International Journal Of Molecular Sciences[JOURNAL]
Sun
200 papers
Diagnostic Potential of Selected Matrilysins and Stromelysins in the Diagnosis of Gynecological Malignancies Based on ROC Curve Analysis.
Gacuta E, Zajkowska M, Ławicki M … +9 more , Urban J, Laudański P, Zbucka-Krętowska M, Józefczak MA, Guszczyn T, Ławicki P, Dubatówka M, Kicman A, Ławicki S
Int J Mol Sci · 2026 Jun · PMID 42353305 · Full text
Matrilysins and stromelysins play a vital role in cancer, facilitating tumor invasion and metastasis. The aim of this study was to investigate the diagnostic significance of selected matrilysins and stromelysins in compa...
Matrilysins and stromelysins play a vital role in cancer, facilitating tumor invasion and metastasis. The aim of this study was to investigate the diagnostic significance of selected matrilysins and stromelysins in comparison to routine tumor markers in gynecological malignancies, relative to a control group (benign tumors and healthy women). Preoperative plasma levels of selected metalloproteinases were determined using ELISA, while levels of CA125, SCC-Ag, and HE4 by CMIA. In endometrial and cervical cancers, matrilysins (MMP-7 and MMP-26) exhibited higher diagnostic utility than routine markers. Similarly, all stromelysins in cervical cancer outperformed CA125; furthermore, MMP-10 also outperformed SCC-Ag, achieving the highest diagnostic utility among all parameters tested in cervical cancer. For ovarian cancer, diagnostic utility remained highest for routine markers. In endometrial and cervical cancers, the AUCs for all studied parameters exceeded those of standard markers, while in ovarian cancer, MMP-7 had an AUC higher than HE4 and comparable to CA 125. Combined analysis of the studied parameters in diagnostic panels demonstrated that their introduction into routine diagnostics could provide tangible benefits in the detection of malignant gynecological lesions, especially the combination of MMP-7 or MMP-10 with routine markers. These results indicate the usefulness and high diagnostic power of selected MMPs in the detection of these malignancies.
A Multicenter Analysis of Patients with Bullous Pemphigoid: Clinical Characteristics and Insights into Drug-Associated Disease.
Małolepsza A, Kośny A, Juczyńska K … +10 more , Czerwińska J, Jałowska M, Dmochowski M, Dańczak-Pazdrowska A, Owczarczyk-Saczonek A, Walecka I, Kowalewski C, Woźniak K, Zajdel R, Żebrowska A
Int J Mol Sci · 2026 Jun · PMID 42353304 · Full text
Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease, predominantly affecting elderly patients with multiple comorbidities. This multicentre retrospective cohort study aimed to characteri...
Bullous pemphigoid (BP) is the most common autoimmune subepidermal blistering disease, predominantly affecting elderly patients with multiple comorbidities. This multicentre retrospective cohort study aimed to characterize the clinical profile, treatment patterns, and drug-associated cases of BP in a real-world setting. The study included 156 patients newly diagnosed with BP between 2020 and 2024 in four dermatology departments in Poland. Diagnosis was based on clinical features, and immunological assessment, including direct immunofluorescence (DIF), ELISA, and BIOCHIP-based indirect immunofluorescence. The mean age at diagnosis was 75.5 ± 10.9 years, and 78.85% of patients had at least one comorbidity, most commonly arterial hypertension, type 2 diabetes mellitus, and dyslipidemia. Severe pruritus was reported in 74.14% of evaluated patients. Blisters and erosions were the predominant clinical manifestations. Topical glucocorticosteroids were the most frequently used treatment, followed by systemic glucocorticosteroids and methotrexate. New drug exposure within 6 months before disease onset was identified in 14.74% of patients and was associated with a shorter time to diagnosis. Drug-associated cases showed lower BP180 ELISA positivity, although this did not remain significant after correction for multiple testing. These findings highlight the clinical complexity of BP and the importance of medication review and direct immunofluorescence in diagnostic evaluation.
Lipid Metabolism Reprogramming in the Aging Brain: Glial-Mediated Pathogenic Mechanisms and Translational Strategies in Neurodegeneration.
Shao W, Wang K, Liu Y … +3 more , Zhang H, Sun Z, Zhou R
Int J Mol Sci · 2026 Jun · PMID 42353303 · Full text
The mammalian brain fundamentally relies on precise lipid homeostasis to maintain structural integrity and complex neural signaling. Emerging evidence positions lipid metabolism reprogramming not merely as a secondary pa...
The mammalian brain fundamentally relies on precise lipid homeostasis to maintain structural integrity and complex neural signaling. Emerging evidence positions lipid metabolism reprogramming not merely as a secondary pathological byproduct but as a core initiating driver of age-related neurodegenerative diseases. This review systematically evaluates the mechanisms of cerebral lipid dyshomeostasis during brain aging, highlighting glial cells as the central mediators of this pathological cascade. We comprehensively dissect the age-associated "lipid drift", emphasizing apolipoprotein E (APOE)-induced cholesterol transport defects and lipid raft pathology, the accumulation of lipid droplets that triggers microglial metabolic stress (LDAMs), and ceramide-driven neuronal apoptosis coupled with the exosome-mediated propagation of pathogenic proteins. Furthermore, we map these aberrant lipid networks to specific pathological signatures in Alzheimer's, Parkinson's, and demyelinating diseases. Finally, we critically evaluate promising therapeutic interventions, including nutritional strategies, LXR/RXR agonists, and nanotechnology-enabled delivery systems designed to bypass the blood-brain barrier. By integrating high-throughput lipidomics for early diagnostic biomarker discovery, we underscore the translational imperative of restoring cerebral lipid homeostasis as a disease-modifying strategy for neurodegeneration.
E3 Ligases and Deubiquitinases in Controlling High-Mobility Group Box (HMGB) Protein Functions.
Chikhirzhina EV, Tomilin AN, Tsimokha AS
Int J Mol Sci · 2026 Jun · PMID 42353302 · Full text
High-Mobility Group Box (HMGB) proteins belong to the family of high-mobility proteins characterized by two DNA-binding domains and an unstructured, negatively charged C-terminal domain that modulates DNA-protein and pro...
High-Mobility Group Box (HMGB) proteins belong to the family of high-mobility proteins characterized by two DNA-binding domains and an unstructured, negatively charged C-terminal domain that modulates DNA-protein and protein-protein interactions. These proteins participate in multiple cellular processes, including DNA replication, transcription, recombination, and repair. The functional activity of HMGB proteins is associated with various physiological and pathological conditions, including malignant tumors and cardiovascular diseases, highlighting the need for strict regulation of their levels and activity to maintain cellular homeostasis. Such regulation can occur at multiple levels, including proteolytic degradation. In recent years, a number of E3 ubiquitin ligases that promote the degradation of HMGB proteins, as well as deubiquitinases (DUBs) that stabilize them by removing ubiquitin tags, have been identified. This review summarizes these enzymes and their proposed roles in controlling the functions of the HMGB family proteins, both through direct interaction with these proteins and via mediator proteins.
Limits of a Glycine Betaine-Derived Xenobiotic as a Trojan Horse Antimicrobial.
Dornes A, Lauterbach L, Dickschat JS … +2 more , Bange G, Bremer E
Int J Mol Sci · 2026 Jun · PMID 42353301 · Full text
Glycine betaine transport systems are widely exploited by bacteria to survive osmotic stress and represent potential entry routes for antimicrobial delivery. Here, we investigate the bactericidal glycine betaine analog T...
Glycine betaine transport systems are widely exploited by bacteria to survive osmotic stress and represent potential entry routes for antimicrobial delivery. Here, we investigate the bactericidal glycine betaine analog Tox-GB and its uptake, intracellular fate, and antimicrobial activity in K-12 under osmotic stress. We show that the xenobiotic enters cells via a hierarchical uptake route involving the osmotically regulated compatible solute transporters ProU and ProP, ABC- and MFS-type transporters, respectively. ProU functions as the primary high-affinity transporter at low concentrations, whereas ProP provides a secondary uptake route at somewhat higher substrate levels. Loss of either transporter confers partial resistance, while simultaneous inactivation of both systems causes full resistance, underscoring their functional redundancy and the robustness of Tox-GB import. Intracellularly, Tox-GB undergoes oxygen-dependent degradation, yielding 4-nitrobenzaldehyde and dimethylglycine. While 4-nitrobenzaldehyde contributes to toxicity under aerobic conditions, Tox-GB remains bactericidal under anaerobic conditions, indicating additional oxygen-independent mechanisms involving either the parent compound or unidentified metabolites. These findings suggest a complex intracellular fate and multifactorial mode of action. Despite initial promise as a Trojan horse antimicrobial strategy, the use of Tox-GB for practical applications faces key limitations. Resistance readily emerges via transporter inactivation, and intrinsic resistance occurs in species lacking appropriate compatible solute uptake systems. Structural constraints in glycine betaine transporters further restrict design flexibility. Osmotic regulation limits activity to specific niches, and potential host toxicity stemming from reactive metabolites raises safety concerns. Collectively, these findings highlight the mechanistic complexity and translational challenges faced by glycine betaine-derived xenobiotics as antimicrobial agents.
CRISPR Gene Tagging for Illuminating Endogenous Protein Dynamics.
Afifi N, Colussi D, Perez-Leal O
Int J Mol Sci · 2026 Jun · PMID 42353300 · Full text
Endogenous gene tagging using CRISPR has changed the understanding of the role played by different proteins due to the ability to track and study proteins in their natural state. With CRISPR-based gene tagging, it is pos...
Endogenous gene tagging using CRISPR has changed the understanding of the role played by different proteins due to the ability to track and study proteins in their natural state. With CRISPR-based gene tagging, it is possible to insert fluorescent, luminescent, epitope, affinity, and proximity labels into the target protein at its endogenous genomic location without affecting its physiological expression and dynamics. Here, we discuss the DNA-repair mechanisms employed in endogenous gene tagging, including homology-dependent repair, NHEJ-based integration, and alternative approaches that can be used with challenging cell types. Key aspects of efficient CRISPR tagging experiments are also described. Additionally, we review recent advances in the increasing array of protein tag technologies, including fluorescent proteins, split-reporter technologies, NanoLuc/HiBiT, peptide epitopes, and proximity biotinylation enzymes. Lastly, we review the scalability of endogenous tagging approaches using multiplex editing, atlas-scale proteome tagging, iPSC-based disease modeling, and drug discovery platforms for assessing target engagement, protein degradation, phenotype screening, and mechanism of action of compounds. Although difficult in primary and pluripotent cells, new methods based on avoiding double-strand breaks, such as prime editing, PASTE, and CRISPR associated transposases, will drive the future expansion of endogenous tagging approaches. Such developments firmly set up CRISPR gene tagging as a fundamental technology in quantitative cell biology and translational pharmacology.
Circulating Cell-Free DNA Analysis for Diagnostic and Prognostic Assessment of Hepatocellular Carcinoma in Cirrhosis.
Aznar-Peralta I, Roa-Colomo A, López Hidalgo J … +3 more , Fresno C, Denninghoff V, José Serrano M
Int J Mol Sci · 2026 Jun · PMID 42353299 · Full text
Early detection of hepatocellular carcinoma (HCC) is crucial for curative treatment, yet current screening strategies for high-risk liver cirrhosis (LC) patients lack sufficient sensitivity. This study evaluates plasma c...
Early detection of hepatocellular carcinoma (HCC) is crucial for curative treatment, yet current screening strategies for high-risk liver cirrhosis (LC) patients lack sufficient sensitivity. This study evaluates plasma cell-free DNA(cfDNA) concentration and fragmentomics as biomarkers to improve HCC diagnosis and prognosis. Plasma samples from 39 HCC and 46 LC patients were analyzed for cfDNA concentration and fragment patterns. A multivariate logistic regression model (CMAC), integrating cfDNA concentration, mononucleosome proportion (%MN), alpha-fetoprotein (AFP), and c-reactive protein (CRP), was developed and validated using Leave-One-Out Cross-Validation and bootstrapping. HCC patients exhibited significantly higher cfDNA concentrations ( < 0.0001) and longer fragment lengths ( < 0.05) compared to LC patients. The CMAC model demonstrated superior diagnostic performance (AUROC = 0.946) compared to AFP alone (AUROC = 0.777, < 0.001). Notably, in early-stage HCC, the CMAC model remained highly accurate (AUROC = 0.941), whereas AFP failed to reach statistical significance. Higher CMAC scores were significantly associated with advanced BCLC stages ( = 0.009), lymphovascular invasion ( = 0.0063) and reduced overall survival ( = 0.0037). Integration of cfDNA analysis with established clinical markers in the CMAC model shows promise as a complementary tool for the early detection of HCC in LC patients. Validation in larger, multicenter cohorts will be necessary to confirm these findings and their clinical applicability.
The Research Progress in Targeted Therapy for Hypertension via Heat Shock Proteins.
Sun B, Jiao Y, Lin L … +3 more , Cui X, Li C, Li Y
Int J Mol Sci · 2026 Jun · PMID 42353298 · Full text
As the core molecular chaperones of the cellular stress response, the heat shock protein (HSP) family has gained extensive attention for its role in the occurrence, development, and target organ damage of hypertension. T...
As the core molecular chaperones of the cellular stress response, the heat shock protein (HSP) family has gained extensive attention for its role in the occurrence, development, and target organ damage of hypertension. This review aimed to comprehensively summarize the research progress of the HSP family in the field of hypertension, and to analyze its key roles in the pathogenesis of hypertension, including its regulatory effects on key pathological processes such as endothelial dysfunction, proliferation and migration of vascular smooth muscle cells, oxidative stress, and inflammatory responses. It also summarized the potential value of HSPs as biomarkers in the early diagnosis, condition monitoring, and prognostic evaluation of hypertension. Moreover, it discussed in depth the efficacy and safety of intervention strategies targeting HSPs, including the regulation of HSPs by gene editing, the targeted effects of small-molecule inhibitors, and the modulatory effects of natural products. We need to strengthen interdisciplinary collaboration mechanisms, accelerate the transformation of basic research results into clinical applications, carry out large-scale clinical trials, and develop specific modulators in the future, so as to ultimately provide solid scientific theoretical support and a practical clinical basis for the precise prevention and treatment of hypertension. The findings of this review not only provide novel insights into the pathogenesis of hypertension but also lay a theoretical foundation for the development of HSP-based biomarkers and targeted therapeutic strategies.
Hepatic Alpha-1 Antitrypsin Globules in Compound Heterozygous SERPINA1 Variants Previously Considered Non-Polymerizing: A Case Report.
Finamore P, Santangelo S, Gallo P … +8 more , Ferrarotti I, Balderacchi AM, Falcomatà A, Colombo D, Del Nonno F, Vespasiani-Gentilucci U, Antonelli Incalzi R, Scarlata S
Int J Mol Sci · 2026 Jun · PMID 42353297 · Full text
Alpha-1 antitrypsin deficiency (AATD) is a genetically heterogeneous disorder with well-established pulmonary and hepatic manifestations; however, the clinical significance of rare compound heterozygous SERPINA1 variants...
Alpha-1 antitrypsin deficiency (AATD) is a genetically heterogeneous disorder with well-established pulmonary and hepatic manifestations; however, the clinical significance of rare compound heterozygous SERPINA1 variants remains incompletely defined. We report the case of a 61-year-old never-smoking woman with chronically elevated liver transaminase who was found to carry a compound heterozygous SERPINA1 genotype (PI*V/M) previously classified as non-polymerogenic and not previously associated with hepatic inclusions. This case expands the phenotypic spectrum of AATD and highlights the importance of considering SERPINA1 genotyping in adults with unexplained chronic transaminase elevation, while raising clinically relevant questions regarding surveillance and management in atypical AATD phenotypes.
Ethylene as the Molecular Coordinator of the Plant Growth-Defense Trade-Off Under Biotic and Abiotic Stresses.
Mia MR, Sahu A, Kundu M … +5 more , Khan MEU, Rupa MA, Sultana F, Mostofa MG, Hossain MM
Int J Mol Sci · 2026 Jun · PMID 42353296 · Full text
Plants must continuously balance the trade-offs between growth and defense, a constraint that is exacerbated by biotic and abiotic stresses, particularly when they occur together. Ethylene (ET) serves as a central, integ...
Plants must continuously balance the trade-offs between growth and defense, a constraint that is exacerbated by biotic and abiotic stresses, particularly when they occur together. Ethylene (ET) serves as a central, integrative regulatory node controlling this by linking developmental programs to stress-responsive signaling networks. Advances at the molecular and systems levels have revealed that ET mediates the redistribution of metabolic resources via coordinated regulation of its synthesis, perception, and downstream signaling. The ETR (Ethylene Receptor)-CTR1 (Constitutive Triple Response 1)-EIN2 (Ethylene Insensitive 2)-EIN3(Ethylene Insensitive 3) signaling module lies at the core of this network, integrating multiple hormonal pathways. Through dynamic crosstalk with jasmonic acid (JA), salicylic acid (SA), abscisic acid (ABA), auxin (AUX), and gibberellins (GA), ET enables the fine-tuned coordination of growth inhibition, immune activation, and stress acclimation in response to environmental fluctuations. Processes such as induced systemic resistance, programmed cell death, and architectural plasticity further reinforce this regulatory framework, with ethylene-responsive transcription factors, including ERFs (ethylene responsive factor gene family) and WRKYs, acting as critical convergence points. Emerging insights into ACC (1-aminocyclopropane-1-carboxylic acid)-dependent signaling, chromatin remodeling, and tissue-specific regulation expand the functional scope of ET beyond traditional hormone paradigms. At the same time, the ability of pathogens to manipulate ET signaling underscores its dual role in both promoting immunity and facilitating susceptibility. By integrating molecular, physiological, and ecological perspectives, this review highlights ET as a central coordinator of plant stress resilience and growth optimization, providing a unifying framework for understanding how plants adapt to complex and dynamic environments.
The Thyroid Under Pressure: Heavy Metals, Endocrine Disruptors and Translational Insights into Carcinogenesis and Thyroid Dysfunctions.
Capezzone M, Pellegriti G, Ronchi A … +3 more , Gianì F, Corsello A, Paragliola RM
Int J Mol Sci · 2026 Jun · PMID 42353295 · Full text
The thyroid gland is particularly vulnerable to the effects of environmental pollutants, due to its high vascularization, dependence on iodine uptake, and intrinsic oxidative environment required for hormone biosynthesis...
The thyroid gland is particularly vulnerable to the effects of environmental pollutants, due to its high vascularization, dependence on iodine uptake, and intrinsic oxidative environment required for hormone biosynthesis. Therefore, environmental exposure to heavy metals (HMs) and endocrine-disrupting chemicals (EDCs) has emerged as a potential contributor to thyroid dysfunction and carcinogenesis. Despite increasing interest, the clinical relevance of these exposures remains incompletely defined. Available epidemiological data suggest heterogeneous associations across EDCs and HMs classes. While evidence is more consistent for some pollutants, for other compounds it remains limited. Furthermore, while experimental studies provide strong mechanistic support for the key pathways linking environmental exposure to thyroid dysfunction and carcinogenesis, the clinical interpretation of epidemiological data is constrained by important methodological limitations. This narrative review aims to integrate current epidemiological and experimental evidence on the role of HMs and EDCs in thyroid diseases, including both non-neoplastic disorders and thyroid cancer, examining their environmental distribution, exposure pathways, and biological effects.
A Comparison of the Properties of Mesenchymal Stem Cells Derived from Different Synovial Sources: A Systematic Review.
Ahmad M, Kapoor JS, Wilegoda WADCS … +2 more , Liu M, Khan W
Int J Mol Sci · 2026 Jun · PMID 42353294 · Full text
Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation into different cellular lineages, including adipocytes, chondrocytes, and osteocytes. This makes them strong candidates for repairing degenera...
Mesenchymal stem cells (MSCs) are capable of self-renewal and differentiation into different cellular lineages, including adipocytes, chondrocytes, and osteocytes. This makes them strong candidates for repairing degenerative joint conditions such as osteoarthritis, in which native cartilage lacks repair capacity. The synovium is an attractive MSC source, with synovial MSCs demonstrating superior chondrogenic and proliferative potential compared to those from bone marrow or adipose tissue. The synovial joint is a heterogeneous environment, and MSCs can be isolated from the membrane, fluid, different histological subtypes of fibrous and adipose synovium, and different anatomical regions of synovium. This systematic review assesses whether MSCs from different synovial sources possess distinct properties. 2312 papers were identified, of which 10 met the inclusion and exclusion criteria and were included in the final review. Significant differences were identified in proliferation characteristics, immunophenotype and differentiation potential. Proximity to vasculature appeared to correlate with proliferation and differentiation potential, and MSCs from the synovial membrane may have superior proliferative characteristics compared to those from synovial fluid. More work is required to fully characterise these differences and understand their underlying molecular bases, but these findings may help inform the choice of MSC source for regenerative therapies.
Extracellular Vesicle-Derived MicroRNAs as Early Diagnostic Biomarkers of Diabetic Nephropathy and Cardiovascular Diseases in Type 2 Diabetes.
Arailym Y, Abaildayev A, Ayaz B
Int J Mol Sci · 2026 Jun · PMID 42353293 · Full text
Type 2 diabetes mellitus (T2DM) is a major driver of chronic kidney disease and cardiovascular morbidity worldwide. Extracellular vesicles (EVs), particularly exosomes, carry microRNAs (miRNAs) that reflect the pathophys...
Type 2 diabetes mellitus (T2DM) is a major driver of chronic kidney disease and cardiovascular morbidity worldwide. Extracellular vesicles (EVs), particularly exosomes, carry microRNAs (miRNAs) that reflect the pathophysiological state of their parent cells and represent promising non-invasive biomarkers. This review comprehensively examines the diagnostic and mechanistic roles of EV-derived miRNAs in diabetic nephropathy (DN) and cardiovascular diseases (CVDs) associated with T2DM. A PRISMA-guided literature search of PubMed, Scopus, Web of Science, and Embase identified 847 articles published between January 2020 and June 2026, of which 156 studies met the inclusion criteria. Several urinary exosomal miRNAs demonstrated significant diagnostic performance for DN, including miR-4534 (AUC = 0.786), miR-136-5p (sensitivity 72.2%, specificity 78.4%), and miR-142-3p. A meta-analysis of circulating miRNAs in diabetic kidney disease reported a pooled AUC of 0.79. In the cardiovascular setting, exosomal miR-155-5p (AUC = 0.901), miR-15a-3p (AUC = 0.874), and a four-miRNA panel (miR-433-3p/let-7b/miR-30-5p/miR-122-5p; AUC = 0.833) demonstrated strong diagnostic performance for ischemic heart disease and carotid atherosclerosis in T2DM. Mechanistically, key EV-associated miRNAs, including miR-21, miR-192, and the anti-fibrotic miR-29 family, participate in fibrosis, inflammation, oxidative stress, endothelial dysfunction, and cardiac remodeling pathways. EV-derived miRNAs therefore represent highly promising non-invasive biomarkers for the early diagnosis and monitoring of diabetic renal and cardiovascular complications. However, clinical translation requires standardized EV isolation and miRNA detection protocols, together with validation in large multicenter prospective cohorts. This review highlights the considerable diagnostic and translational potential of EV-derived miRNAs for precision medicine and liquid biopsy applications in T2DM complications.
MicroRNA Biogenesis Pathway Gene Variants Are Associated with Prostate Cancer Susceptibility.
Gilyazova I, Timasheva Y, Ivanova E … +8 more , Gimalova G, Izmailov A, Abdeeva G, Dzaubermezov M, Balkhiyarova Z, Prokopenko I, Pavlov V, Khusnutdinova E
Int J Mol Sci · 2026 Jun · PMID 42353292 · Full text
Prostate cancer (PrC) is one of the most common malignancies among men worldwide. However, the contribution of genetic variation in microRNA (miRNA) biogenesis pathway genes to PrC susceptibility remains poorly character...
Prostate cancer (PrC) is one of the most common malignancies among men worldwide. However, the contribution of genetic variation in microRNA (miRNA) biogenesis pathway genes to PrC susceptibility remains poorly characterized in many ethnically diverse populations. We conducted a case-control study involving 532 PrC patients and 550 controls from the Volga-Ural region of Eurasia to evaluate the association of twenty-one single nucleotide polymorphisms (SNPs) with PrC risk using single-variant and polygenic approaches. Association analyses identified rs595055 in the gene as significantly associated with PrC risk after correction for multiple testing. To evaluate the cumulative effect of genetic variation, weighted and unweighted polygenic risk scores (PRSs) were constructed. The weighted PRS was significantly associated with PrC risk (odds ratio per standard deviation increase = 1.63, 95% CI [1.43-1.85], = 1.37 × 10), and demonstrated moderate discriminatory performance (AUC = 63.1%), outperforming the unweighted model. Individuals in the highest PRS quartile had approximately threefold higher odds of PrC than those in the lowest quartile. Combining the weighted PRS with prostate-specific antigen improved discrimination (AUC = 68.1%). These findings support the contribution of miRNA biogenesis pathway genes to PrC susceptibility and highlight the potential value of pathway-based polygenic risk stratification in understudied populations.
Molecular and Cellular Signaling Pathways of the Effects of Hypoxia and Hypercapnia on the Mechanisms of Neuroinflammation.
Chekulaev PA, Zembatov GM, Namiot ED … +6 more , Alekseeva TM, Ternovykh IK, Manasova ZS, Kulikov VP, Andriutsa NS, Tregub PP
Int J Mol Sci · 2026 Jun · PMID 42353291 · Full text
Recovery after an ischemic stroke depends not only on neuronal survival but also on inflammatory mechanisms that determine secondary injury and reparative plasticity. This review summarizes the evidence on hypoxic condit...
Recovery after an ischemic stroke depends not only on neuronal survival but also on inflammatory mechanisms that determine secondary injury and reparative plasticity. This review summarizes the evidence on hypoxic conditioning, permissive hypercapnia, and their combined application as modulators of neuroinflammation and neurorehabilitation. This review does not aim to describe the fundamental mechanisms of neuroinflammation, but rather to examine how hypoxia, hypercapnia, and their interaction provide potential targets for its modulation. Prolonged or severe hypoxia exacerbates neuroinflammation through NF-κB activation, NLRP3 inflammasome signaling, pro-inflammatory cytokine production, and microglial activation. In contrast, controlled intermittent hypoxia in pre-/postconditioning protocols suppresses inflammatory processes, promotes reparative microglial phenotypes, activates PI3K/Akt-dependent survival pathways, and modulates the fractalkine/CX3CR1 axis. Permissive hypercapnia also has context-dependent immunomodulatory properties: moderate exposure may reduce NF-κB-driven inflammation, oxidative damage, apoptosis, and blood-brain barrier disruption, whereas prolonged hypercapnia, especially with hypoxemia, may enhance inflammasome activation and microglial reactivity. Therefore, combined intermittent hypercapnic hypoxia may act as a therapeutic stimulus integrating anti-inflammatory, cytoprotective, barrier-stabilizing, and neuroplastic mechanisms. Clinical evidence regarding ischemic stroke and cerebral palsy is encouraging but limited. Future studies should determine optimal gas exposure protocols, precisely define the mechanisms underlying the anti-inflammatory effects, and establish whether pharmacological potentiation using modulators of the NLRP3, PI3K/Akt, BDNF/TrkB, and JNK signaling pathways is feasible.
Multi Omics Analysis Reveals That Compound Radix Pulsatillae and Lactic Acid Bacteria Reprogram the Microbiome Metabolome Network in Silage.
Jing Y, Wang H, Jiang H … +6 more , Qu H, Yang G, He Z, Wang S, Liu B, Gao F
Int J Mol Sci · 2026 Jun · PMID 42353290 · Full text
( L.) silage fermentation often fails due to insufficient lactic acid bacteria (LAB) and low water-soluble carbohydrate content. We investigated the effects of Compound Radix Pulsatillae (CRP; 40 g/kg FM) alone or combin...
( L.) silage fermentation often fails due to insufficient lactic acid bacteria (LAB) and low water-soluble carbohydrate content. We investigated the effects of Compound Radix Pulsatillae (CRP; 40 g/kg FM) alone or combined with a commercial LAB inoculant (containing , , and , CRP_LA) on silage after 60 days. Compared to control (CK), both CRP and CRP_LA increased dry matter and water-soluble carbohydrate retention while reducing fiber components and ammonia nitrogen ( < 0.05). CRP_LA exhibited superior fermentation quality (lowest pH 4.82, highest lactic acid 47.83 g/kg DM). Using 16S rRNA sequencing and UPLC-MS/MS metabolomics integrated with weighted gene co-expression network analysis (WGCNA), we identified a brown module strongly associated with CRP_LA treatment. Six hub metabolites, belonging to flavonoids, terpenoids, alkaloids, phenolic acids, and nucleotide derivatives, were significantly elevated in CRP_LA silage and showed strong correlations with abundance and fermentation quality parameters. Correlation-based network analysis revealed that these hub metabolites positively correlated with Lactobacillus abundance, lactic acid, and water-soluble carbohydrate retention, while negatively correlating with spoilage microorganisms (, , ) and ammonia nitrogen. This multi-omics study provides a metabolite-centric molecular map of the silage microecosystem reshaped by CRP and LAB co-fermentation. The identified hub metabolites-with predicted antimicrobial, antioxidant, and plant-protective functions-represent potential quality markers for functional silage additive development. Mechanistic validation via targeted metabolite supplementation or pathway-specific gene expression analysis is warranted in future studies.
Genome Assembly and Annotation for the Okinawan Green Marine Spoon Worm (Polychaeta: Bonelliidae).
Bailey EM, Soghigian J, Lorenzen MD … +5 more , Zhang R, Taniguchi M, Lindsey JS, Wiegmann BM, Jin X
Int J Mol Sci · 2026 Jun · PMID 42353289 · Full text
, an echiuran polychaete that inhabits infralittoral rocky habitats around the Atlantic, Mediterranean, and Southeastern Pacific coastlines, exhibits environmentally mediated sexual dimorphism: planktonic larvae develop...
, an echiuran polychaete that inhabits infralittoral rocky habitats around the Atlantic, Mediterranean, and Southeastern Pacific coastlines, exhibits environmentally mediated sexual dimorphism: planktonic larvae develop into dwarf males after exposure to bonellin, a green pigment produced by adult females. Bonellin is a chlorin with a structure consistent with derivation from uroporphyrinogen III, the last universal precursor of all known tetrapyrroles, yet its biosynthesis remains unknown. Here, the de novo genome assembly for a single adult female specimen of isolated from Okinawa has been generated (via Illumina sequencing) and found to comprise 429.95 Mb across 95,859 contigs, with an N50 of 6505 bp, recovering 83.3% of near-universal metazoan BUSCO orthologs. Homologs of all canonical enzymes of the heme biosynthetic pathway (termed hem genes) were identified across the genome. The genomic resources establish a foundation for research into the biochemical basis of pigment production, chemically mediated sex determination, and the distinct biology of .
Hormonal Adaptations in Professional Soccer Players: Ethnic Differences and Pathophysiological Mechanisms.
La Vignera S, Condorelli RA
Int J Mol Sci · 2026 Jun · PMID 42353288 · Full text
Professional soccer imposes substantial physiological demands eliciting complex neuroendocrine responses. This review synthesizes evidence on hormonal adaptations in professional soccer players, with emphasis on ethnic a...
Professional soccer imposes substantial physiological demands eliciting complex neuroendocrine responses. This review synthesizes evidence on hormonal adaptations in professional soccer players, with emphasis on ethnic and national differences and underlying pathophysiological mechanisms. We analyzed 21 key studies investigating testosterone, cortisol, the testosterone-to-cortisol (T:C) ratio, growth hormone (GH), and insulin-like growth factor-1 (IGF-1) responses to training and competition. Acute cortisol elevations that may persist for up to 72 h post-match in some professional populations and T:C ratio reductions following congested fixture periods are reported across available studies, while somatotropic responses vary considerably across studies. Preliminary evidence suggests that ethnic and geographic background may influence circulating testosterone and urinary steroid excretion profiles, with UGT2B17 genetic polymorphisms identified as one contributing factor; however, the evidence base is limited and requires replication. Approximately 7.4% of elite junior cohorts-though not necessarily professional adult populations-develop non-functional overreaching (NFOR), characterized by blunted GH and ACTH responses. Pathophysiological mechanisms involve hypothalamic-pituitary--adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axis dysregulation producing anabolic-catabolic imbalance. Individualized, longitudinal T:C monitoring and post-match load moderation may be warranted; future research should establish ethnicity-specific normative values and investigate links between hormonal dysregulation and injury risk.
Systemic AAV-h Gene Therapy Alleviates Glutaric Acid Accumulation and Attenuates Chronic Brain Vacuolation in a Novel Mouse Model of Glutaric Aciduria Type I.
Kim SJ, Nam YH, Joo EY … +4 more , Park J, Park S, Jung SC, Jin DK
Int J Mol Sci · 2026 Jun · PMID 42353287 · Full text
Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic cri...
Glutaric aciduria type 1 (GA1) is a rare neurometabolic disorder caused by glutaryl-CoA dehydrogenase (GCDH) deficiency, leading to the accumulation of neurotoxic metabolites that can cause both acute encephalopathic crises and progressive, insidious brain injury. Current management primarily relies on a protein-restricted diet, which remains therapeutically insufficient and burdensome for patients, highlighting the need for disease-modifying therapies. In this study, we established a novel GA1 mouse model using CRISPR/Cas9 technology and evaluated the preclinical efficacy of systemic recombinant adeno-associated virus (rAAV)-mediated gene therapy. Under standard dietary conditions without high-lysine challenge, our GA1 model exhibited sustained cerebral and hepatic glutaric acid (GA) accumulation and distinct chronic vacuolation in the hippocampus and cerebellum, mirroring the insidious-onset GA1 phenotype. Five-week-old mice received a single intravenous injection of rAAV-h using either rAAV2/8 or rAAV2/9 serotypes. Systemic rAAV-mediated gene therapy significantly reduced GA accumulation and attenuated chronic neuropathological changes in this GA1 mouse model for both serotypes. Our findings support the hypothesis that peripheral metabolic correction may play an important role in preventing the chronic neuropathological changes associated with deficiency. However, further investigation using tissue-specific expression systems is required to definitively delineate the relative contributions of hepatic versus central restoration to the observed neuroprotection.
Evaluation of Antimicrobial Peptide-Antibiotic Combination Treatment for Tackling Ocular and Systemic Infections.
Barahim EK, Smith EP, Yong ST … +8 more , Aung TT, Lakshminarayanan R, Mohammed I, Dua HS, Wallace GR, Hombrebueno JR, Rauz S, Ting DSJ
Int J Mol Sci · 2026 Jun · PMID 42353286 · Full text
is a leading cause of bacterial keratitis and antimicrobial resistance-associated death globally. This study aimed to evaluate the efficacy of CaD23, a human-derived hybrid antimicrobial peptide (AMP), in combination wit...
is a leading cause of bacterial keratitis and antimicrobial resistance-associated death globally. This study aimed to evaluate the efficacy of CaD23, a human-derived hybrid antimicrobial peptide (AMP), in combination with antibiotics in treating infections. The efficacy of CaD23 and six medically important antibiotics (amikacin, cefuroxime, chloramphenicol, fosfomycin, vancomycin and levofloxacin) was examined against six strains of methicillin-sensitive and methicillin-resistant using a minimum inhibitory concentration (MIC) assay. CaD23-antibiotic interactions were evaluated using checkerboard and time-kill kinetics assays. 3,3'-dipropylthiadicarbocyanine iodide (DiSC) cytoplasmic membrane depolarisation assay was performed to examine the mechanism of action. Overall, CaD23 exhibited good efficacy against all MSSA and MRSA (MIC = 16-32 μg/mL [6.7-13.3 μM]). Of 20 peptide-antibiotic-organism combinations, 19 (95%) combinations demonstrated positive interactions, with six (31.6%) and 13 (68.4%) exhibiting synergistic (FICI = 0.293-0.412) and additive effects (FICI = 0.521-0.890), respectively. CaD23 was able to achieve complete bacterial eradication significantly faster than cefuroxime and levofloxacin (15 min vs. 8-24 h). When used at a sub-MIC concentration, CaD23 could accelerate the killing of of cefuroxime from 8-24 h to within 1 h and enhance the activity of levofloxacin by 90%. CaD23 was shown to rapidly depolarise the inner membrane of within seconds of the treatment. In conclusion, CaD23-antibiotic combination therapy serves as a useful strategy for tackling drug-resistant ocular and systemic infections.
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