International Journal Of Molecular Sciences[JOURNAL]
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200 papers
Co-Phosphoregulatory Network Underlying Functional Coherence of TLK1 and TLK2 Kinase Paralogs.
Vijayan J, Subair S, Ahmed M … +5 more , Gopalakrishnan AP, Sambreena A, John L, Raju R, Rajeev AC
Int J Mol Sci · 2026 Jun · PMID 42353285 · Full text
Tousled-like kinases 1 and 2 (TLK1 and TLK2) are paralogous serine/threonine kinases that share high sequence similarity yet exhibit functional divergence in cellular processes such as DNA replication, damage response, a...
Tousled-like kinases 1 and 2 (TLK1 and TLK2) are paralogous serine/threonine kinases that share high sequence similarity yet exhibit functional divergence in cellular processes such as DNA replication, damage response, and chromatin organization. This study elucidates the paralog-specific co-phosphoregulatory networks underlying this divergence through a comprehensive analysis of 3825 human phosphoproteomic articles. Predominant phosphosites were identified as S134 and T38 for TLK1 and S73, S99, and S111 for TLK2, revealing context-dependent regulation across cancers and perturbations. Co-phosphoregulation analyses uncovered distinct networks: TLK1 associates with DNA damage signaling via proteins like ABRAXAS1, PML, and RAD9A, while TLK2 integrates with chromatin remodeling and replication through CHD4, DOT1L, NASP, and RNF20. Upstream kinases for TLK2, predominantly CDKs, link it to cell-cycle progression, whereas downstream substrates and binary interactors converge on genome stability pathways with paralog-specific nuances. These findings highlight the potential role of TLK1 on checkpoint activation and TLK2 on replication-coupled chromatin maintenance, providing insights into their roles in cancer amplification and therapeutic resistance, as well as neurodevelopmental disorders, where emerging evidence also support the involvement of TLK1 alongside TLK2.
Amplicon-Based Multiregion Genomic Characterization of HIV-1 in a Tertiary-Care Hospital in Mexico: Antiretroviral Resistance Mutations and Subtype Diversity.
García-Moncada E, Cortés-Malagón EM, Pineda-Migranas JA … +9 more , Ruiz Santana M, Cortés-Ortíz IA, Escutia Domínguez JF, Bravata-Alcántara DA, Acosta-Altamirano G, Razo-González SD, Castillo Mendez MA, Sierra-Martínez M, Bravata-Alcántara JC
Int J Mol Sci · 2026 Jun · PMID 42353284 · Full text
Human immunodeficiency virus type 1 exhibits extensive genetic diversity, which has important implications for molecular epidemiology, recombinant-pattern assessment, and antiretroviral resistance surveillance. In Mexico...
Human immunodeficiency virus type 1 exhibits extensive genetic diversity, which has important implications for molecular epidemiology, recombinant-pattern assessment, and antiretroviral resistance surveillance. In Mexico, HIV-1 molecular surveillance has historically relied mainly on partial gene sequencing, limiting the ability to compare lineage assignments across , , and regions. We analyzed plasma samples from 40 treatment-naïve adults receiving care at a tertiary-care hospital in Mexico using a commercial amplicon-based multiregion HIV-1 genomic sequencing workflow. DeepChek was used as the primary workflow for read processing, mutation calling, region-level subtype assignment, and antiretroviral resistance interpretation. Resistance interpretation was restricted to antiretroviral target regions with sufficient coverage, mainly reverse transcriptase, protease, integrase, and capsid, when available. Drug resistance mutations were identified in 6/40 participants (15.0%) when mutation-level resistance findings in RT, PR, and IN were considered; one additional sample showed a capsid inhibitor-nonsusceptible NGS call. NNRTI-associated findings were identified in 2/40 patients (5.0%), whereas NRTI- and PI-associated findings were identified in 1/40 patients (2.5%). Accessory or secondary INSTI-associated substitutions were detected in 2/40 patients (5.0%). Region-level subtype analysis revealed frequent discordant assignments across amplified segments, which is consistent with complex mosaic profiles; however, these findings are interpreted as region-level subtypes and recombinant-pattern assignments rather than continuous whole-genome recombination maps. One sample had insufficient RT/PROT/INT coverage for drug resistance interpretation in the complete DeepChek report and was retained only for regions meeting quality thresholds. These findings support the value of multiregion HIV-1 sequencing for local molecular surveillance while emphasizing the need for transparent region-level coverage reporting, cautious interpretation of recombinant-pattern calls, and transparent repository reporting.
Molecular Mechanisms Underlying the Higher Prevalence of Anemia in Crohn's Disease Compared with Ulcerative Colitis: A Systematic Review.
Tesoi DF, Trandafir LM, Bozomitu L … +5 more , Frasinariu OE, Filip N, Mircea C, Hancianu M, Badulescu OV
Int J Mol Sci · 2026 Jun · PMID 42353283 · Full text
Anemia represents one of the most frequent systemic complications of inflammatory bowel disease (IBD), with a consistently higher prevalence reported in patients with Crohn's disease (CD) compared with ulcerative colitis...
Anemia represents one of the most frequent systemic complications of inflammatory bowel disease (IBD), with a consistently higher prevalence reported in patients with Crohn's disease (CD) compared with ulcerative colitis (UC). While chronic inflammation, impaired iron absorption, and intestinal blood loss are recognized contributors, microbiome-mediated mechanisms influencing host iron availability remain insufficiently explored. Emerging evidence indicates that CD-associated dysbiosis is characterized by an increased abundance of siderophore-producing bacteria, particularly members of the Enterobacteriaceae family. Because siderophores are high-affinity iron-chelating molecules capable of competing with host iron acquisition systems and partially escaping lipocalin-2-mediated sequestration, their expansion may contribute to reduced luminal iron bioavailability. In this systematic review, we analyzed comparative microbiome studies published between 2016 and 2026 that directly evaluated microbial differences between CD and UC. CD microbiota consistently demonstrated enrichment in siderophore-associated taxa relative to UC. Based on these findings, we propose that microbiome-driven iron competition may represent an additional mechanistic contributor to the increased prevalence and persistence of anemia observed in CD. Although direct in vivo quantification of siderophore activity in IBD remains limited, the convergence of ecological, functional, and strain-level microbiome evidence supports a biologically plausible interaction between microbial iron-scavenging strategies and host iron metabolism.
The Involvement of the Small GTPase Rac1 in Insulin Signaling That Regulates Plasma Membrane Translocation of the Fatty Acid Transporter CD36 in Mouse White Adipocytes.
Takenaka N, Sakata M, Abe Y … +2 more , Iha K, Satoh T
Int J Mol Sci · 2026 Jun · PMID 42353282 · Full text
A fraction of the insulin-stimulated uptake of long-chain fatty acids (FAs) is mediated by the FA translocase cluster of differentiation 36 (CD36) in white adipocytes. Intracellular vesicle-localized CD36 is redistribute...
A fraction of the insulin-stimulated uptake of long-chain fatty acids (FAs) is mediated by the FA translocase cluster of differentiation 36 (CD36) in white adipocytes. Intracellular vesicle-localized CD36 is redistributed to the plasma membrane following insulin stimulation, enhancing the uptake of long-chain FAs across the plasma membrane. We previously developed an epitope-tagged CD36 reporter, which enabled the visualization and quantification of the plasma membrane translocation of CD36. Herein, we demonstrate that the insulin-stimulated CD36 translocation is regulated by the phosphoinositide 3-kinase (PI3K)/Akt2/Rac1/RalA axis in adipocytes of subcutaneous white adipose tissue (WAT) in living mice. The uptake of long-chain FAs by insulin was completely abrogated in white adipocytes isolated from adipocyte-specific -knockout (adipo--KO) mice. Correspondingly, the translocation of CD36 to the plasma membrane by insulin was also totally inhibited in Rac1-deficient white adipocytes. PI3K and Akt2 acted upstream of Rac1, and the guanin nucleotide exchange factor FLJ00068 served as a regulator for Rac1. Furthermore, the involvement of another small GTPase RalA was suggested by inhibitory effects of a dominant-negative mutant. Taken together, these results support the notion that insulin regulates the plasma membrane translocation of CD36 by mechanisms similar to those for the translocation of the glucose transporter GLUT4 in white adipocytes.
CTLA-4 Blockade Combined with PD-1/PD-L1 Inhibition Enhances Cytokine Production and T-Cell Activation in Ex Vivo Ovarian Cancer Cultures.
Parulekar M, Park WH, Kim M … +4 more , Kim K, No JH, Kim YB, Suh DH
Int J Mol Sci · 2026 Jun · PMID 42353281 · Full text
Immune checkpoint inhibitors (ICIs) show promise in cancer but have limited efficacy in ovarian cancer. This study compared combinations of the PD-1/PD-L1 inhibitor with anti-LAG-3, anti-TIM-3, or anti-CTLA-4 to identify...
Immune checkpoint inhibitors (ICIs) show promise in cancer but have limited efficacy in ovarian cancer. This study compared combinations of the PD-1/PD-L1 inhibitor with anti-LAG-3, anti-TIM-3, or anti-CTLA-4 to identify the most effective regimen by assessing T-cell CD8/CD4 ratios and cytokine production. T cells isolated from ovarian cancer tissues (mean 3.8 × 10 cells) were stimulated and treated with the PD-1/PD-L1 inhibitor alone or combined with anti-LAG-3, anti-TIM-3, or anti-CTLA-4. Flow cytometry measured CD8/CD4 expression; ELISAs quantified TNF-α, IL-6, and IFN-γ. Anti-PD-1 monotherapy produced no significant change in CD8/CD4 ratio (1.36 ± 0.43 vs. 1.41 ± 0.36) or cytokine levels. Combination therapy with PD-1/PD-L1 inhibitor + anti-CTLA-4 induced the largest increase in CD8/CD4 ratio (3.69 ± 1.33, < 0.001) compared with PD-1/PD-L1 inhibitor alone; increases were smaller for PD-1/PD-L1 inhibitor + anti-LAG-3 (2.11 ± 0.63, = 0.009) and PD-1/PD-L1 inhibitor + anti-TIM-3 (1.87 ± 0.48, = 0.026). TNF-α rose significantly only with PD-1/PD-L1 inhibitor + anti-CTLA-4 (106.69 ± 45.42 pg/mL, = 0.008), not with PD-1/PD-L1 inhibitor + anti-LAG-3 (72.46 ± 31.79 pg/mL, = 0.231) or PD-1/PD-L1 inhibitor + anti-TIM-3 (82.06 ± 33.63 pg/mL, = 0.074). IFN-γ increase was greater with PD-1/PD-L1 inhibitor + anti-CTLA-4 than with PD-1/PD-L1 inhibitor + anti-LAG-3 ( = 0.026). In conclusion, dual PD-1/PD-L1 and CTLA-4 blockade induced concomitant increases in T-cell CD8/CD4 proportions and cytokine levels compared to monotherapy or alternative ICI pairings. These descriptive ex vivo observations offer preliminary evidence of altered immune profiles, highlighting this combination as a candidate for further functional validation.
Immunotoxin WPD101a as a Potential Drug Candidate for Targeted Therapy in Muscle Invasive Bladder Cancer Expressing IL-13Rα2-In Vitro Study.
Klimczak A, Krawczenko A, Stamnitz S … +9 more , Bielawska-Pohl A, Piotrowska P, Grzelenska H, Wypychowska A, Kisielewicz A, Mielecki M, Borowski R, Olejniczak M, Pajak-Tarnacka B
Int J Mol Sci · 2026 Jun · PMID 42353280 · Full text
The failure of therapy in muscle invasive bladder cancer (MIBC) is primarily attributed to tumor heterogeneity and therapy resistance. We propose a novel approach targeting interleukin-13 receptor subunit alpha 2 (IL-13R...
The failure of therapy in muscle invasive bladder cancer (MIBC) is primarily attributed to tumor heterogeneity and therapy resistance. We propose a novel approach targeting interleukin-13 receptor subunit alpha 2 (IL-13Rα2), which is expressed on bladder cancer (BC) cells but absent in normal urothelial cells. We investigated the therapeutic effects of WPD101a immunotoxin (IL-13-DT390) on IL-13Rα2-expressing BC cells in relation to BC cell phenotype and functional characteristics in vitro using both 2-dimensional (2D) and 3-dimensional (3D) models. Cell phenotype and IL-13Rα2 expression were assessed using flow cytometry, immunofluorescence, and Western blot analysis. The biological effects of WPD101a were evaluated by measuring cell viability and proliferation using the MTT, sulforhodamine B (SRB), CellTiter-Glo and Live/Dead assays. Apoptosis was assessed using Annexin V/propidium iodide (PI) staining, and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis of genes expression. We found that the reference BC cell lines TCC-SUP, JMSU-1 and UM-UC-3 express IL-13Rα2 at various level in contrast to RT-4, HCV-29 and 5637 cells. Cells expressing IL-13Rα2 were sensitive to WPD101a at lower concentrations in the 2D model (0.1 ng/mL) compared to the 3D model (1.0 ng/mL). IL-13Rα2-negative cells remain resistant to the immunotoxin. WPD101a induces apoptosis in BC cells expressing IL-13Rα2 as confirmed by the presence of apoptotic cells, increase the proportion of cells in the subG1 phase, and by the effector , , and initiator , genes expression. This study confirmed receptor-dependent cytotoxic effects of WPD101a and the ability and specificity to inhibit growth and apoptosis induction in MIBC cells expressing IL-13Rα2.
Insulin Regulates AKT/GSK-3β Signalling, Tau Phosphorylation, and Redox Homeostasis in SH-SY5Y Neuroblastoma Cells.
Jorda A, Alvarez-Gamez K, Vergani S … +5 more , Paba I, Perez M, Aldasoro M, Vila JM, Valles SL
Int J Mol Sci · 2026 Jun · PMID 42353279 · Full text
Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative...
Insulin (Ins) regulates multiple intracellular signalling pathways involved in cell survival, oxidative stress responses, and tau phosphorylation. Dysregulation of these pathways has been implicated in neurodegenerative disorders, including Alzheimer's disease (AD). The present study evaluated the effects of insulin on protein kinase B/glycogen synthase kinase-3 beta (AKT/GSK-3β) signalling, tau phosphorylation, and oxidative stress-related markers in SH-SY5Y neuroblastoma cells. Cell metabolic activity was assessed using the (diphenyltetrazolium bromide) MTT assay, while cell number and viability were evaluated by Trypan Blue exclusion, necrosis by lactate dehydrogenase (LDH) release, and apoptosis by Caspase-3 activity. Western blot analysis was performed to evaluate the expression of phosphorylated AKT (p-AKT), phosphorylated GSK-3β (p-GSK-3β Ser9), phosphorylated TAU (pTAU), nuclear factor erythroid 2-related factor 2 (NRF2), manganese superoxide dismutase (Mn-SOD), and copper/zinc superoxide dismutase (Cu/Zn-SOD). Lipid peroxidation was determined by measuring malondialdehyde (MDA) levels using a colorimetric/fluorometric assay. Insulin treatment increased MTT reduction (31.25%) and cell metabolic activity (119.15%) while reducing LDH release (19.2%) and Caspase-3 activity (31.26%). In addition, insulin significantly increased p-AKT (34.2%) and p-GSK-3β (Ser9) (19.9%) levels. A reduction in pTAU levels (53.39%) was also observed following insulin treatment. Furthermore, insulin increased NRF2 expression (18.77%), Cu/Zn-SOD (37.29%), and Mn-SOD (50.16%) and reduced MDA levels (13.95%). These findings indicate that insulin modulates signalling pathways associated with tau phosphorylation and cellular redox regulation in SH-SY5Y cells. Insulin treatment was associated with increased AKT and GSK-3β phosphorylation, reduced tau phosphorylation, and changes in oxidative stress-related markers in SH-SY5Y neuroblastoma cells. These findings support a role for insulin in the modulation of molecular pathways implicated in cellular stress responses and tau regulation. Further studies using differentiated neuronal models and disease-relevant conditions are required to determine the relevance of these observations to neurodegenerative disorders.
Comprehensive Germline Profiling of High-Grade Serous Ovarian Cancer Using Whole-Exome Sequencing.
Cho HL, Bak SE, Han MR … +1 more , Choi YJ
Int J Mol Sci · 2026 Jun · PMID 42353278 · Full text
While ovarian cancer screening is not recommended in the general population, attention has shifted to screening women with elevated hereditary risks. Although germline pathogenic variants account for 40% of inherited ov...
While ovarian cancer screening is not recommended in the general population, attention has shifted to screening women with elevated hereditary risks. Although germline pathogenic variants account for 40% of inherited ovarian cancer risk and family history (FH) remains important, known germline variants alone do not fully explain familial ovarian cancer risk. Whole-exome sequencing (WES) was performed on blood samples taken from 231 individuals, including 39 patients with high-grade serous ovarian cancer (HGSOC) and 192 healthy controls (HCs) stratified by FH. We analyzed pathogenic or likely pathogenic (P/LP) germline variants in cancer-related genes and assessed their association with family cancer history. Additionally, we performed somatic variant comparisons using 1:4 propensity score matching and analyzed clonal hematopoiesis of indeterminate potential (CHIP)-related somatic variants. P/LP germline variants were detected in 56.4% of HGSOC patients, 49.4% of controls with FH, and 33.3% without. The HGSOC group and controls with FH exhibited similar P/LP germline mutation patterns in ovarian cancer-related genes. From CHIP analysis, somatic CHIP mutations were detected in 6.3% of the HGSOC group and 8.5% in HCs. Our findings demonstrate genomic overlap between ovarian cancer patients and FH-positive individuals. Therefore, germline variant screening could be considered to facilitate early diagnosis.
Ultrafast Photochemical Reaction Dynamics of 3-Phenyl-1,4,2-dioxazol-5-one Revealed by Femtosecond Time-Resolved Infrared Spectroscopy.
Jeon S, Shin J, Park S … +3 more , Bae H, Son J, Lim M
Int J Mol Sci · 2026 Jun · PMID 42353277 · Full text
Dioxazolones are important precursors for generating nitrenes (highly reactive intermediates widely used for carbon-nitrogen bond formation in organic synthesis) upon exposure to light or heat. The photochemical reaction...
Dioxazolones are important precursors for generating nitrenes (highly reactive intermediates widely used for carbon-nitrogen bond formation in organic synthesis) upon exposure to light or heat. The photochemical reaction dynamics of 3-phenyl-1,4,2-dioxazol-5-one in CHCl were investigated using femtosecond time-resolved infrared spectroscopy and electronic structure calculations. Photoexcitation at 267 nm rapidly populates an excited singlet state that serves as the key branching point for subsequent photophysical and photochemical processes. Transient infrared spectra reveal the formation of carbon dioxide, phenyl isocyanate, and singlet benzoyl nitrene through their characteristic vibrational features. Kinetic analysis shows that decarboxylation from the excited singlet state occurs with a time constant of 4.7 ± 1 ns, producing phenyl isocyanate and benzoyl nitrene with time constants of 8.1 ± 2 ns and 11 ± 3 ns, respectively. Competing relaxation pathways include internal conversion to the ground state (7.5 ± 2 ns) and intersystem crossing to the T state (25 ± 5 ns). The T state relaxes to the ground state (350 ± 30 ns) without contributing to product formation. These results demonstrate that both isocyanate and nitrene products originate from the S state and provide detailed mechanistic insight into the competing pathways governing dioxazolone photochemistry in solution.
Quinobenzothiazine-AZT Hybrids Linked via 1,2,3-Triazole: Rational Design, Synthesis, and Biological Evaluation as Anticancer Agents.
Giercuszkiewicz-Haśnik K, Skonieczna M, Morak-Młodawska B … +1 more , Jeleń M
Int J Mol Sci · 2026 Jun · PMID 42353276 · Full text
Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related deaths, while its resistance to treatment continues to represent a major therapeutic challenge. In th...
Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related deaths, while its resistance to treatment continues to represent a major therapeutic challenge. In the present study, a series of phenothiazine derivatives, including hybrids containing a 1,2,3-triazole linker and the zidovudine (AZT) fragment, were synthesized and evaluated for their anticancer activity against colorectal cancer cell lines HCT116 and HT-29 as well as non-cancerous BEAS-2B cells. Cytotoxic activity was determined using the Alamar Blue assay, while the mechanisms of action were investigated by flow cytometric analysis of apoptosis, cell cycle progression, and reactive oxygen species (ROS) generation. Additionally, changes in the expression of genes associated with apoptosis, oxidative stress, and DNA damage response were analyzed by RT-qPCR. The obtained results demonstrated that AZT-containing derivatives exhibited stronger anticancer activity than non-conjugated phenothiazine analogs. Compounds induced pronounced apoptosis and significant disturbances in cell cycle progression, particularly in HCT116 cells. Among the analyzed derivatives, compound displayed the most favorable overall biological profile, combining strong proapoptotic and cytotoxic activity with relatively high selectivity toward cancer cells and moderate effects on non-cancerous cells. The results indicate that molecular hybridization of phenothiazine derivatives with the AZT scaffold represents a promising strategy for the development of novel anticancer agents targeting colorectal cancer.
Identification of β-Lapachone as a Potent USP22 Inhibitor That Suppresses Cancer Stemness and Enhances Chemosensitivity in Lung Adenocarcinoma.
Gao Y, Zhang K, Li W … +9 more , Liu J, Kwon D, Gu L, Li A, Yin HH, Kowolik C, Raul M, Horne DA, Raz DJ
Int J Mol Sci · 2026 Jun · PMID 42353275 · Full text
Ubiquitin-specific protease 22 (USP22) regulates epigenetic gene expression by deubiquitinating histone H2B (H2Bub1) and upregulating oncogenic proteins and pathways, while antagonizing p53-mediated tumor suppression. US...
Ubiquitin-specific protease 22 (USP22) regulates epigenetic gene expression by deubiquitinating histone H2B (H2Bub1) and upregulating oncogenic proteins and pathways, while antagonizing p53-mediated tumor suppression. USP22 is frequently overexpressed in cancers and associated with therapy resistance and poor prognosis yet remains largely untargeted pharmacologically. Here, using a fluorescence-based USP22 deubiquitinase assay to screen the LOPAC library, we identified β-Lapachone, a natural ortho-naphthoquinone with strong anticancer activities, as a potent USP22 inhibitor. β-Lapachone potently inhibited USP22 enzymatic activity, with a half-maximal inhibitory concentration (IC) of ~0.75 μM, and molecular docking revealed its occupation of the catalytic pocket adjacent to the USP22 active-site triad, supporting a potential binding mode. Functionally, β-Lapachone suppressed proliferation and induced apoptosis in A549 and H1299 RAS-mutant lung adenocarcinoma (LUAD) cells, while USP22 knockout conferred marked resistance, indicating partial USP22 dependence. In patient-derived LUAD models, β-Lapachone inhibited sphere formation and reduced CD133 cancer stem cell populations. Notably, it synergized with cisplatin to enhance DNA damage and apoptosis. In vivo, β-Lapachone significantly suppressed tumor growth in a syngeneic KRAS-mutant/p53-Null mouse lung cancer model and further potentiated cisplatin-induced antitumor effects. Collectively, these findings identify β-Lapachone as a potent inhibitor of USP22 and validate USP22 inhibition as a key mechanism underlying its anticancer activity in LUAD cells, both in vitro and in vivo.
Functional Characterization and Potential Regulatory Role of in Cold Tolerance.
Liang Y, Wang G, Yang X … +4 more , Zhang B, Ma Y, Ji Y, Han D
Int J Mol Sci · 2026 Jun · PMID 42353274 · Full text
Identifying cold-resistance genes is essential for improving the ability of apples ( × ) to tolerate low temperatures, as cold stress significantly limits their growth and productivity. The gene was cloned from apple, a...
Identifying cold-resistance genes is essential for improving the ability of apples ( × ) to tolerate low temperatures, as cold stress significantly limits their growth and productivity. The gene was cloned from apple, and its sequence characteristics, expression pattern, and biological function were systematically investigated. Bioinformatic analysis indicated that belongs to the group II WRKY transcription factors and is localized in the nucleus. Expression analysis revealed that transcript levels were markedly upregulated under low-temperature stress. To further explore its function, was heterologously overexpressed in tomato (). Following low-temperature treatment, transgenic tomato plants exhibited significantly reduced accumulation of reactive oxygen species, markedly enhanced activities of antioxidant enzymes (SOD, POD, and CAT), increased contents of proline and soluble protein, and a notable decrease in malondialdehyde levels. Additionally, transcript levels of , , , , along with the ABA signaling-related genes and , were markedly elevated. Further molecular docking showed that the MdWRKY31 protein has strong binding affinity to the W-box elements in the promoters of suggesting that it may regulate the expression of these genes through direct protein-DNA interactions. These findings indicate that improves plant cold tolerance by CBF-dependent pathways to modulate antioxidant defenses and osmotic balance. These findings identify candidate genetic resources for breeding cold-resistant apple cultivation.
Cross-Presentation and Activation of CD8+ T Cells: The Role of Pannexin-1 in Dendritic Cells.
Bravo F, Troncoso P, Mena J … +5 more , Bascuñan C, Varas N, Sauma D, Acuña-Castillo C, Barrera-Avalos C
Int J Mol Sci · 2026 Jun · PMID 42353273 · Full text
Cross-presentation of exogenous antigens by dendritic cells (DCs) relies on the cytosolic pathway, enabling proteasomal processing and subsequent loading of antigenic peptides onto major histocompatibility complex class...
Cross-presentation of exogenous antigens by dendritic cells (DCs) relies on the cytosolic pathway, enabling proteasomal processing and subsequent loading of antigenic peptides onto major histocompatibility complex class I (MHC-I) molecules. Although this pathway is central to CD8 T-cell activation, the molecular mechanisms that regulate intracellular antigen processing and redistribution during cross-presentation remain incompletely defined. In this study, we investigated the contribution of the large-pore channel Pannexin-1 (Panx1) to antigen handling during cross-presentation. Using confocal microscopy and quantitative image analysis in granulocyte-macrophage colony-stimulating factor/interleukin-4 (GM-CSF/IL-4)-derived inflammatory bone marrow-derived dendritic cell (BMDC)-like cellsexposed to ovalbumin (OVA)-Alexa Fluor 488, we observed time-dependent changes in intracellular antigen distribution that were altered upon pharmacological inhibition of Panx1 with the blocking peptide 10Panx1. In parallel, functional assays revealed that Panx1 inhibition significantly reduced SIINFEKL peptide-dependentactivation of B3Z CD8 T-cell hybridomas following pulsing with full-length OVA. Similar effects were observed in the cross-presentation-competent MUTU1940 dendritic cell line. Importantly, Panx1 inhibition did not significantly affect dendritic-cell viability or LPS-induced activation under the experimental conditions tested. In contrast, pharmacological inhibition or genetic deficiency of P2X7 receptor (P2X7) did not produce comparable reductions in cross-presentation, and combined inhibition did not result in additive effects under the experimental conditions tested. Together, these findings provide functional evidence supporting a role for Panx1 in regulating intracellular antigen redistribution associated with cross-presentation. While not establishing direct genetic causality, our data identify Panx1 as a modulatory component influencing antigen-processing events that culminate in CD8 T-cell activation, thereby expanding the current framework of intracellular antigen-processing mechanisms involved in dendritic-cell-mediated cross-presentation.
An Immunothrombotic Extracellular Vesicle mRNA Profile Associated with Thrombosis in Lung Adenocarcinoma.
Marcos-Jubilar M, Fernandez-Arias C, Herrero-Carrasco C … +6 more , Guruceaga E, Valencia K, Elizalde P, Inoges S, Lecumberri R, Orbe J
Int J Mol Sci · 2026 Jun · PMID 42353272 · Full text
Venous thromboembolism (VTE) significantly impacts lung adenocarcinoma outcomes, yet current predictive tools lack precision. We investigated plasma extracellular vesicle (EV) mRNA as a liquid biopsy source to identify a...
Venous thromboembolism (VTE) significantly impacts lung adenocarcinoma outcomes, yet current predictive tools lack precision. We investigated plasma extracellular vesicle (EV) mRNA as a liquid biopsy source to identify a pro-thrombotic molecular profile in VTE patients. Within a prospective cohort of 260 patients, we performed a retrospective nested case-control study, matching 10 VTE cases with 11 thrombosis-free controls. Plasma EV-RNA was analyzed via high-throughput sequencing. Differentially expressed genes (DEGs) were integrated with functional enrichment and explored across public non-cancer VTE datasets, buffy coat samples, and cell lines. RNA-seq identified 483 DEGs within the VTE patient EV compartment, predominantly linked to neutrophil degranulation (NETosis), inflammation, and coagulation. We identified a set of EV-associated candidate genes (SELP, ELANE, MYL9, DNASE1L3) distinguishing cancer-associated thrombosis from non-malignant VTE, along with transcripts (TFPI, FCGR2A) selectively enriched within the EV compartment relative to circulating blood cells. P-selectin (SELP) was the only significantly increased marker, providing the strongest complementary support at the protein level. This molecular state was detectable prior to the occurrence of VTE. Plasma EVs capture a multicellular mRNA profile, reflecting the systemic immunothrombotic activation in lung adenocarcinoma. Despite sample size limitations, these findings should be considered exploratory and hypothesis-generating, but they suggest the EV-derived mRNA in combination with circulating markers such as SELP may provide a framework for future studies aimed at improving risk stratification.
The Digestive System of the Greater Weever ( L.) as a Potential Alternative Source of Collagen: A Preliminary Study.
Kević N, Ivić E, Žikov JŠ … +5 more , Racetin A, Dimlić MR, Kelam N, Bočina I, Restović I
Int J Mol Sci · 2026 Jun · PMID 42353271 · Full text
This preliminary study characterises type I collagen in the digestive system of the greater weever ( L.) by integrating histochemical and biochemical techniques. To the best of our knowledge, this study represents the fi...
This preliminary study characterises type I collagen in the digestive system of the greater weever ( L.) by integrating histochemical and biochemical techniques. To the best of our knowledge, this study represents the first baseline mapping of type I collagen within the gastrointestinal tract of this species. Mallory staining and indirect immunofluorescence confirmed collagen presence across the oesophagus, stomach, and intestine. The histochemical quantification of the fluorescent area (100 measurements per organ across 15 fish specimens) showed no significant differences ( = 0.1315), indicating a uniform spatial distribution. However, biochemical analysis via hydroxyproline assay and a two-way ANOVA revealed significant differences in collagen content among organs ( = 0.0308). The stomach yielded the highest concentration (4.199 µg/mg), significantly exceeding that of the intestine (1.713 µg/mg; Šídák's post hoc, = 0.0300). This discrepancy suggests that the higher gastric content is due to greater fibre density rather than distribution area. SDS-PAGE and Western blot confirmed protein molecular weights of 100-130 kDa, corresponding to α1 and α2 chains typical of type I collagen. The combination of these histochemical and biochemical methods effectively detects and characterises collagen in fish gastrointestinal by-products. By introducing as a novel subject in this context, these findings provide essential baseline anatomical and histological data and offer a clear scientific justification for the biotechnological valorisation of unutilised commercial fishing by-products, fully aligning with sustainable marine circular economy principles.
Expression of Immune Checkpoint-Associated Proteins for CD24, Siglec-10, CD47, and SIRPα in Breast Phyllodes Tumor.
Shin E, Koo JS
Int J Mol Sci · 2026 Jun · PMID 42353270 · Full text
This study aimed to investigate the expression of immune checkpoint-associated proteins in phyllodes tumors (PTs) and assess their clinicopathologic and prognostic significance. Surgical resection specimens from 200 pati...
This study aimed to investigate the expression of immune checkpoint-associated proteins in phyllodes tumors (PTs) and assess their clinicopathologic and prognostic significance. Surgical resection specimens from 200 patients were included, and the expressions of CD24, Siglec-10, CD47, and SIRPα in both the epithelial and stromal components of the tumor were assessed, with ≥1% positivity considered positive. Of 200 cases, 145 were benign, 44 borderline, and 11 malignant. The expressions of CD24, Siglec-10, CD47, and SIRPα in stromal cells increased with tumor grade: CD24 was associated with stromal cellularity, atypia, and mitosis; Siglec-10 with stromal cellularity and atypia; CD47 with stromal atypia and mitosis; and SIRPα with stromal overgrowth and atypia. While expressions of CD24, CD47, and SIRPα were associated with either shorter disease-free survival (DFS) or shorter overall survival, multivariate analysis identified stromal CD24 expression as an independent predictor of shorter DFS. Immune checkpoint-associated proteins, particularly stromal CD24, CD47, and SIRPα, are associated with adverse features and poor outcomes in PTs, implicating potential prognostic and therapeutic relevance.
Novel Mitogenome of Reveals Gene Rearrangement, Purifying Selection, and Matrilineal Phylogenetic Insights in Garrini (Cypriniformes: Cyprinidae).
Shangningam B, Putra A, Abonmai T … +5 more , Hikam AM, Torisha P, Kim HW, Kang K, Kundu S
Int J Mol Sci · 2026 Jun · PMID 42353269 · Full text
Prior to this study, knowledge on the evolutionary lineage of remained inadequate, as previous phylogenetic investigations were primarily based on partial gene sequences. Although several mitogenomes of species have be...
Prior to this study, knowledge on the evolutionary lineage of remained inadequate, as previous phylogenetic investigations were primarily based on partial gene sequences. Although several mitogenomes of species have been reported, their structural organization and comprehensive genomic characteristics have not been thoroughly evaluated. In this study, , endemic to the Indo-Burma biodiversity hotspot, was identified based on its detailed morphology and meristic counts. The circular mitogenome of is 16,776 bp in length and contains the canonical set of 37 genes, along with duplicated control regions separated by tRNA-Proline. The comparative assessments across species indicate predominantly conserved GTG start codons, occasional alternative ATA initiation codons, and incomplete stop codons. The selection pressure examinations within Garrini taxa reveal a purifying selection across all protein-coding genes. The control region comprises four conserved sequence blocks and species-specific tandem repeats, reflecting a balance between functional constraint and lineage-dependent evolutionary dynamics. The phylogenetic inference supports the monophyly of and places in close affinity with , which is native to the western slope of Rakhine Yoma in Myanmar and Mizoram State in northeastern India. The genetic diversity analyses revealed haplotype differentiation, with shallow intraspecific genetic distances (0.000-0.011) observed samples between two distinct drainage systems in Manipur and Mizoram, northeastern India. The observed pattern of haplotype divergence in may reflect the historical or seasonal hydrological connectivity among the western-slope drainages of the Chin Hills, with the subsequent geographic isolation potentially contributing to the emergence of distinct genetic lineages. Nevertheless, the extent and evolutionary significance of this differentiation remain uncertain and warrant further investigation through expanded geographic sampling and the incorporation of additional molecular data. Collectively, these findings provide in-depth insights into the mitogenomic architecture, comparative gene arrangements, phylogenetic patterns, and matrilineal evolutionary history of and other congeners, thereby improving our understanding of the systematics and genetic diversity of this important cyprinid fish lineage.
Trifluoromethanesulfonamide Induces Male Sterility Through Systemic Metabolic Reprogramming and Anther-Specific Proline Deficiency.
Sekiguchi Y, Gao Y, Tabeta H … +4 more , Sato M, Hirai MY, Kamal NM, Ishii T
Int J Mol Sci · 2026 Jun · PMID 42353268 · Full text
Chemical hybridization agents (CHAs) enable efficient, large-scale hybrid seed production, yet their mechanisms remain poorly understood. Understanding how CHAs induce male sterility at the metabolic level is important f...
Chemical hybridization agents (CHAs) enable efficient, large-scale hybrid seed production, yet their mechanisms remain poorly understood. Understanding how CHAs induce male sterility at the metabolic level is important for both basic pollen biology and crop breeding. Here, we performed integrated metabolomic analyses to investigate the metabolic basis of the action of trifluoromethanesulfonamide (TFMSA) across multiple species and tissues. TFMSA treatment induced systemic metabolic reprogramming across species, prominently affecting amino acid metabolism, central carbon metabolism, and one-carbon metabolism. Although individual metabolite responses varied among species, pathway-level analyses consistently revealed coordinated modulation of carbon-nitrogen metabolic networks. In reproductive tissues, TFMSA induced tissue-specific metabolic changes. In cowpea anthers, proline was the only metabolite significantly altered and was strongly depleted, whereas in floral tissues several amino acids, including phenylalanine and tyrosine, were accumulated. Pathway analysis revealed altered amino acid metabolism, suggesting that systemic metabolic responses accompanied the proline reduction in anthers. These findings indicate that TFMSA induces male sterility through coordinated metabolic reprogramming across tissues and species, leading to depletion of key metabolites required for pollen development. This study provides a metabolic framework for understanding CHA-induced male sterility and highlights TFMSA as a powerful tool for probing metabolic regulation of pollen development.
Neuroprotection in Early Diabetic Retinal Disease Using Eyedrop Delivery.
Ramos H, Simó-Servat O, Hernández C … +1 more , Simó R
Int J Mol Sci · 2026 Jun · PMID 42353267 · Full text
Diabetic retinal disease (DRD) has classically been defined as a microvascular complication of diabetes; however, the recent evidence highlighted the key role of neuronal degeneration during the earliest stages of its pa...
Diabetic retinal disease (DRD) has classically been defined as a microvascular complication of diabetes; however, the recent evidence highlighted the key role of neuronal degeneration during the earliest stages of its pathogenesis. Therefore, neuroprotection has emerged as a promising therapeutic strategy to prevent disease progression. Topical administration via eyedrops represents a non-invasive approach to deliver neuroprotective agents directly to the retina. This review summarizes the current advances in the field of neuroprotective therapies against early DRD with a special focus on topical delivery, including preclinical and clinical evidence, while discussing the relevance of the transscleral route of absorption in all of them. In this review, the most promising neuroprotective compounds under development will be discussed, highlighting the opportunity that they represent for treating early stages of DRD.
Integrative Transcriptomic Analysis Reveals Distinct and Shared Host Responses in Dengue and Chikungunya Infections.
Rezapour M, Shupe TD, Ornelles DA … +2 more , Murphy SV, Atala A
Int J Mol Sci · 2026 Jun · PMID 42353266 · Full text
Dengue virus (DENV) and chikungunya virus (CHIKV) co-circulate in many regions and present with overlapping clinical features, which complicate accurate diagnosis and disease management. This study develops an integrativ...
Dengue virus (DENV) and chikungunya virus (CHIKV) co-circulate in many regions and present with overlapping clinical features, which complicate accurate diagnosis and disease management. This study develops an integrative transcriptomic framework to identify robust host gene signatures that distinguish between dengue, chikungunya, and healthy states. Publicly available RNA sequencing (RNA-seq) datasets derived from human blood samples were analyzed using a cross-validation design to ensure robustness and prevent information leakage. Differential expression analysis was performed independently within each dataset using the Generalized Linear Models with Quasi-Likelihood F-tests and Magnitude-Altitude Scoring (GLMQL-MAS) framework, followed by Cross-Magnitude-Altitude Scoring (Cross-MAS) integration to identify shared and virus-specific gene signatures. A strict consensus approach across folds was applied to derive reproducible gene sets. These signatures were used for dimensionality reduction and multinomial logistic regression to evaluate classification performance. A small subset of selected genes showed strong discriminative performance within the cross-validation framework, with test balanced accuracy reaching 0.97, which improved upon models using all genes. Biologically, both infections exhibited a shared antiviral response characterized by interferon signaling and innate immune activation. However, distinct virus-specific patterns were identified. Dengue infection was associated with cell-cycle and DNA replication pathways, while chikungunya infection showed stronger enrichment of inflammatory and immune signaling pathways, including NF-kappaB and Toll-like receptor signaling. Overall, this study provides a cross-validation-based framework for integrative transcriptomic analysis and identifies compact, reproducible host-response signatures with strong discriminative signals in the analyzed cohorts. These signatures require validation in larger independent cohorts before any clinical or diagnostic application.
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