International Journal Of Molecular Sciences[JOURNAL]
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200 papers
Quantifying PD1 Saturation by PDL1 in Tumor Tissue Using a Novel RNA Aptamer-Based Assay.
Veeramani S, Yin C, Yu N … +3 more , Coleman K, Smith BJ, Weiner GJ
Int J Mol Sci · 2026 Jun · PMID 42353185 · Full text
Therapeutic agents targeting the PD1-PDL1 interaction, commonly called PD1 blockade, are of great clinical value; however, predicting which patients will benefit has been inconsistent, in part, due to a lack of reliable...
Therapeutic agents targeting the PD1-PDL1 interaction, commonly called PD1 blockade, are of great clinical value; however, predicting which patients will benefit has been inconsistent, in part, due to a lack of reliable biomarkers. Quantifying PD1 saturation by PDL1 in tumor tissue has the potential to serve as a biomarker; unfortunately, few diagnostic technologies are available to reliably quantify PD1 saturation in clinical biospecimens. Here, we report on a novel bioassay based on RNA aptamers, called the PD1 LIRECAP assay, that allows for quantification of the saturation of PD1 by PDL1 in formalin-fixed, paraffin-embedded (FFPE) tumor biospecimens. The assay is technically straightforward, high-throughput capable and reproducible. Results showed that quantification of PD1 saturation determined by PD1 LIRECAP assay correlates closely with PD1-mediated signaling and PD1-PDL1 proximity. Analysis of sarcoma FFPE biospecimens confirmed the assay to be consistent and revealed significant differences between patients as well as considerable intratumoral heterogeneity in PD1 saturation by PDL1. We conclude that this novel PD1 LIRECAP platform is technically feasible, reproducible and has the potential to be a superior predictive biomarker assay to predict the outcome of PD1/PDL1-based therapy. Similar assays based on this platform could be used in other systems and settings to quantify the interaction between two molecules.
Phage-Encoded Depolymerase DepKP144 with Therapeutic Potential Against Both K1- and K2-Type .
Kondakova EA, Golosova NN, Kravchuk BI … +6 more , Khlusevich YA, Yakubovskij VI, Kozlova YN, Grishkova SA, Tikunova NV, Matveev AL
Int J Mol Sci · 2026 Jun · PMID 42353184 · Full text
Multidrug resistance (MDR) is a global problem for the healthcare system, complicating the therapy of bacterial infections. It is noted that patients infected with MDR strains often require prolonged hospitalization, hav...
Multidrug resistance (MDR) is a global problem for the healthcare system, complicating the therapy of bacterial infections. It is noted that patients infected with MDR strains often require prolonged hospitalization, have a high risk of mortality, and remain vulnerable to reinfection after recovery. In this study, recombinant phage-encoded depolymerase DepKP144 was produced using the expression system and purified. The depolymerase DepKP144 protein was able to reduce viable bacterial counts following capsule degradation in 95% of the tested strains of type K1 and 85% of the tested strains of type K2 . The depolymerase DepKP144 was active against K1-type and K2-type planktonic cells and destroyed the biofilms formed by clinical MDR strains of In in vivo experiments, DepKP144 at a dose of 180 μg/mouse resulted in a 50% survival of the mice infected with K2-type and in a 17% survival of the mice infected with K1-type . This depolymerase is promising for further development of prevention and therapeutic candidates against MDR .
Liquid Biopsy-Derived microRNAs in Pancreatic Ductal Adenocarcinoma: Matrix-Specific Evidence and Translational Challenges.
Wołyniak M, Zheng E, Polak M … +2 more , Trojanowski S, Małecka-Wojciesko E
Int J Mol Sci · 2026 Jun · PMID 42353183 · Full text
MicroRNAs are small noncoding RNA molecules that regulate gene expression at the post-transcriptional level and play a key role in cancer development, progression, and response to therapy. Their relative stability in bio...
MicroRNAs are small noncoding RNA molecules that regulate gene expression at the post-transcriptional level and play a key role in cancer development, progression, and response to therapy. Their relative stability in biological fluids and disease-associated expression patterns have positioned microRNAs as promising candidates for non-invasive cancer biomarkers. Liquid biopsy enables the detection of circulating and fluid-derived microRNAs in a range of biological materials, including blood, urine, saliva, stool, pancreatic cyst fluid, and bile, offering a minimally invasive complement to tissue-based diagnostics. This approach is particularly relevant in pancreatic ductal adenocarcinoma, a malignancy with high mortality driven largely by late diagnosis, aggressive disease course, and limited opportunities for curative treatment. This review summarizes current evidence on microRNA-based liquid biopsy approaches in this cancer, with a focus on diagnostic, prognostic, and predictive relevance. Serum and plasma remain the most extensively studied sources, while urine-based microRNA profiling has shown relatively consistent diagnostic performance across available studies, including in early-stage disease. Pancreatic cyst fluid and bile offer more lesion-proximal molecular information but are limited to selected clinical scenarios because of invasive sampling requirements. In contrast, salivary microRNA signatures show greater variability and lower reproducibility across studies. Overall, liquid biopsy based on microRNA analysis shows promise as a complementary tool for pancreatic ductal adenocarcinoma detection and risk stratification. However, substantial methodological heterogeneity and limited cross-study reproducibility currently limit clinical translation, underscoring the need for standardized workflows and prospective validation of clinically relevant microRNA panels.
Dysregulation of the Tau-Microtubule-End-Binding Protein Axis in Alzheimer's Disease and Related Tauopathies.
Hasan M, Abd-ElRaouf K, Moran SR … +1 more , Lo CH
Int J Mol Sci · 2026 Jun · PMID 42353182 · Full text
Alzheimer's disease (AD) and related tauopathies are marked by progressive cognitive decline, synaptic dysfunction, and neuronal loss. The microtubule (MT)-associated protein tau, encoded by the gene, plays a central ro...
Alzheimer's disease (AD) and related tauopathies are marked by progressive cognitive decline, synaptic dysfunction, and neuronal loss. The microtubule (MT)-associated protein tau, encoded by the gene, plays a central role in neurodegenerative pathology. Although the dissociation of hyperphosphorylated tau from MTs and their subsequent aggregation has been extensively studied, the broader landscape of other MT-associated proteins remains largely underexplored. Among these, the end-binding protein (EBP) family, which comprises MT plus-end-tracking proteins, has emerged as a critical regulator of MT dynamics and stability. EBPs modulate MT polymerization, interact with various MT-associated proteins, and influence cytoskeletal organization. Recent studies suggest that pathological tau impairs end-binding protein 3 (EB3) function by limiting its localization to MT plus-ends and inhibiting EB3-mediated MT elongation and stability. In addition, EB1 appears to interfere with tau aggregation in an in vitro study involving biomolecular condensates. Dysregulation of dynamic tau-MT-EBP interactions may result in structural and functional consequences throughout the entire network, potentially increasing MT instability under neurodegenerative conditions. Hence, the tau-MT-EBP network is an emerging mechanistic axis for advancing the understanding of physiological processes, disease pathology, and therapeutic interventions. In this review, we summarize recent advances in understanding the tau-MT-EBP axis and highlight the molecular mechanisms underlying key pathological interactions within this network. Finally, we discuss current therapeutic strategies and future directions for targeting this dynamic axis to mitigate AD and related tauopathies.
Research Progress on the Treatment of Renal Injury with Esculetin: Multi-Target Pharmacological Mechanism and Clinical Translation Prospect.
Zhou R, Chen J, Xia B … +3 more , Chen M, Zhu Y, Li G
Int J Mol Sci · 2026 Jun · PMID 42353181 · Full text
Kidney injury is a major clinical syndrome that can arise from nephrotoxins, ischemia-reperfusion, metabolic disease, infection, and immune dysregulation and can progress from acute kidney injury (AKI) to chronic kidney...
Kidney injury is a major clinical syndrome that can arise from nephrotoxins, ischemia-reperfusion, metabolic disease, infection, and immune dysregulation and can progress from acute kidney injury (AKI) to chronic kidney disease (CKD). Esculetin, a natural 6,7-dihydroxycoumarin derived from Cortex Fraxini, has antioxidant, anti-inflammatory, mitochondrial regulatory, anti-apoptotic, anti-ferroptotic, and anti-fibrotic activities. Preclinical studies report renoprotection in cisplatin-induced AKI, diabetes complicated by ischemia-reperfusion-induced AKI, and adenine-induced chronic renal injury, with changes in Nrf2/HO-1, NF-kappaB/MAPK, PINK1/Parkin-associated mitophagy, endoplasmic reticulum stress, regulated cell death, and fibrotic signaling. However, the evidence is based on a small number of heterogeneous cell and rodent studies, direct molecular targets remain uncertain, and no human studies have validated efficacy, dosing, or safety. Low oral bioavailability, rapid conjugative metabolism, limited long-term toxicology, and the absence of pharmacokinetic-pharmacodynamic relationships are major barriers to translation. This review critically synthesizes the renal evidence for esculetin and identifies the experimental, pharmaceutical, and clinical studies required to determine whether it can progress from a promising multi-target natural product to a renoprotective therapeutic candidate.
Evaluation of Antimicrobial Activity of Gallic Acid, Quercetin-3-D-Glucuronide, and Apigenin Against Gram-Negative Uropathogens: A Novel Approach to Urinary Tract Infection Therapy.
Fydrych D, Jeziurska-Pavlenko J, Kwiecińska-Piróg J
Int J Mol Sci · 2026 Jun · PMID 42353180 · Full text
Urinary tract infections (UTIs), particularly catheter-associated UTIs (CAUTIs), represent a significant clinical problem due to the predominance of Gram-negative uropathogens, their ability to form biofilms, and the inc...
Urinary tract infections (UTIs), particularly catheter-associated UTIs (CAUTIs), represent a significant clinical problem due to the predominance of Gram-negative uropathogens, their ability to form biofilms, and the increasing prevalence of antimicrobial resistance, which together reduce the effectiveness of conventional antibiotic therapy. This study aimed to evaluate the antimicrobial activity of selected natural plant-derived compounds against clinical Gram-negative uropathogens isolated from CAUTIs. The antibacterial effects of gallic acid, quercetin-3-D-glucuronide, and apigenin were assessed against , , and , including both ciprofloxacin-susceptible and -resistant strains. Antimicrobial activity was determined using the broth microdilution method, followed by quantitative assessment of bacterial viability based on colony-forming unit (CFU) enumeration. Gallic acid exhibited the strongest concentration-dependent inhibitory activity, reducing bacterial viability by up to 2-3 log CFU across all tested species. Quercetin-3-D-glucuronide demonstrated moderate antibacterial effects with a predominantly bacteriostatic profile, resulting in a partial but consistent reduction in CFU counts. In contrast, apigenin showed only weak effects on bacterial viability under the applied experimental conditions. None of the tested compounds achieved complete bacterial eradication. These findings indicate that gallic acid and quercetin-3-D-glucuronide possess inhibitory activity against Gram-negative uropathogens, including antibiotic-resistant strains, supporting their potential use as adjunctive agents targeting bacterial persistence in UTIs rather than as standalone antimicrobials. In the present study, the viability of planktonic bacterial cells was assessed; however, future studies should focus on evaluating the direct impact of the tested compounds on biofilm structure and biofilm formation dynamics.
BDNF Deficiency Preserves Shoal Structure but Selectively Modulates Horizontal Exploration in an Adult BDNF Zebrafish Line.
Sanchez Garcia AS, Frabetti F, Brighi G … +4 more , Tedeschi G, Racca A, Alleva E, Toni M
Int J Mol Sci · 2026 Jun · PMID 42353179 · Full text
Brain-derived neurotrophic factor (BDNF) is a key regulator of neural development, plasticity, and behaviour. Recent work has enabled the generation of a viable adult zebrafish line, which provides a unique opportunity...
Brain-derived neurotrophic factor (BDNF) is a key regulator of neural development, plasticity, and behaviour. Recent work has enabled the generation of a viable adult zebrafish line, which provides a unique opportunity to investigate how complete loss of affects social behaviour. Here, we examined three-dimensional shoaling behaviour in adult male and female AB wild-type and knock-out zebrafish to determine whether the extensive molecular and behavioural alterations previously observed in individual-based assays extend to collective contexts. The shoals showed no differences in group structure, as inter-fish distance, shoal volume, shoal area, distance to the centroid, and homogeneity index were comparable to wild-type groups. Vertical spatial distribution was also largely preserved, although fish shifted toward the upper regions of the tank earlier during the trial. By contrast, horizontal distribution revealed a clear genotype effect: shoals spent more time in peripheral regions and displayed a pronounced early peak in peripheral occupancy. These findings indicate that loss does not impair shoal formation or cohesion but selectively modulates specific components of spatial exploration. The results also highlight a dissociation between the vertical and horizontal axes of behaviour, as well as between individual- and group-based phenotypes, underscoring the importance of social context in shaping the behavioural consequences of BDNF deficiency.
Queue Gaps Among the IQGAPs in .
Filić V, Weber I
Int J Mol Sci · 2026 Jun · PMID 42353178 · Full text
Based on their domain organisation, four proteins from the protist have been assigned to the IQGAP family of scaffold proteins. Although these proteins are shorter than animal IQGAPs, their involvement in the regulation...
Based on their domain organisation, four proteins from the protist have been assigned to the IQGAP family of scaffold proteins. Although these proteins are shorter than animal IQGAPs, their involvement in the regulation of the actin cytoskeleton in cell motility, macroendocytosis, cytokinesis, and adhesion appears to be broadly conserved between these evolutionarily distant organisms. In this article, we show that the putative three-dimensional structure of IQGAP-related proteins, as predicted by AlphaFold 3, closely corresponds to the C-terminal half of human IQGAP1, thus supporting their common origin. IqgD is the largest IQGAP-related protein in , with an overall domain organisation similar to human IQGAPs. IqgD is localised in the cell cortex, interacts with F-actin and Rac1 GTPases, and primarily supports cell adhesion to the underlying surface and cell growth on bacterial lawns. DGAP1 and GAPA are truncated proteins that have retained a 700-residue-long C-terminal region of homology compared to their animal relatives. They play important, yet opposite, roles in regulating contractile cortical assemblies comprising F-actin, myosin II, and the actin-bundling proteins cortexillins, which are especially important for cytokinesis and epithelial morphogenesis. Finally, IqgC, although structurally resembling other IQGAPs, turns out to be more closely related to GAP1 proteins from fungi. This multifaceted protein carries RasGAP activity, interacts with several other small GTPases, and positively regulates macroendocytosis and cell-substratum adhesion.
β-Amyloid (Aβ) and Human Cathelicidin LL-37: Two Sides of the Same Coin?
Asti AL
Int J Mol Sci · 2026 Jun · PMID 42353177 · Full text
Physiologically produced circulating β-amyloid (Aβ) exerts critical physiological functions. Although Aβ is a key player in Alzheimer's disease (AD), it may initially be beneficial at the onset of infection. As an evolut...
Physiologically produced circulating β-amyloid (Aβ) exerts critical physiological functions. Although Aβ is a key player in Alzheimer's disease (AD), it may initially be beneficial at the onset of infection. As an evolutionary conserved antimicrobial peptide (AMP), Aβ contributes to innate immune defense against pathogens. Host defense peptides such as Aβ and human cathelicidin (LL-37) not only kill pathogens through their antimicrobial activity but also exhibit high affinity for bacterial lipopolysaccharides (LPSs) and membrane receptors. LL-37, which is upregulated in the brain, binds to Aβ, modulating its aggregation; Aβ and LL-37 are protective under physiological conditions, but during chronic infection or dysregulation, their interaction becomes toxic and contributes to AD pathology. Similarly to Aβ, LL-37 can induce neuroinflammation by stimulating human microglia to release inflammatory cytokines, such as TNF-α and IL-6. Neuroinflammation is essential for protecting the brain from pathogens-when prolonged, it drives pathological processes underlying AD, Parkinson's disease (PD), and other neurodegenerative disorders.
Risk Assessment for Venous Thrombosis in Lymphoma and Emerging Biomarkers.
Piperidou A, Nikolaou PE, Fotiou D
Int J Mol Sci · 2026 Jun · PMID 42353176 · Full text
Venous Thrombosis is a frequent and clinically significant complication in lymphoma patients, resulting in increased morbidity, mortality and therapeutic challenges. The pathophysiological mechanisms underlying lymphoma-...
Venous Thrombosis is a frequent and clinically significant complication in lymphoma patients, resulting in increased morbidity, mortality and therapeutic challenges. The pathophysiological mechanisms underlying lymphoma-associated thrombosis are multifactorial, involving patients' clinical characteristics, tumour biology, systemic inflammation, endothelial dysfunction and therapy-induced prothrombotic changes. Traditional predictive tools for cancer-associated thrombosis (CAT) have shown suboptimal application in lymphoma patients due to disease-specific heterogeneity. The ThroLy score was developed as a lymphoma-specific model incorporating parameters such as extranodal involvement, mediastinal disease, performance status, a prior venous thromboembolic event, and specific laboratory values. While it shows improved predictive value compared with general CAT models, its accuracy remains limited, particularly across different lymphoma subtypes and treatment regimens. Research in the field has therefore focused on evaluating emerging biomarkers-D-dimer, microparticles and inflammatory cytokines-as risk assessment tools. Integrative approaches that combine clinical variables with such biomarkers may yield a more dynamic and individualised risk-prediction model to guide thromboprophylactic strategies. The present review summarises current knowledge on thrombotic risk assessment across lymphoma subtypes and highlights the potential role of novel biomarkers in developing a more precise approach to thrombosis prevention and management. Importantly, it provides a comprehensive overview of currently available literature, highlighting the need for personalised thrombosis risk stratification strategies in lymphoma.
Novel Experimental Therapeutic Approaches in Glioma-New Hydrazide-Hydrazones as Chemical Agents Sensitizing Glioblastoma Cell Line to Radiotherapy.
Natorska-Chomicka D, Gawrońska-Grzywacz M, Patrejko P … +5 more , Herbet M, Piątkowska-Chmiel I, Iwan M, Dudka J, Popiołek Ł
Int J Mol Sci · 2026 Jun · PMID 42353175 · Full text
Gliomas are highly aggressive tumors of the nervous system and remain difficult to treat with currently available therapeutic approaches. Due to their poor prognosis and resistance to standard treatments, there is a grow...
Gliomas are highly aggressive tumors of the nervous system and remain difficult to treat with currently available therapeutic approaches. Due to their poor prognosis and resistance to standard treatments, there is a growing need for novel strategies, including therapies based on the combined use of radiotherapy and chemotherapy. The aim of this study was to evaluate the potential of newly synthesized hydrazide-hydrazones to sensitize glioblastoma tumor cells to X-ray irradiation. Two novel hydrazide-hydrazones of 5-bromo-2-iodobenzoic acid ( and ) were synthesized on the basis of condensation reaction. The chemical structure of obtained compounds was established with the use of IR, H NMR and C NMR spectroscopy. In vitro biological studies demonstrated that the radiosensitizing effect of the tested hydrazide-hydrazones was strongly dependent on both compound concentration and glioblastoma cell line. In LN-229 cells, compound at 164 μM combined with 2 Gy irradiation reduced cell viability by 65% and increased the subG1 population, indicating enhanced cytotoxicity and induction of cell death. Similarly, compound at 242 μM combined with 2-5 Gy irradiation decreased LN-229 cell viability by more than 50% and promoted cell cycle arrest and apoptosis, whereas both compounds showed limited or even proliferative effects in U-87MG cells, highlighting the importance of tumor-specific biological characteristics in determining treatment response.
Kilovoltage Energy Significantly Enhances the Therapeutic Efficacy of Low-Dose Radiation in a 3xTg-AD Mouse Model of Alzheimer's Disease.
Lee S, Yoo YJ, Kim G … +5 more , Kim E, Yun S, Kim J, Ryu H, Chung W
Int J Mol Sci · 2026 Jun · PMID 42353174 · Full text
Low-dose radiation (LDR) has emerged as a promising therapeutic modality for Alzheimer's Disease (AD). Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic effica...
Low-dose radiation (LDR) has emerged as a promising therapeutic modality for Alzheimer's Disease (AD). Although different irradiation protocols have been explored, the optimal parameters for maximizing therapeutic efficacy remain unclear. Radiation energy has been shown to influence radiobiological responses, with more pronounced effects at lower energy ranges. We therefore investigated whether kilovoltage LDR (KLDR) provides superior therapeutic efficacy compared with megavoltage LDR (MLDR) in a murine model of AD(3xTg-AD). To this end, we directly compared the efficacy of MLDR and KLDR in AD model mice to identify an optimal irradiation strategy for LDR treatment with potential relevance to clinical translation in AD. X-rays with 110-kV or 6-MV energy were applied to the brain of AD model mice at an early-stage of disease progression (26-28 weeks age; 0.6 Gy × 5 fractions for 2.5 weeks). After LDR treatment, cognitive function was assessed in AD model mice using passive avoidance (PA) test and novel object recognition (NOR) test. In addition, different molecular markers associated with inflammation, amyloid-beta (Aβ) plaques, tau burden, and neuronal and synaptic degeneration were analyzed in the brain of AD model mice. KLDR (110 kV) significantly inhibited cognitive decline in AD model mice, as demonstrated by both the PA and NOR tests. In addition, KLDR significantly reduced hippocampal levels of GFAP, Iba-1, and pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), while increasing anti-inflammatory cytokines (TGF-α, TGF-β, and IL-10), and was associated with marked reductions in Aβ and tau levels. Furthermore, the expression levels of Aβ40 and Aβ42 were quantified by ELISA following KLDR and MLDR treatment, revealing a statistically significant reduction in the KLDR group. The degeneration of neurons and synapses was significantly suppressed also at the kilovoltage energy level. Conversely, MLDR (6 MV) exerted minimal effects and did not produce statistically significant improvements. Taken together, our findings demonstrate that radiation energy level is a key determinant of LDR therapeutic efficacy in AD model mice, with KLDR showing significantly greater effectiveness in improving AD-related pathological features than MLDR. Therefore, KLDR may be recommended as a novel radiation protocol for AD treatment.
The Role of Vasoactive Intestinal Peptide in Glucagon-like Peptide-2-Mediated Intestinal Lipid Handling.
Mukherjee K, Wang R, Tabatabaeian F … +1 more , Xiao C
Int J Mol Sci · 2026 Jun · PMID 42353173 · Full text
The gut hormone glucagon-like peptide-2 (GLP-2) plays important roles in regulating lipid handling and promoting anti-inflammatory functions in the intestine. During the postprandial state, it increases lipid absorption....
The gut hormone glucagon-like peptide-2 (GLP-2) plays important roles in regulating lipid handling and promoting anti-inflammatory functions in the intestine. During the postprandial state, it increases lipid absorption. During post-absorptive state, it mobilizes pre-formed chylomicrons. GLP-2 acts through vasoactive intestinal peptide (VIP) in reducing inflammation in rat ileum. However, this pathway has not yet been tested for GLP-2's effects on intestinal lipid handling. Here, in mesenteric lymph duct cannulated rats, we examined whether VIP signaling mediates GLP-2's effects on postprandial lipid absorption and post-absorptive lipid mobilization in the intestine. We administered a VIP receptor antagonist and analyzed lipid output in response to intraperitoneal GLP-2 or PBS during postprandial and post-absorptive states. VIP receptor antagonism reduced GLP-2 mediated lipid output in the post-absorptive state but had no effect during the postprandial state. These results show that GLP-2 functions differently during postprandial and post-absorptive states and VIP aids in GLP-2-mediated lipid output during the post-absorptive state.
Lactate-Mediated Brain Acidosis Drives Epigenetic Dysregulation of TGFB2 and Associated Gene Networks in Schizophrenia and Bipolar Disorder.
Abdolmaleky HM, Nohesara S, Subramonian R … +5 more , Duraiarasan K, Dorzin M, Zhou JR, Pettinato G, Thiagalingam S
Int J Mol Sci · 2026 Jun · PMID 42353172 · Full text
Gene expression analyses of postmortem brains have identified hundreds of dysregulated genes in schizophrenia (SCZ) and bipolar disorder (BD). Lactate accumulation and reduced brain pH are also consistently reported in t...
Gene expression analyses of postmortem brains have identified hundreds of dysregulated genes in schizophrenia (SCZ) and bipolar disorder (BD). Lactate accumulation and reduced brain pH are also consistently reported in these disorders. As increased TGFB expression has been implicated in major psychiatric diseases and lactic acid induces upregulation in metabolic diseases, we hypothesized that lactate-induced brain acidosis may drive widespread gene dysregulation through TGFB2 activation. In our previous microarray studies, increased expression was observed in postmortem brains of SCZ and BD patients, while pathway analyses suggested a key role for in the dysregulation of other genes, particularly astrocytic genes. itself also exhibited promoter DNA hypomethylation in postmortem brains of these patients. Here, while brain pH was lower in SCZ and BD patients, we investigated the effects of pH alteration on the expression and promoter DNA methylation of and -correlated genes in iPSC-derived neurons, astrocytes, and brain organoids (brainoids). Cultures were treated with lactic acid, HCl, bicarbonate, or NaOH to alter culture medium pH by ±0.4 units, and gene expression and promoter DNA methylation were evaluated by qPCR analyses. In our reanalysis of postmortem brain microarray data, nearly 80% of dysregulated genes, together with , exhibited inverse correlations with brain pH. Lactic acid treatment induced increased expression and promoter DNA hypomethylation of and several correlated genes in astrocytes and brainoids, whereas bicarbonate and NaOH treatments showed opposite effects. These findings suggest that lactate-mediated brain acidosis may contribute to upregulation and widespread gene dysregulation implicated in SCZ and BD pathogenesis. Therapeutic interventions targeting lactic acid accumulation or hyperexpression may mitigate disease-associated brain gene dysregulation.
Benzovindiflupyr Is Associated with Metabolic Homeostasis Disturbance and Gut-Liver Axis Alterations in Zebrafish: Insights from a Multi-Omics Approach.
Miao J, Han S, Dang X … +3 more , Chen Q, Diao J, Zhu W
Int J Mol Sci · 2026 Jun · PMID 42353171 · Full text
Benzovindiflupyr (BZF) is a newly developed succinate dehydrogenase inhibitor (SDHI) fungicide that is widely used in crop protection, but its potential effects on non-target aquatic organisms remain a concern. In this s...
Benzovindiflupyr (BZF) is a newly developed succinate dehydrogenase inhibitor (SDHI) fungicide that is widely used in crop protection, but its potential effects on non-target aquatic organisms remain a concern. In this study, we exposed adult zebrafish () to 5.0 and 50 μg/L BZF for 28 days. We investigated its impact on the gut-liver axis using a combination of microbiome, biochemical, histological, and metabolomic analyses. BZF exposure damaged intestinal structure, downregulated barrier-related genes, and altered the composition of the gut microbiota. At the same time, serum lipopolysaccharide (LPS) levels increased, which indicates impaired intestinal barrier integrity and microbial dysbiosis. In the liver, BZF caused histopathological alterations, increased serum ALT, AST, and ALP activities, enhanced oxidative stress, and upregulated inflammation-related genes. Liver metabolomic profiling further showed marked disturbances in redox balance and metabolic homeostasis. Correlation analysis also revealed significant associations between altered microbial taxa and differential liver metabolites. Taken together, these results suggest that BZF exposure disrupted intestinal homeostasis and was associated with hepatic metabolic disturbance in zebrafish, potentially through gut-liver axis perturbation. This study expands current understanding of the toxic effects of SDHI fungicides and provides useful evidence for the ecological risk assessment of BZF in aquatic environments.
Comparative Evaluation of Real-Time PCR, Immunochromatographic Assay, and Modified Carbapenem Inactivation Method for Carbapenemase Detection in Enterobacterales Isolates.
Güner ET, Çiçek C, Bakır A … +1 more , Aral M
Int J Mol Sci · 2026 Jun · PMID 42353170 · Full text
Carbapenem-resistant Enterobacterales represent a major global public health concern, and the rapid and reliable detection of carbapenemase production is of critical importance. In this study, real-time PCR was used as t...
Carbapenem-resistant Enterobacterales represent a major global public health concern, and the rapid and reliable detection of carbapenemase production is of critical importance. In this study, real-time PCR was used as the reference method for carbapenemase detection, and the performance of immunochromatographic and phenotypic methods was comparatively evaluated. A total of 96 carbapenem-resistant Enterobacterales isolates were included, and all were identified as carbapenemase producers by the reference method. Diagnostic performance was assessed using positive percent agreement (PPA) and overall percent agreement (OPA); negative percent agreement and negative predictive value could not be calculated due to the absence of negative isolates. The immunochromatographic test showed complete agreement with real-time PCR in detecting carbapenemase production (PPA and OPA: 100%). At the gene level, sensitivity and specificity were 100% for OXA-48 and NDM, while sensitivity for KPC was 91.7%. In the modified carbapenem inactivation method (mCIM), PPA and OPA values were 97.9% due to false-negative results observed in two isolates producing OXA-48 and NDM by the reference method, and its performance was slightly lower than that of the immunochromatographic method. These findings indicate that the immunochromatographic method is a rapid, reliable, and practical option for carbapenemase detection, particularly in OXA-48-endemic intensive care settings where rapid identification is critical for timely infection control and appropriate antimicrobial therapy.
Integrative Single-Cell Transcriptomic, Mendelian Randomization and In Silico Perturbation Analyses Prioritize MUC20 as a Candidate Gene Associated with Osteoporosis and Metabolic Dysfunction-Associated Steatotic Liver Disease in the Liver-Bone Axis.
Jin H, Ye X, Jian G … +1 more , Xiong H
Int J Mol Sci · 2026 Jun · PMID 42353169 · Full text
Metabolic dysfunction-associated steatotic liver disease (MASLD) and osteoporosis (OP) are epidemiologically linked, but shared cell-type-specific molecular features remain unclear. We integrated public single-cell/singl...
Metabolic dysfunction-associated steatotic liver disease (MASLD) and osteoporosis (OP) are epidemiologically linked, but shared cell-type-specific molecular features remain unclear. We integrated public single-cell/single-nucleus transcriptomic datasets for OP (GSE147287) and MASLD (GSE289173) with two-sample Mendelian randomization (MR), colocalization, network annotation, macrophage-focused in silico perturbation, and exploratory serum assessment. After quality control, 13,753 OP cells and 42,438 MASLD cells/nuclei were analyzed. Macrophages were consistently identified in both datasets and showed disease-associated expansion. Directionally concordant macrophage differentially expressed genes yielded 147 shared candidate genes, with enrichment mainly involving lipid/sterol metabolism, extracellular matrix and adhesion processes, immune presentation, lysosomal processing, and phagocytic pathways. MR prioritized as the only candidate with concordant odds ratios greater than 1 for both OP (OR = 1.044, 95% CI 1.003-1.086) and MASLD (OR = 1.111, 95% CI 1.038-1.189). Colocalization supported shared genetic signals for in OP (PP.H4 = 0.855) and MASLD (PP.H4 = 0.816). In silico perturbation suggested a limited but pathway-enriched predicted transcriptional footprint. Serum MUC20 was higher in patients with OP+MASLD than in healthy controls. This integrative analysis identified shared macrophage-associated transcriptional themes and prioritized as a candidate molecule for future liver-bone crosstalk studies.
Microplastics as Vectors Influencing Oxidative Stress, Inflammation, and Endocrine Function During Early Development.
Kurhaluk N, Kołodziejska R, Rymuszka A … +5 more , Bilski R, Kaczorowska-Bilska K, Tomin V, Kamiński P, Tkaczenko H
Int J Mol Sci · 2026 Jun · PMID 42353168 · Full text
Microplastics and nanoplastics (MNPLs) are increasingly recognized as dynamic vectors capable of transporting a wide range of environmental contaminants, as well as acting as physical particulates. Their small size, high...
Microplastics and nanoplastics (MNPLs) are increasingly recognized as dynamic vectors capable of transporting a wide range of environmental contaminants, as well as acting as physical particulates. Their small size, high surface reactivity and strong sorption capacity allow them to carry metals, pesticides, pharmaceuticals and endocrine-active compounds into biological systems. This narrative review examines how these particle-contaminant complexes influence oxidative stress, inflammatory signaling and endocrine function during early development. Relevant literature was identified through structured searches of PubMed, Scopus, Web of Science and Google Scholar, with a focus on the physicochemical properties of plastics, sorption mechanisms, gut barrier physiology and developmental toxicology. Early developmental stages are particularly sensitive, as immature mucus layers, permeable epithelial junctions and underdeveloped detoxification pathways facilitate the uptake and systemic distribution of MNPLs. Once internalized, these particles and their chemical cargo promote the generation of reactive oxygen species through redox-active contaminants, surface-catalysed reactions and mitochondrial dysfunction. The resulting oxidative imbalance activates stress-responsive pathways, including Nrf2-Keap1 signaling, and promotes lipid peroxidation, DNA damage and cellular dysfunction. MNPLs also stimulate inflammatory cascades by activating pattern-recognition receptors, altering cytokine profiles and disrupting epithelial homeostasis. These responses are intensified in the presence of sorbed pollutants, leading to sustained inflammatory states that can be particularly detrimental during organogenesis and immune maturation. Endocrine function is likewise affected, as MNPLs transport hormonally active chemicals and can interfere with hormone-responsive pathways through oxidative and inflammatory mechanisms. These interactions may disrupt thyroid signaling, metabolic regulation and the development of the reproductive axis, with potential long-term physiological consequences. Integrating evidence from polymer chemistry, contaminant behavior and developmental physiology, this review shows that MNPLs act as biologically active vectors that may increase oxidative, inflammatory and endocrine disturbances during early development. These findings highlight the importance of considering particle-contaminant interactions as a critical component of early-life risk assessment.
Fecal Extracellular Vesicle Metabolomics as a Non-Invasive Biomarker Source in Colorectal Cancer: TPOT AutoML Superiority over Tree-Based Models with SHAP and LIME Clinical Interpretability.
Yagin FH, Korkmaz Y, Colak C … +4 more , Al-Hashem F, Alzakari SA, Alkhalifa AK, Aghaei M
Int J Mol Sci · 2026 Jun · PMID 42353167 · Full text
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, highlighting the critical need for non-invasive, accurate, and interpretable diagnostic tools. Metabolomic profiling of fec...
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, highlighting the critical need for non-invasive, accurate, and interpretable diagnostic tools. Metabolomic profiling of fecal microbial extracellular vesicles (EVs) offers a promising yet underexplored avenue for biomarker discovery when integrated with explainable machine learning (ML) frameworks. This study aimed to identify stool-derived microbial EV metabolite biomarkers that discriminate CRC patients from healthy controls and to develop interpretable ML classifiers for non-invasive CRC detection. Metabolomic profiles of fecal microbial EVs from 76 age- and sex-comparable participants (36 CRC, 40 controls) were obtained using LC/QTOFMS and GC/TOFMS. Three ML classifiers (TPOT, LightGBM, XGBoost) were trained and evaluated through 100-repeat stratified hold-out and nested 5-fold cross-validation, with SHAP and LIME applied for global and local interpretability. Fourteen metabolites were significantly dysregulated between the CRC and control groups (adjusted < 0.05), with 13 upregulated and one (aminoisobutyric acid) downregulated. Furoic acid exhibited perfect diagnostic discrimination, followed by palmitic acid and tyramine. Nested cross-validation demonstrated robust performance: TPOT achieved AUC = 0.997 ± 0.005, sensitivity = 0.973 ± 0.022, and MCC = 0.957 ± 0.033. Hold-out validation corroborated these findings (AUC = 0.998 ± 0.008). SHAP analysis identified furoic acid, palmitic acid, and tyramine as the dominant predictive features, while aminoisobutyric acid exhibited a distinctive protective pattern. LIME analysis corroborated these findings at the individual prediction level. The identified fecal EV-derived metabolite panel-particularly furoic acid, palmitic acid, and tyramine-shows strong potential to predict CRC in a non-invasive, interpretable manner; however, given the modest sample size, these findings should be considered hypothesis-generating and require validation in larger, prospective, multi-center cohorts before clinical translation.
Non-Invasive Multimarker Strategy Combining IL-17A, Neutrophil-Albumin Ratio, and Fecal Calprotectin for Accurate Discrimination of IBD from IBS-D.
Othman G, El Sayed Zaki M, Elmalki Elmalki N … +2 more , Badawy AA, Afifi SA
Int J Mol Sci · 2026 Jun · PMID 42353166 · Full text
Differentiating inflammatory bowel disease (IBD) from diarrhea-predominant irritable bowel syndrome (IBS-D) remains a major clinical challenge due to overlapping symptoms and the limited specificity of single biomarkers....
Differentiating inflammatory bowel disease (IBD) from diarrhea-predominant irritable bowel syndrome (IBS-D) remains a major clinical challenge due to overlapping symptoms and the limited specificity of single biomarkers. A reliable, non-invasive multimarker approach is needed to improve diagnostic accuracy and reduce unnecessary endoscopic procedures. To evaluate the diagnostic performance of serum interleukin-17A (IL-17A), neutrophil-to-albumin ratio (NAR), and fecal calprotectin (FCP), individually and in combination, for discriminating IBD from IBS-D and healthy controls in Egyptian patients. In this case-control study, 300 participants (100 with IBD, 100 with IBS-D, and 100 healthy controls) were enrolled. Serum IL-17A, NAR, and FCP were measured, and subgroup analysis was performed for infected and non-infected IBS-D patients. Diagnostic performance was assessed using receiver operating characteristic (ROC) curve analysis, with optimal cutoffs determined by the Youden index. A combined biomarker model was constructed using logistic regression. All biomarkers demonstrated a significant stepwise increase from healthy controls to IBS-D and IBD ( < 0.001). IL-17A, NAR, and FCP were elevated in IBS-D compared with controls, indicating low-grade inflammation, but were highest in IBD. No significant differences were observed between infected and non-infected IBS-D patients. Among individual markers, NAR showed the highest diagnostic accuracy (AUC = 0.923), followed by FCP (AUC = 0.884) and IL-17A (AUC = 0.859). The combined model significantly improved performance (AUC = 0.973), achieving 89% sensitivity and 96% specificity. IBS-D is associated with measurable systemic and intestinal inflammation independent of infection status. The combined biomarker model integrating IL-17A, neutrophil-albumin ratio, and fecal calprotectin demonstrated promising discriminatory performance for differentiating IBD from IBS-D. These findings suggest the potential applicability of combined non-invasive biomarkers in future diagnostic stratification approaches. However, the model was developed and evaluated within a single cohort, and external validation in independent populations is required before future potential clinical application. A multimarker diagnostic panel integrating IL-17A, neutrophil-albumin ratio, and fecal calprotectin demonstrated promising diagnostic performance for differentiating inflammatory bowel disease from IBS-D. The combined model may contribute to future diagnostic stratification strategies in patients with chronic diarrhea. However, these findings were derived from a single cohort and require validation in independent populations before broader clinical application.
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