent stages at the University of California, San Francisco. From 333 Gene Ontology gliogenesis-annotated genes (GO:0042063), a 48-gene promoter panel was derived, with ≥2 probes per gene. Promoter methylation was summarized as the median β-value and tested using one-sample Wilcoxon with FDR correction. Functional enrichment, longitudinal variation, and patient-level methylation burden were assessed. Validation analyses were performed using independent IDH-wildtype GBM datasets from The Cancer Genome Atlas (RNA-seq and 450K methylation; n = 347). Promoter hypomethylation predominated across all stages, with 25 genes consistently hypomethylated and 7 hypermethylated. Functional enrichment highlighted gliogenesis, glial cell differentiation, neurogenesis, and Notch-related signaling. In TCGA, promoter methylation inversely correlated with expression for 11 of 33 genes (FDR < 0.05). An Expression Score contrasting hypomethylated and hypermethylated genes was positively associated with improved overall survival, where higher scores predicted better outcome (HR = 0.87, p = 0.016; Q4 vs. Q1 HR = 0.68, p = 0.025), and a complementary Methylation Score showed that higher promoter hypermethylation predicted poorer outcome (HR = 1.73, p < 0.001). CNTN2 and TSPAN2 were adverse prognostic genes (FDR < 0.05). The Expression Score was highest in Proneural tumors and lowest in Mesenchymal tumors (p < 0.001), reflecting a proneural-like state associated with better prognosis. Promoter methylation within gliogenesis genes defines a stable yet prognostically informative epigenetic signature in IDH-WT GBM. Hypomethylation promotes transcriptional activation and a favorable outcome, whereas hypermethylation represses lineage programs and predicts poorer survival. Full article

(This article belongs to the Special Issue Hallmarks of Cancer: Emerging Insights and Innovations)

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17 pages, 2521 KB

Open AccessArticle

SUMOylation Protects Endothelial Cell-Expressed Leukocyte-Specific Protein 1 from Ubiquitination-Mediated Proteasomal Degradation and Facilitates Its Nuclear Export

by Mokarram Hossain, Jiannan Huang, Yang Su, Md Rafikul Islam, Mohammad Alinoor Rahman, Francisco S. Cayabyab and Lixin Liu

Int. J. Mol. Sci. 2026, 27(2), 1111; https://doi.org/10.3390/ijms27021111 - 22 Jan 2026

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Abstract

Leukocyte-specific protein 1 (LSP1) is known as an endothelial gatekeeper because it controls endothelial permeability and transendothelial cell migration, including that of leukocytes and potentially metastatic cancer cells. In endothelial cells, LSP1 is predominantly in the nucleus under resting conditions but translocates to [...] Read more.

Leukocyte-specific protein 1 (LSP1) is known as an endothelial gatekeeper because it controls endothelial permeability and transendothelial cell migration, including that of leukocytes and potentially metastatic cancer cells. In endothelial cells, LSP1 is predominantly in the nucleus under resting conditions but translocates to extranuclear compartments upon stimulation with TNF-α. The discrepancy between its predicted molecular weight (~37 kDa) and its observed migration on SDS-PAGE (≥52 kDa), along with its dynamic subcellular distribution, suggests a possible post-translational modification by SUMOylation. To investigate this, we examined endogenous LSP1 in murine primary endothelial cells and overexpressed recombinant LSP1 in murine endothelial (SVEC4-10EE2) and HEK293T cells. Our results demonstrate that LSP1 is SUMOylated by SUMO1, with Ubc9 serving as the conjugating enzyme and SENP1 as the deSUMOylating protease. Site-directed mutagenesis of lysines K270 and K318 abolished SUMOylation, resulting in a marked reduction in LSP1 steady-state levels. This reduction was attributed to enhanced ubiquitination and accelerated proteasomal degradation of LSP1 in the SUMOylation-deficient state. Furthermore, deSUMOylation impaired the TNF-α-induced translocation of LSP1 from the nucleus to extranuclear compartments, particularly the cytoskeleton. In summary, our findings establish that LSP1 is a SUMO1-modified protein. SUMOylation stabilizes LSP1 by preventing proteasomal degradation and is essential for its proper subcellular trafficking in endothelial cells in response to inflammatory stimuli. Full article

(This article belongs to the Special Issue Advances and Insights in Tumorigenesis and Tumor Metastasis)

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13 pages, 929 KB

Open AccessArticle

Effect of Bladder Injections of Botulinum Neurotoxin A on Biomarkers Associated with Inflammation and Urinary Infections in Patients with Neurogenic Detrusor Overactivity-Associated Incontinence: A Pilot, Prospective, Human Study

by Sotirios Gatsos, Elena Constantinou, Dimitrios Koutsoumparis, Michael Samarinas, Konstantinos Drosos, Maria Papaioannou, Andigoni Malousi, Eudoxia G. Hatzivassiliou and Apostolos Apostolidis

Int. J. Mol. Sci. 2026, 27(2), 1110; https://doi.org/10.3390/ijms27021110 - 22 Jan 2026

Viewed by 210

Abstract

Conflicting data exist regarding the effect of intradetrusor BoNT/A on the incidence of urinary tract infections (UTIs) in patients with neurogenic detrusor overactivity (NDO), contrary to the increase in UTIs noted in patients with idiopathic OAB. Associations between UTIs, chronic inflammation, and bladder [...] Read more.

Conflicting data exist regarding the effect of intradetrusor BoNT/A on the incidence of urinary tract infections (UTIs) in patients with neurogenic detrusor overactivity (NDO), contrary to the increase in UTIs noted in patients with idiopathic OAB. Associations between UTIs, chronic inflammation, and bladder overactivity are acknowledged, albeit not fully understood. Chronic bladder inflammation is common in both NDO and OAB patients, and both animal and human studies suggest a beneficial effect of BoNT/A on both urinary and systemic levels of inflammatory markers. To explore whether intradetrusor BoNT/A injections affect the background for the incidence of UTIs in humans, we investigated in parallel the effect of intradetrusor BoNT/A on the incidence of UTIs and on the urine mRNA levels of urinary pathogen-detecting Toll-like receptors TLR2, TLR4, and TLR5 and of factors acting as intermediates of immune response and promoters of inflammatory reactions (IL1β, IL6, TNFα, and PGE₂). For this purpose, we recruited 22 patients with NDO-associated incontinence who received at least one bladder BoNT/A injection. Urine specimens for the study of UTIs were obtained before the procedure and at routine urodynamic follow-ups at 4–6 weeks, 6 and 12 months post-BoNT/A, and at clinical relapse, while urine specimens for the study of biomarkers were collected at the time of BoNT/A injection and at the abovementioned follow-ups thereafter. Urine specimens from 10 adult healthy volunteers with no OAB symptoms served as the control group in the biomarker study. The genes of interest in the urine were studied by RNA isolation, reverse transcription, and real-time PCR. The urine mRNAs of all biomarkers tested appeared to be upregulated in the patients’ samples compared with the controls, albeit only TLR2 and TLR5 mRNA increases were statistically significant. A progressive downregulation of TLR2, TLR5, IL1β, and IL6 urine mRNAs was noted at one and six months post-BoNT/A. TNFα and PGE₂ mRNAs showed a transient increase at one month post-BoNT/A followed by a dramatic drop at the six months’ follow-up. A similar trend for progressive decline was also noticed in the prevalence of both positive urine cultures and symptomatic UTIs in the same timepoints and additionally at 12 months post-treatment in patients who still benefited from the BoNT/A treatment. Upon clinical relapse, the mRNA levels of PGE₂, IL1β, and IL6 increased in parallel with an increase in the prevalence of UTIs, while the levels of TLRs and TNF-α did not follow the same trend. In summary, intradetrusor BoNT/A injections achieved significant decreases in the urine mRNA levels of pathogen-detecting TLRs, immune response, and inflammation mediator cytokines and PGE₂ in our cohort of patients with NDO-associated incontinence. In parallel, decreases were noted in both the incidence of symptomatic UTIs and rates of positive urine cultures. At the time of clinical relapse, the markers of inflammation and immune response, but not TLRs, were upregulated in parallel with the increased incidence of UTIs, suggesting that the studied genes PGE₂, IL1β, and IL6 could be further explored as potential biomarkers for inflammation/immune response and UTIs in the neurogenic population. Full article

(This article belongs to the Special Issue Primary and Secondary Bladder Disorders in Neurourology and Inflammatory Diseases)

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14 pages, 798 KB

Open AccessArticle

Association of MMP9 and NOS3 Polymorphisms with Distinct Clinical Forms of Juvenile Scleroderma and Characteristics of Humoral Immunity

by Maria Osminina, Vera Podzolkova, Maria Litvinova, Natalia Geppe, Svetlana Chebysheva, Lusine Khachatryan, Natalia Golovanova, Yulia Kostina, Oksana Lazareva-Batyreva, Angelina Polyanskaya, Olga Shpitonkova, Tatiana Subbotina, Tigran Areian and Nadezhda Podchernyaeva

Int. J. Mol. Sci. 2026, 27(2), 1109; https://doi.org/10.3390/ijms27021109 - 22 Jan 2026

Viewed by 195

Abstract

Juvenile scleroderma (JS), comprising localized (JLSd) and systemic (JSSc) forms, is a rare autoimmune disorder. This study investigated associations of polymorphisms in extracellular matrix (MMP1, MMP9) and vascular homeostasis (NOS3) genes with JS risk and immunological phenotypes. A [...] Read more.

Juvenile scleroderma (JS), comprising localized (JLSd) and systemic (JSSc) forms, is a rare autoimmune disorder. This study investigated associations of polymorphisms in extracellular matrix (MMP1, MMP9) and vascular homeostasis (NOS3) genes with JS risk and immunological phenotypes. A case–control study involved 215JS patients (194 JLSd, 21 JSSc) and 72 controls. SNPs (MMP1 rs1799750, MMP9 rs3918242, NOS3 rs1799983) were genotyped using real-time PCR followed by minisequencing and mass spectrometric analysis of reaction products. Associations with disease risk, subtypes, and immunological markers were analyzed statistically. The MMP9 (rs3918242) CT genotype was significantly associated with JLSd (OR = 2.23, 95% CI: 1.14–4.37, p = 0.022), showing a trend in linear facial forms. The NOS3 (rs1799983) GG genotype demonstrated a trend toward association with JSSc (OR = 2.61, 95% CI: 0.92–7.37, p = 0.065). No significant associations were found for rs1799750 MMP1 and risk of disease development. The MMP9 risk genotype did not correlate with scleroderma-specific autoantibodies, while the NOS3 GG genotype was associated with lower serum levels of anti-collagen IV antibodies (p = 0.039). Genetic associations differ for JS subtypes: MMP9 with JLSd and NOS3 with JSSc. Children with CT polymorphism MMP9 (rs3918242) and with NOS3 (rs1799983) GG genotype were found to be genetically predisposed for the development of JS. Full article

(This article belongs to the Special Issue Genetics and Omics in Autoimmune Diseases)

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23 pages, 6461 KB

Open AccessArticle

Enhanced Qualities of High-Density Lipoproteins (HDLs) with Antioxidant Abilities Are Associated with Lower Susceptibility of Hypertension in Middle-Aged Korean Participants: Impaired HDL Quality and Hypertension Risk

by Kyung-Hyun Cho, Chae-Eun Yang, Sang Hyuk Lee, Yunki Lee and Ashutosh Bahuguna

Int. J. Mol. Sci. 2026, 27(2), 1108; https://doi.org/10.3390/ijms27021108 - 22 Jan 2026

Viewed by 441

Abstract

The quality of high-density lipoproteins (HDLs) is characterized by lipid and protein composition, oxidation and glycation extent, and particle size, while the quantity of HDL-C is just the cholesterol amount in HDL. The inverse association between HDL-C and cardiovascular disease (CVD) and hypertension [...] Read more.

The quality of high-density lipoproteins (HDLs) is characterized by lipid and protein composition, oxidation and glycation extent, and particle size, while the quantity of HDL-C is just the cholesterol amount in HDL. The inverse association between HDL-C and cardiovascular disease (CVD) and hypertension has been well established; however, the U-shaped mortality risk observed from HDL-C underscores that HDL quality and function are equally important. The present cross-sectional study assessed the correlations of serum lipid and glucose profiles, and low-density lipoprotein (LDL) and HDL characteristics, with blood pressure (BP) distribution in ordinary middle-aged Korean participants (n = 50; mean age 47.0 ± 11.7 years; males: n = 25, 49.2.0 ± 11.7 years; females: n = 25, 44.8 ± 11.5 years), with particular focus on HDL quality and its antioxidant capacity. This study observed that serum elevated triglyceride (TG) and glucose levels were directly proportional to elevated systolic BP (SBP) and diastolic BP (DBP), whereas serum total cholesterol (TC), LDL-C, and HDL-C were not correlated with BP. However, HDL-C/TC (%) was negatively associated with SBP (p = 0.036), while TG/HDL-C and glucose/HDL-C ratios were positively associated with both SBP and DBP, suggesting that TG and glucose proportions relative to HDL-C are probable predictors of hypertension. Elevations of TG, oxidation, and glycation in LDL were positively associated with elevations of BP, whereas LDL particle size was negatively correlated with BP. Similarly, elevations of TG and glycation in HDL₂ and HDL₃ were positively correlated with elevations of BP, while the particle size of HDL₂ was negatively correlated with BP. The heightened HDL₂-associated paraoxonase (PON) activity and ferric ion reduction ability (FRA) negatively correlated with LDL oxidation and particle size, whereas elevated HDL₃-associated PON and FRA activities were inversely related to LDL glycation. An enhanced glycation in HDL₂ was negatively correlated with HDL₂-associated PON activity and FRA, while an increase in HDL₂ particle size was only dependent on the associated PON activity but not on FRA. In conclusion, observational outcomes demonstrated that improved HDL quality and functionality (characterized by large particle size, reduced glycation, and higher FRA and PON activities) were inversely correlated with LDL oxidation, glycation, particle shrinkage, and the risk of hypertension. Full article

(This article belongs to the Special Issue The Role of Diet in Lipid and Lipoprotein Metabolism)

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16 pages, 2311 KB

Open AccessArticle

High Cell Density Fermentation of Yarrowia lipolytica on n-Hexadecane for the Valorization of Pyrolyzed Plastic Waste

by Antonia Keil, Joost Woestenborghs, Oleksii Lyzak, Elodie Vlaeminck, Evelien Uitterhaegen, Karel De Winter, Kevin J. Verstrepen and Wim Soetaert

Int. J. Mol. Sci. 2026, 27(2), 1107; https://doi.org/10.3390/ijms27021107 - 22 Jan 2026

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Abstract

The recycling of fossil-based plastic waste remains a key challenge in reducing environmental pollution and greenhouse gas emissions. An innovative approach is the biotechnological conversion of the n-alkane mixture obtained from thermal pyrolysis of plastic waste. This study focuses on the use of [...] Read more.

The recycling of fossil-based plastic waste remains a key challenge in reducing environmental pollution and greenhouse gas emissions. An innovative approach is the biotechnological conversion of the n-alkane mixture obtained from thermal pyrolysis of plastic waste. This study focuses on the use of the oleaginous yeast Yarrowia lipolytica for the valorization of polyethylene (PE)-derived pyrolysis oil. From a screening of 50 Y. lipolytica strains, the most promising candidate was selected, and its single-cell phenotype was stabilized by MHY1 deletion. In shake flask experiments, this strain grew similarly on 5–20 vol% of n-hexadecane, revealing no inhibitory effects. Subsequently, a high cell density fermentation was established in a 4 L bioreactor using a pulsed fed-batch approach, resulting in biomass concentrations of up to 145.6 g·L⁻¹, which contained 22.0% triacylglycerols. In addition, cultivation at pH 2.5, compared to pH 4.0, reduced citrate formation from 95.6 to 0.8 g·L⁻¹, while biomass and TAG titers remained similar. Overall, these results highlight the potential of integrating plastic waste-derived pyrolysis oil into future bioprocesses using Y. lipolytica as an effective platform for high cell density production. Full article

(This article belongs to the Special Issue Molecular Insights into Microbial Adaptations to Marine Plastics)

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27 pages, 2777 KB

Open AccessArticle

The Fortification of Fruit Mousses with Encapsulated Bioactive Compounds in a Potato Starch Matrix as an Example of Novel Functional Foods

by Magdalena Krystyjan, Gohar Khachatryan, Karen Khachatryan, Anna Lenart-Boroń, Robert Socha and Zuzanna Potoniec

Int. J. Mol. Sci. 2026, 27(2), 1106; https://doi.org/10.3390/ijms27021106 - 22 Jan 2026

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Abstract

The increasing consumption of highly processed foods has resulted in a reduced intake of essential vitamins, minerals, and bioactive compounds, thereby intensifying interest in the development of functional food. This study aimed to enrich fruit mousses with bioactive compounds derived from elderberry extract [...] Read more.

The increasing consumption of highly processed foods has resulted in a reduced intake of essential vitamins, minerals, and bioactive compounds, thereby intensifying interest in the development of functional food. This study aimed to enrich fruit mousses with bioactive compounds derived from elderberry extract using an encapsulation strategy. Three formulations were prepared: a control mousse, a mousse enriched via direct addition of the extract, and a mousse supplemented with a nanoemulsion. Comprehensive analyses, including SEM (Scanning Electron Microscopy), FTIR (Fourier Transform Infrared Spectroscopy), colorimetry, texture and rheological measurements, phenolic acid and flavonoid content, antioxidant and reducing activity, sensory evaluation, and microbiological assessment, confirmed the successful formation of submicron capsules (400–900 nm), effective incorporation of grape seed oil into the fruit mousse formulations, and minimal color alteration (ΔE* < 1). The enriched mousses exhibited slightly higher hardness (7.5%) and adhesiveness (5.4%) as well as enhanced antioxidant and reducing activity compared to the control. Rheological analyses indicated improved structural stability resulting from fortification. Sensory evaluation demonstrated good consumer acceptance, while microbiological analyses suggested a potential shelf-life extension due to inhibited microbial growth. Overall, encapsulation proved to be an effective approach for incorporating elderberry-derived bioactive substances into fruit mousses while preserving product quality. Full article

(This article belongs to the Special Issue Cutting-Edge Advances in Natural Bioactive Compounds)

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18 pages, 2420 KB

Open AccessArticle

Effects and Molecular Mechanisms of Heat-Killed Postbiotic Enterococcus faecalis EF-2001 on Muscle Volume and Grip Strength in Dexamethasone-Induced Muscle Atrophy in SD Rats

by Jin-Ho Lee, Kwon-Il Han, Eunwoo Jeong, Juyeong Moon, Min-ah Kim, Bon Seo Koo, Yura Lee, Sunhwa Baek, Han Sung Kim and Tack-Joong Kim

Int. J. Mol. Sci. 2026, 27(2), 1105; https://doi.org/10.3390/ijms27021105 - 22 Jan 2026

Viewed by 212

Abstract

The interaction between the gut microbiota and human health has gained increasing recognition, accelerating advances in microbiome research. While early studies have emphasized probiotics, concerns regarding antibiotic resistance and adverse effects, such as sepsis, have shifted research interest towards heat-treated microbial cells or [...] Read more.

The interaction between the gut microbiota and human health has gained increasing recognition, accelerating advances in microbiome research. While early studies have emphasized probiotics, concerns regarding antibiotic resistance and adverse effects, such as sepsis, have shifted research interest towards heat-treated microbial cells or postbiotics. This study investigated the therapeutic potential of heat-killed postbiotic Enterococcus faecalis EF-2001—one of the most widely used postbiotics worldwide—for the prevention and treatment of muscle atrophy. In vitro, mouse C2C12 myotubes were pretreated with heat-killed postbiotic EF-2001 (50–500 μg/mL) for 48 h and then treated with dexamethasone (100 μM) to induce muscle atrophy. In vivo, male Sprague Dawley rats were treated with low-dose (3 mg/kg) and high-dose (30 mg/kg) EF-2001 for efficacy studies. Heat-killed postbiotic EF-2001 attenuated cellular and DNA damage in dexamethasone-induced C2C12 myotubes. Specifically, heat-killed postbiotic EF-2001 increased AKT phosphorylation while suppressing Atrogin-1 expression, thereby alleviating muscle atrophy. In a Sprague Dawley rat model, heat-killed postbiotic EF-2001 significantly reduced dexamethasone-induced muscle loss by regulating muscle atrophy-associated signaling pathways, including Atrogin-1 expression. Collectively, these findings demonstrate that heat-killed EF-2001 alleviates dexamethasone-induced muscle atrophy and support its potential as a postbiotic. This study provides a solid foundation for future human clinical studies by establishing preclinical evidence for the biological activity of heat-killed EF-2001. Full article

(This article belongs to the Section Molecular Pharmacology)

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18 pages, 2082 KB

Open AccessArticle

Proline Accumulation in Barley Under Salinity Is ABA-Independent, but Relies on the Level of Oxidative Stress When Modulated by Mo and W Ions

by Moldir Beisekova, Beata Michniewska, Weronika Kusek, Alua Zh. Akbassova, Rustem Omarov, Sławomir Orzechowski and Edyta Zdunek-Zastocka

Int. J. Mol. Sci. 2026, 27(2), 1104; https://doi.org/10.3390/ijms27021104 - 22 Jan 2026

Viewed by 272

Abstract

The accumulation of proline, an important osmoprotective and antioxidant compound, is a key defense mechanism induced in plants in response to stress factors, including salinity, and is likely dependent on abscisic acid (ABA). However, in barley grown for 8 days under salinity conditions [...] Read more.

The accumulation of proline, an important osmoprotective and antioxidant compound, is a key defense mechanism induced in plants in response to stress factors, including salinity, and is likely dependent on abscisic acid (ABA). However, in barley grown for 8 days under salinity conditions (125 mM NaCl), proline accumulation was not accompanied by changes in ABA content. Co-application of 0.5 mM molybdenum (Mo) significantly reduced NaCl-induced oxidative stress, as measured by H₂O₂, O₂⁻, MDA, and chlorophyll content, and increased the activity of Mo-containing aldehyde oxidase (AO), an enzyme involved in de novo ABA synthesis. As a result, elevated ABA levels were observed, but proline content under salinity conditions was similar in Mo-treated and non-Mo-treated plants. In contrast, exposing plants to 0.5 mM tungsten (W), an antagonist of Mo, inhibited AO activity without significantly altering ABA content, while proline and oxidative stress marker levels increased dramatically under both non-saline and saline conditions. The observed changes in proline content are mainly due to modulation of the rate of synthesis and, to a lesser extent, the rate of degradation, as revealed by transcript abundance of P5CS1 and PDH, which encode D1-pyrroline-5-carboxylate synthetase and proline dehydrogenase, respectively. The results indicate that in barley grown under salinity conditions, proline accumulation is ABA-independent but depends on the level of oxidative stress modulated by Mo and W ions. Full article

(This article belongs to the Special Issue Abiotic Stress in Plants: Physiological and Molecular Responses)

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16 pages, 2237 KB

Open AccessArticle

Altered AADAC Modulates Trophoblast Invasion and Suggests a Potential Angiogenic Regulatory Role in Severe Preeclampsia

by Hyo Jung An, Dae Hyun Song, Yu-min Kim, Hyen Chul Jo, Jong Chul Baek, Juseok Yang and Ji Eun Park

Int. J. Mol. Sci. 2026, 27(2), 1103; https://doi.org/10.3390/ijms27021103 - 22 Jan 2026

Viewed by 158

Abstract

Preeclampsia (PE) is a serious pregnancy complication characterized by hypertension and organ dysfunction. Its pathogenesis involves impaired trophoblast invasion and inadequate spiral artery remodeling; however, the underlying molecular mechanisms remain unclear. This study investigated the role of arylacetamide deacetylase (AADAC) in PE and [...] Read more.

Preeclampsia (PE) is a serious pregnancy complication characterized by hypertension and organ dysfunction. Its pathogenesis involves impaired trophoblast invasion and inadequate spiral artery remodeling; however, the underlying molecular mechanisms remain unclear. This study investigated the role of arylacetamide deacetylase (AADAC) in PE and its effects on trophoblast function by analyzing placental tissues from 30 patients with PE and 15 controls. Exploratory RNA sequencing was performed on pooled placental samples from six patients with severe PE and six controls, and AADAC expression was validated by semi-quantitative PCR and Western blotting. HTR8/SVneo cells were exposed to cobalt chloride (CoCl₂) under hypoxia-mimicking conditions, and AADAC expression was manipulated by siRNA-mediated knockdown (KD) and overexpression (OE). RNA sequencing revealed increased AADAC expression in PE placentas (fold change > 2.0, raw p < 0.05). Although AADAC mRNA levels were elevated in PE tissues, protein levels were reduced. CoCl₂ exposure was associated with increased expression of AADAC and hypoxia-inducible factor-1 alpha (HIF-1α). Under hypoxia-mimicking conditions, AADAC silencing was associated with increased trophoblast invasion and tube formation, whereas AADAC overexpression reduced tube formation without significantly affecting invasion. These findings suggest that dysregulated, hypoxia-responsive AADAC expression influences trophoblast invasive and angiogenic behavior in preeclampsia. Full article

(This article belongs to the Special Issue Molecular and Cellular Biology of Pregnancy Complications)

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16 pages, 1790 KB

Open AccessArticle

The NFAT5–AR Axis Is Associated with Hyperosmolarity, Renal Dysfunction, and Neutrophil-Related Inflammatory Markers in Diabetic Retinopathy

by Fátima Sofía Magaña-Guerrero, Beatriz Buentello-Volante, Norma Angélica Magaña-Guerrero, Óscar Vivanco-Rojas, Alfredo Domínguez-López and Yonathan Garfias

Int. J. Mol. Sci. 2026, 27(2), 1102; https://doi.org/10.3390/ijms27021102 - 22 Jan 2026

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Abstract

Diabetic retinopathy (DR) is a major microvascular complication of type 2 diabetes (T2D) and is strongly associated with chronic inflammation. Neutrophils contribute to this inflammatory milieu, and the hyperosmolar stress-responsive transcription factor NFAT5 and its downstream effector aldose reductase (AR) may play crucial [...] Read more.

Diabetic retinopathy (DR) is a major microvascular complication of type 2 diabetes (T2D) and is strongly associated with chronic inflammation. Neutrophils contribute to this inflammatory milieu, and the hyperosmolar stress-responsive transcription factor NFAT5 and its downstream effector aldose reductase (AR) may play crucial roles in this process. NFAT5 regulates AR, which converts glucose to sorbitol; excessive sorbitol accumulation promotes endothelial and retinal cell damage. Given the links between NFAT5, metabolic stress and immune activation, dysregulation of the NFAT5–AR axis in neutrophils may contribute to DR pathophysiology. This study evaluated NFAT5 and AR expression in peripheral blood neutrophils from 150 individuals classified as nondiabetic (n = 50), T2D without DR (n = 50), or T2D with DR (n = 50). Clinical, metabolic, and ophthalmic assessments were performed, and neutrophils were isolated to quantify NFAT5 and AR via ELISA. Associations with renal function, plasma osmolarity (pOSM), and hematological inflammatory ratios (NLR, NMR, NPAR, and SII) were analyzed. T2D-DR subjects presented impaired renal parameters, increased pOSM, reduced eGFR, and elevated NLR and NPAR. NFAT5 and AR levels were significantly increased in T2D-DR neutrophils and correlated positively with pOSM and the inflammatory ratios, whereas NFAT5 correlated inversely with the eGFR. These findings suggest that activation of the NFAT5–AR pathway contributes to neutrophil-driven inflammatory and hyperosmolar dysregulation in T2D and may influence DR progression. Full article

(This article belongs to the Special Issue Molecular Therapeutics for Diabetes and Related Complications, 2nd Edition)

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15 pages, 2857 KB

Open AccessArticle

Transcriptome Analysis and Hub Gene Identification in the Brain Cell Lines of the Spotted Knifejaw (Oplegnathus punctatus) After Poly (I:C) Stimulation

by Ruiqi Guo, Kaimin Li, Jinfeng Liu, Songlin Chen and Lei Wang

Int. J. Mol. Sci. 2026, 27(2), 1101; https://doi.org/10.3390/ijms27021101 - 22 Jan 2026

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Abstract

The spotted knifejaw (Oplegnathus punctatus) has emerged as a species with substantial potential for aquaculture development in China. However, its industrial cultivation is severely constrained by viral diseases. Among these, viral nervous necrosis (VNN), caused by nervous necrosis virus (NNV), represents [...] Read more.

The spotted knifejaw (Oplegnathus punctatus) has emerged as a species with substantial potential for aquaculture development in China. However, its industrial cultivation is severely constrained by viral diseases. Among these, viral nervous necrosis (VNN), caused by nervous necrosis virus (NNV), represents a critical bottleneck to the sustainable development of this industry. In order to elucidate the immune response mechanisms of the brain cells of spotted knifejaw, this study established a poly (I:C) stimulation model in vitro and performed transcriptomic sequencing to analyze the differentially expressed genes (DEGs) after stimulation. There were 3169, 3228, and 3262 DEGs at 3 h, 6 h, and 12 h compared to 0 h (control), respectively. Co-expression time clustering of DEGs identified two gene clusters (cluster 6 and cluster 10), which included several immune-related genes. GO and KEGG enrichment analyses indicated that DEGs among the four time points were significantly enriched in immune signaling pathways, including the NOD-like receptor, RIG-I-like receptor, C-type lectin receptor, and Toll-like receptor pathways, as well as disease-response pathways. In total, 1398 common DEGs were identified among three comparative groups, which delineated six interaction clusters and 30 hub genes in protein–protein interaction (PPI) network analysis. By integrating a cellular model with transcriptomics, this study provides preliminary insights into the molecular immune mechanisms underlying the response of brain cells to poly (I:C) stimulation, offering important theoretical support for future research on disease-resistant breeding and disease control strategies in spotted knifejaw. Full article

(This article belongs to the Special Issue Genomic, Transcriptomic, and Epigenetic Approaches in Fish Research)

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Int. J. Mol. Sci., Volume 27, Issue 2 (January-2 2026) – 575 articles

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