International Journal Of Molecular Sciences[JOURNAL]
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200 papers
Ionizing Radiation Actively Reshapes Bone Marrow-Derived Extracellular Vesicle MicroRNA Cargo with the Involvement of hnRNP A2b1.
Csordás IB, Forgács M, Szatmári T … +5 more , Balázs K, Moussong É, Visnovitz T, Badie C, Lumniczky K
Int J Mol Sci · 2026 Jun · PMID 42353225 · Full text
Bone marrow (BM) is highly sensitive to ionizing radiation: high doses cause extensive cell death, BM failure, and immune suppression, whereas low doses may increase long-term cancer risk without acute toxicity. Radiatio...
Bone marrow (BM) is highly sensitive to ionizing radiation: high doses cause extensive cell death, BM failure, and immune suppression, whereas low doses may increase long-term cancer risk without acute toxicity. Radiation-induced BM effects are partly mediated by disrupted intercellular communication via extracellular vesicles (EVs), including alterations in their microRNA cargo. EV-microRNA packaging remains unclear, although RNA-binding proteins are thought to contribute. To address this, murine BM cells and EVs were isolated 24 h after total body irradiation (0, 0.1, or 3 Gy). MicroRNAs were analyzed using nCounter and validated by RT-qPCR, while RNA-binding proteins (hnRNP A2b1, hnRNP Q) were assessed by Western blotting and confocal microscopy. Protein-microRNA interactions were examined using motif analysis and immunoprecipitation, and functional associations were explored via KEGG pathway analysis. High-dose irradiation induced widespread microRNA changes, whereas low-dose irradiation had minimal effects. Distinct cellular and EV microRNA profiles indicated selective sorting, with specific microRNAs enriched in cells but depleted in EVs. hnRNP A2b1 emerged as a potential regulator, showing nuclear relocalization and reduced EV association after irradiation; these changes correlated with decreased export of motif-containing microRNAs, possibly linked to key BM pathways. Overall, radiation alters EV-microRNAs through dose-dependent, protein-mediated selective sorting, potentially affecting BM communication and homeostasis.
Potential Health Benefits of Bee Bread from Stingless Bees on Reproductive Health: A Review.
Bashah NAK, Hamid AA, Jaffar FHF … +6 more , Mustafa MZ, Adam SH, Zaid SSM, Ismail WIW, Putra MADT, Mokhtar MH
Int J Mol Sci · 2026 Jun · PMID 42353224 · Full text
Bees are social insects belonging to the Apidae family, which includes stingless bees, honeybees, and related groups. Their ability to produce various products, such as bee bread, bee pollen, propolis, beeswax, and royal...
Bees are social insects belonging to the Apidae family, which includes stingless bees, honeybees, and related groups. Their ability to produce various products, such as bee bread, bee pollen, propolis, beeswax, and royal jelly, has attracted scientific interest due to their nutritional composition, biological activities, and potential therapeutic value. Bee bread is a fermented mixture of pollen, honey, and salivary bee enzymes, rich in bioactive compounds with potential benefits for reproductive health and other biological activities. However, bee bread remains one of the least explored bee products in relation to reproductive health. This narrative review summarises the potential health benefits of bee bread from stingless bees for male and female reproductive function. Evidence from animal studies shows that bee bread has promising effects on reproductive function, possibly through its antioxidant properties, support of spermatogenesis and steroidogenesis, improvement of pregnancy outcomes, enhancement of ovarian function, regulation of metabolism, and modulation of inflammatory activity. Findings from animal studies suggest potential benefits for both male and female reproductive health. However, well-designed randomised controlled trials are needed to evaluate its efficacy, optimal dosage, safety profile, and long-term effects on reproductive outcomes in both males and females.
Metabolic Pathways and Molecular Regulatory Mechanisms of Nervonic Acid Biosynthesis in .
Xu Q, Jiang C, Dong M … +5 more , Liao L, Pang G, Xing Z, Qi S, Zhou B
Int J Mol Sci · 2026 Jun · PMID 42353223 · Full text
Nervonic acid (NA, C24:1 Δ15) is a vital extra-long-chain monounsaturated fatty acid essential for neural development, myelin sheath formation, and neurological health. As the most abundant natural source of NA, Chun &...
Nervonic acid (NA, C24:1 Δ15) is a vital extra-long-chain monounsaturated fatty acid essential for neural development, myelin sheath formation, and neurological health. As the most abundant natural source of NA, Chun & S.K.Lee has become a key model for studying NA biosynthesis and regulation. This review systematically summarizes the metabolic pathways of nervonic acid biosynthesis in , including plastidial fatty acid synthesis, endoplasmic reticulum (ER)-based very-long-chain fatty acid elongation, and Δ15 desaturation. We focus on the catalytic mechanisms and rate-limiting roles of the elongase complex (KCS, KCR, HCD, ECR) and Δ15 desaturase. Additionally, we integrate recent multi-omics data to analyze key enzyme KCS gene families, their phylogenetic relationships, and syntenic distribution patterns. Furthermore, transcriptional regulatory networks (MYB, bZIP, WRI1, ABI3, FUS3) and epigenetic regulation underlying NA accumulation are also discussed. Finally, we highlight advances, challenges, and prospects in metabolic engineering and synthetic biology for sustainable NA production. This review provides a theoretical basis for the conservation, molecular breeding, and biotechnological utilization of .
Structural Basis of pppGpp Binding to the N-Terminal Domain of the Bifunctional RelA/SpoT Homolog Rel: Crystal Structure and MD Analysis.
Korban SA, Spiridonova ZA, Kasatsky PS … +6 more , Shvetsov AV, Gurzhiy VV, Paleskava A, Kulminskaya AA, Konevega AL, Vinogradova DS
Int J Mol Sci · 2026 Jun · PMID 42353222 · Full text
RelA/SpoT homologue family enzymes participate in controlling the cellular levels of the alarmone (p)ppGpp, thereby activating the stringent response and promoting survival under stress conditions. These proteins contain...
RelA/SpoT homologue family enzymes participate in controlling the cellular levels of the alarmone (p)ppGpp, thereby activating the stringent response and promoting survival under stress conditions. These proteins contain an N-terminal catalytic domain and a C-terminal regulatory domain. They catalyze both the synthesis of ppGpp/pppGpp from ATP and GDP/GTP and their hydrolysis to GDP/GTP and pyrophosphate. Here, we report the crystal structure of the N-terminal domain of Rel from in complex with pppGpp at 3.2 Å resolution. The asymmetric unit contains a dimer with asymmetric ligation: pppGpp occupies only the synthetase site in one monomer, whereas in the other monomer, it is bound in both the hydrolase and synthetase sites. The two monomers exhibit distinct conformational states, with pronounced rearrangements of the flexible loops surrounding the binding pockets, including the α2/α3 and α8/α9 loops that act as steric gates. Molecular dynamics simulations support the dual binding arrangement and reveal additional probable transient binding sites, including a region in the linker between hydrolase and synthetase subdomains. These findings provide a structural framework for understanding how pppGpp binding modulates the opposing catalytic activities of bifunctional Rel enzymes and suggest possible mechanisms for (p)ppGpp-mediated autoregulation.
Opposing Changes in Cerebellar Dopaminergic Genes Co-Expression Networks in Different Models of Neurodevelopmental Disorders.
Belskaya AD, Fesenko ZS, Volnova AB … +2 more , Gainetdinov RR, Vaganova AN
Int J Mol Sci · 2026 Jun · PMID 42353221 · Full text
While the cerebellar dopaminergic system is suggested to be implicated in neurodevelopmental disorders, especially autism spectrum disorder (ASD), the details of its disturbances remain unclear. We performed a comparativ...
While the cerebellar dopaminergic system is suggested to be implicated in neurodevelopmental disorders, especially autism spectrum disorder (ASD), the details of its disturbances remain unclear. We performed a comparative analysis of human (GTEx) and mouse (GSE144046, GSE144277) transcriptomes, complemented by RT-qPCR in DAT-KO rats, to identify dopaminergic gene associations in the normal cerebellum and neurodevelopmental disorder models. Pairwise dopaminergic gene correlations were generally weak, with a slight increase in interaction complexity in ASD models. However, weighted gene co-expression network analysis identified a robust gene module involving , which was consistently associated with synaptic translation across mouse datasets. These associations reflect regulatory processes in the whole cerebellum, which is commonly represented in rodent studies but absent in human data, which are acquired in studies of cerebellar subregions. ASD modeling exerted contrasting effects: haploinsufficiency increased the number of genes involved in the module with a decrease in connectivity, while haploinsufficiency led to module collapse. These findings confirm neurodevelopmental disorders as a heterogeneous condition where divergent backgrounds uniquely rewire cerebellar dopaminergic networks. Considering the cerebellum's role in ASD and that some ASD medications target the dopamine system, further investigation of these identified trends may support the development of more personalized therapeutic approaches.
Effects of Haplotypes of the Rice Sucrose Transporter Genes and on Grain Traits in Local Yunnan Germplasm Resources.
Li F, Kong D, Li Y … +2 more , Li K, Xu J
Int J Mol Sci · 2026 Jun · PMID 42353220 · Full text
The translocation of sucrose into spike grains during the grain-filling stage directly affects rice yield and quality. The sugar transporters and are key sucrose transporters essential for rice ( L.) grain filling. To...
The translocation of sucrose into spike grains during the grain-filling stage directly affects rice yield and quality. The sugar transporters and are key sucrose transporters essential for rice ( L.) grain filling. To elucidate their effects on grain traits, we analyzed sequence polymorphisms of these two genes in 139 landrace rice varieties from Yunnan, China, and conducted association and haplotype analyses. Our results indicated that grain filling degree was closely associated with grain shape, where wider grains negatively impacted grain plumpness. The association analysis revealed eight significant SNPs: six located in the coding region of that influenced grain length, thickness, density, and 1000-grain weight (TGW), while two SNPs in affected TGW and the thickness of milled rice grains. Haplotype analysis further validated these trait associations: Hap2 and Hap3 conferred longer grains (with Hap2 additionally increasing TGW and Hap3 enhancing grain density/plumpness), whereas Hap1 produced narrower and thicker grains. Consistently, Hap2 was also linked to higher TGW. The superior haplotypes identified here deepen our understanding of the genetic basis of rice grain filling and serve as potential molecular markers for marker-assisted rice breeding.
Roxadustat Inhibits Osteoclast Differentiation and Function by Disrupting Cell Cycle Exit.
Li A, Zuo L, Li L … +5 more , Gan L, Wang M, Liang Y, Li Q, Zhao X
Int J Mol Sci · 2026 Jun · PMID 42353219 · Full text
Bone remodeling relies on a balance between osteoclast-mediated resorption and osteoblast-mediated formation. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, promotes osteoblast differentiation but i...
Bone remodeling relies on a balance between osteoclast-mediated resorption and osteoblast-mediated formation. Roxadustat, a hypoxia-inducible factor prolyl hydroxylase inhibitor, promotes osteoblast differentiation but its effects on osteoclasts remain unclear. This study investigated roxadustat's impact on osteoclast differentiation and function in vitro using primary murine bone marrow-derived mononuclear cells differentiated with M-CSF and RANKL. Cell viability, TRAP staining, bone resorption assays, RNA-seq, flow cytometry, immunofluorescence, Western blot for p27, and rescue experiments with the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor abemaciclib were performed. Roxadustat suppressed osteoclast differentiation and resorption without cytotoxicity in a concentration-dependent manner. RNA-seq revealed enrichment of cell cycle pathways; although differentiation was inhibited, roxadustat paradoxically promoted osteoclast precursor proliferation, evidenced by increased Ki67 and decreased p27 expression. The inhibitory effects on osteoclastogenesis and resorption were partially reversed by abemaciclib. Given that terminal differentiation typically requires cell cycle exit, these findings suggest that roxadustat may inhibit osteoclast differentiation at least in part by disrupting this process, promoting precursor proliferation, and downregulating p27. Together with its known anabolic effects on osteoblasts, roxadustat might have dual therapeutic potential for bone disorders with renal anemia, such as osteoporosis in chronic kidney disease.
Aloin Induces Selective Cytotoxicity and Apoptotic Pathway Activation in Breast and Prostate Cancer Cells via Intrinsic and Extrinsic Mechanisms.
Dastouri M, Sanli B
Int J Mol Sci · 2026 Jun · PMID 42353218 · Full text
Breast and prostate cancers remain among the most prevalent epithelial malignancies worldwide, and conventional treatments often lack tumor selectivity. Aloin, an anthraquinone glycoside derived from Aloe vera, has demon...
Breast and prostate cancers remain among the most prevalent epithelial malignancies worldwide, and conventional treatments often lack tumor selectivity. Aloin, an anthraquinone glycoside derived from Aloe vera, has demonstrated promising anticancer properties. This study investigated the differential cytotoxic and apoptotic effects of Aloin under in vitro conditions in MCF-7 (breast cancer) and PC-3 (prostate cancer) cell lines compared with normal prostate epithelial cells (PNT-A1). Cells were treated with Aloin (1000-1500 µg/mL); cytotoxicity was assessed by CCK-8 assay, apoptotic morphology by DIC microscopy, protein expression by immunofluorescence with quantitative CTCF analysis (BAX, Caspase-3, Caspase-8, Caspase-9), and gene expression by qRT-PCR (2 method). An integrated log fold change heatmap, pathway enrichment analysis across three independent databases (KEGG 2026, Reactome 2024, WikiPathways 2024), and STRING v12.0-based protein-protein interaction (PPI) network were constructed. Aloin exerted significant dose-dependent cytotoxicity in both cancer cell lines, while PNT-A1 viability exceeded 50% across all concentrations (Selectivity Index > 1.30 for MCF-7 at 48 h). Immunofluorescence and qRT-PCR confirmed significant upregulation of BAX (up to 6.14×), CASP8 (up to 15.51×), CASP9 (up to 9.27×), and CASP3 (3.03× in PC-3), indicating concurrent activation of intrinsic and extrinsic apoptotic pathways, while all genes remained unchanged in PNT-A1 cells. Pathway enrichment analysis confirmed that these genes are statistically central nodes in conserved apoptotic signaling networks (adj. < 10). To the best of our knowledge, this is the first in vitro characterization of Aloin-induced pro-apoptotic activity in prostate cancer cells, establishing a mechanistic foundation for further investigation of this phytochemical in epithelial-derived cancer models.
Food Matrix Effects on Plant-Derived Bioactive Compounds and Micronutrients: Implications for Functional Food Development.
Vareltzis P, Kyroglou S, Pasidi E … +5 more , Oikonomou G, Gkogkou T, Govari M, Kalogiannis K, Gortzi O
Int J Mol Sci · 2026 Jun · PMID 42353217 · Full text
Even though the functional food market has rapidly increased in recent years, the links between bioactive-rich formulations and consumers' health benefit are not fully established, mainly because of insufficient consider...
Even though the functional food market has rapidly increased in recent years, the links between bioactive-rich formulations and consumers' health benefit are not fully established, mainly because of insufficient consideration of food matrix effects. This review provides a comprehensive and integrated evaluation of how food matrix properties (structural and physicochemical) affect the bioaccessibility of plant bioactive compounds. Unlike many reviews that focus on a single nutrient approach, we highlight quantitative evidence of how bioaccessibility can be affected by matrix properties, illustrating the interactions between main food components (lipids, proteins, dietary fiber and minerals). This review integrates fragmented information among different areas of food and nutrition sciences, i.e., food structure, gastrointestinal science, mineral chemistry, protein chemistry, providing a holistic framework for Quality by Design (QbD) functional food development. Synergisms and antagonistic behaviors, threshold effects, and concentration-dependent behaviors are analyzed comparatively for the most common plant-derived bioactives, such as polyphenols, carotenoids, curcuminoids and minerals (iron, zinc and calcium). We propose a matrix-informed optimization as a prerequisite for credible health claims and sustainable plant-based nutrition strategies. This can ultimately serve as a foundation for next-generation functional food development based on bioaccessibility, supporting the central argument .
as a Modulator of Oxidative Stress and Inflammatory Responses.
Costa EP, Pires AR, Sarandy MM … +6 more , Novaes RD, Brandão GC, Leite JPV, Salustiano IV, Esposito D, Gonçalves RV
Int J Mol Sci · 2026 Jun · PMID 42353216 · Full text
Oxidative stress plays a central role in the progression of inflammatory and degenerative diseases, highlighting the need for natural compounds with antioxidant and anti-inflammatory potential. This study investigated th...
Oxidative stress plays a central role in the progression of inflammatory and degenerative diseases, highlighting the need for natural compounds with antioxidant and anti-inflammatory potential. This study investigated the biological activity of the dichloromethane extract of leaves (DcMt), which was selected for further analyses after initial screening demonstrated superior antioxidant activity compared with the hexane extract (HxMt). Antioxidant capacity was evaluated by DPPH and FRAP assays, while cellular effects were assessed in RAW 264.7 macrophages through analyses of viability, cytokine gene expression, COX-2 modulation, catalase activity, and cell migration. LC-DAD-ESI-MS profiling revealed a well-defined chromatographic composition dominated by four major constituents, which were isolated and structurally elucidated by NMR and MS as prenylated flavonoids, several of which are reported here for the first time in . DcMt exhibited strong antioxidant activity and preserved cell viability under oxidative stress, with optimal effects at 25 µg/mL, accompanied by increased catalase activity. The extract modulated inflammatory markers by increasing IL-10 and IL-6 gene expression, maintaining IL-1β levels, and regulating COX-2 expression. In addition, DcMt promoted macrophage migration, further supporting its potential role in modulating inflammatory responses. Importantly, all biological assays were performed using the crude extract, and the contribution of individual compounds remains to be further investigated. These findings support as a promising source of bioactive compounds with antioxidant and immunomodulatory potential.
Gestodene Accelerates Cutaneous Wound Healing via PAR1-Selective Positive Allosteric Modulation.
Jeon H, Heo Y, Lee Y … +3 more , Park SH, Kang M, Namkung W
Int J Mol Sci · 2026 Jun · PMID 42353215 · Full text
Protease-activated receptor 1 (PAR1), a G protein-coupled receptor, plays a central role in coordinating multiple phases of cutaneous wound healing, including hemostasis, cell proliferation, migration, and extracellular...
Protease-activated receptor 1 (PAR1), a G protein-coupled receptor, plays a central role in coordinating multiple phases of cutaneous wound healing, including hemostasis, cell proliferation, migration, and extracellular matrix remodeling. Despite its therapeutic potential, PAR1-selective positive allosteric modulators (PAMs) remain limited. Here, we characterized the wound healing efficacy of gestodene, a third-generation progestin previously identified as a selective PAM of PAR1. Gestodene exhibited no intrinsic agonist activity but selectively potentiated PAR1-activating peptide (PAR1-AP)-induced calcium signaling without affecting PAR2 or PAR4 responses. Consistently, gestodene induced a concentration-dependent leftward shift in the PAR1-AP dose-response curve. Notably, gestodene enhanced PAR1-dependent cell proliferation, migration, and ERK1/2 activation, effects abolished by PAR1 knockout or pharmacological inhibition with vorapaxar in human keratinocytes (HaCaT) and dermal fibroblasts (HDF). Gestodene also potentiated the expression of wound healing-associated genes, including matrix metalloproteinases (MMP-1, -2, -3, -10), fibronectin, and type I collagen (COL1A1). In a murine wound model, topical administration of gestodene accelerated wound closure, achieving complete re-epithelialization by Day 8 and significantly enhancing collagen deposition, effects reversed by vorapaxar. Collectively, these findings demonstrate that gestodene accelerates cutaneous wound healing through PAR1-selective positive allosteric modulation and supports its potential as a drug repositioning candidate for wound repair.
Dysbiosis and Immune Crosstalk in Experimental Diabetic Periodontitis: A Systemic Review and Meta-Analysis of Preclinical Murine Studies.
Harrandah AM
Int J Mol Sci · 2026 Jun · PMID 42353214 · Full text
Diabetes mellitus (DM) fundamentally disrupts the oral microbiome, initiating a dysbiotic shift that drives progressive periodontal tissue breakdown. This transition is mediated by complex, bidirectional immune crosstalk...
Diabetes mellitus (DM) fundamentally disrupts the oral microbiome, initiating a dysbiotic shift that drives progressive periodontal tissue breakdown. This transition is mediated by complex, bidirectional immune crosstalk, primarily centering on the upregulation of the Th17/Interleukin-17 (IL-17) inflammatory pathway. This systematic review and meta-analysis quantified the specific impact of this diabetic microbiota on immune activation and periodontal destruction. A comprehensive search of PubMed/MEDLINE, Scopus, Web of Science, and the Cochrane Library was conducted for studies published up to 2026. Eligible studies included assessing oral/salivary microbiome shifts and their localized or systemic immunological consequences in diabetic periodontitis. A random-effects meta-analysis synthesized standardized mean differences (Hedges' g) to evaluate the magnitude of these effects. Quantitative synthesis of preclinical data (four studies yielding eight discrete comparisons) revealed that exposure to a diabetic/dysbiotic microbiota significantly increased overall immune activation and periodontal inflammation relative to eubiotic controls (pooled Hedges' g = 3.73, 95% CI 2.96-4.51). Subgroup analyses confirmed profound, statistically significant effects specifically on the Th17/IL-17 axis (g = 4.03) and periodontal bone destruction pathways (g = 3.37). Preclinical murine data suggests diabetes-associated oral dysbiosis may contribute to periodontal destruction by upregulating the Th17/IL-17 immune axis. However, direct extrapolation to humans is restricted, necessitating further clinical studies to validate these findings.
Cellular Models and Functional Assays for Assessing CFTR Function: A Comprehensive Review.
Lopatina M, Demchenko A, Smirnikhina S
Int J Mol Sci · 2026 Jun · PMID 42353213 · Full text
Cystic fibrosis (CF) is a genetic disorder caused by dysfunction of the CFTR chloride ion channel. Progress in molecular understanding and therapy development relies on advanced cellular models and robust assays for eval...
Cystic fibrosis (CF) is a genetic disorder caused by dysfunction of the CFTR chloride ion channel. Progress in molecular understanding and therapy development relies on advanced cellular models and robust assays for evaluating CFTR function. This review traces the evolution of in vitro models, from primary and immortalized cell lines to patient-specific induced pluripotent stem cells (iPSCs) and complex three-dimensional systems. These advanced models, including air-liquid interface (ALI) cultures, organoids, and microfluidic organ-on-a-chip platforms, enable recapitulation of tissue architecture, cellular heterogeneity, and key pathological features such as impaired mucociliary clearance and chronic inflammation. A critical component of CF research is the accurate functional assessment of CFTR activity. We compare established high-resolution techniques (patch-clamp, Ussing chamber) with high-throughput screening assays, including fluorescence quenching of halide-sensitive YFP assay and organoid swelling tests. The article provides a framework for choosing the most appropriate CFTR functional assay tailored to specific research goals.
Comparative Genomic Analysis and Data About the Metabolism of the Genus Provide the First Evidence of Methylotrophic Growth and Reveal Two Strategies of Methanol Oxidation and C1 Compound Assimilation.
Smolyakov DD, Rudenko TS, Grabovich MY
Int J Mol Sci · 2026 Jun · PMID 42353212 · Full text
For the first time in this study, the ability for methylotrophic growth on methanol was demonstrated in representatives of the genus . The analysis of 20 genomes and the physiological verification of genomic predictions...
For the first time in this study, the ability for methylotrophic growth on methanol was demonstrated in representatives of the genus . The analysis of 20 genomes and the physiological verification of genomic predictions regarding C1 compound metabolism were carried out using HS, DSM 566, and D-501 as model strains. Genes involved in the direct oxidation of methanol to carbon dioxide were identified, including the lanthanide-dependent methanol dehydrogenase XoxF, the NAD-dependent methanol dehydrogenase Mdh2, genes of the tetrahydromethanopterin (HMPT) and tetrahydrofolate (HF) pathways, and the NAD-dependent formate dehydrogenase. In addition, a number of genes associated with C1 assimilation were identified, including genes of the Calvin-Benson-Bassham cycle and the incomplete serine cycle. Experimental data suggest that the bacteria are capable of using two strategies of methylotrophic growth: methanol oxidation via the lanthanide-dependent methanol dehydrogenase XoxF and the HMPT pathway, as well as oxidation via the NAD-dependent methanol dehydrogenase Mdh2 and the HF pathway. Both strategies provide CO assimilation via the Calvin-Benson-Bassham, but additionally the second strategy demonstrates additional involvement of the incomplete serine cycle in the process of the C1 compounds. A hypothetical model of C1 compound assimilation in representatives of the genus was constructed.
Insulin Resistance as a Systemic Metabolic Risk State for Cancer: Mechanisms, Biomarkers, and Prevention.
Matek Sarić M, Lisica Šikić N, Sorić T … +4 more , Sarić A, Ivanišin A, Brodić I, Milić M
Int J Mol Sci · 2026 Jun · PMID 42353211 · Full text
Insulin resistance (IR) is traditionally viewed within the context of type 2 diabetes. However, it increasingly appears to represent a broader systemic metabolic risk state with potential relevance for carcinogenesis. Ch...
Insulin resistance (IR) is traditionally viewed within the context of type 2 diabetes. However, it increasingly appears to represent a broader systemic metabolic risk state with potential relevance for carcinogenesis. Chronic hyperinsulinemia can activate insulin-like growth factor-1-dependent pathways, including phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin and mitogen-activated protein kinase signaling, promoting cellular proliferation while limiting apoptosis. At the same time, IR is closely linked to oxidative stress, chronic low-grade inflammation, and epigenetic alterations, together shaping a tumor-promoting microenvironment. Epidemiological studies report consistent associations between IR and increased cancer risk, particularly for endometrial, liver, and colorectal cancers. Yet causality remains uncertain and likely varies by tumor type. Notably, metabolic dysfunction may also occur in individuals with normal body mass index (BMI), underscoring the limitations of BMI-based risk assessment. Unlike previous reviews that primarily focused on individual mechanisms or epidemiological associations, this review examines IR as a systemic metabolic risk state by integrating molecular, epidemiological, biomarker-based, and prevention-oriented perspectives. Particular emphasis is placed on strategies for earlier risk identification using integrated biomarker approaches, including fasting glucose, homeostatic model assessment of insulin resistance, triglyceride-to-high-density lipoprotein ratio, high-sensitivity C-reactive protein, and insulin-like growth factor-1. Emerging tools such as continuous glucose monitoring and hepatokine profiling may further refine risk detection. Sustained lifestyle modification-diet, physical activity, sleep, and stress regulation-remains central to prevention. Pharmacological therapies, including glucagon-like peptide-1 receptor agonists and dual incretin agents, offer additional metabolic benefits, although their long-term impact on cancer risk is still unclear. Therefore, IR is best understood not as an isolated risk factor, but as a systemic metabolic risk state that may influence cancer development, with implications for prevention and early risk stratification.
Selective Alterations of Thiol Redox Homeostasis and Antioxidant Enzyme Activity in Advanced Atherosclerosis.
Marić R, Ćurčić B, Vidonja Uzelac T … +5 more , Grahovac T, Oreščanin Dušić Z, Radanović S, Batinić-Škipina D, Drakul D
Int J Mol Sci · 2026 Jun · PMID 42353210 · Full text
Atherosclerosis is a progressive vascular disease characterized by lipid-rich plaque accumulation, oxidative stress, and chronic inflammation, contributing to coronary heart disease, stroke, and peripheral arterial disea...
Atherosclerosis is a progressive vascular disease characterized by lipid-rich plaque accumulation, oxidative stress, and chronic inflammation, contributing to coronary heart disease, stroke, and peripheral arterial disease. This study investigated the impact of inflammation, vascular calcification, and statin therapy on redox balance in blood and carotid artery plaques, aiming to identify potential biomarkers for disease assessment. Thirty-two patients undergoing carotid endarterectomy provided 34 plaque samples. Enzyme activities in plaque/erythrocytes and -SH group concentration in plasma/plaque were measured. Pathological analysis was performed to determine inflammation/calcification grade, the presence of mast cells and plaque composition. The results showed that mast cells were associated with reduced non-protein -SH groups, indicating selective thiol consumption and serving as a qualitative marker of oxidative burden. Reduced catalase activity in erythrocytes was associated with advanced calcification, pointing to long-standing systemic oxidative stress. Statin therapy enhanced systemic superoxide-dismutase 1 activity, increased -SH groups, and modulated plaque-specific glutathione reductase activity, attenuating sex-related differences in redox regulation. These findings highlight the complex interplay between systemic and local oxidative processes in atherosclerosis through alterations in redox-related biomarkers such as plasma -SH group concentrations and catalase activity.
The Influence of Humic Substances and Auxin-Producing Bacteria on Plants in Relation to Auxin-Humate Binding.
Timergalin M, Ivanov R, Zaitsev G … +10 more , Ryazanova N, Abdullina R, Chetverikov S, Shigapov Z, Timergalina L, Nazarov A, Khamitov E, Kayukova V, Khursan S, Kudoyarova G
Int J Mol Sci · 2026 Jun · PMID 42353209 · Full text
Silver maple is a fast-growing, adaptable tree that often frequents wet places and thus can play an important ecological role in replanting schemes. For this, robust, high-quality seedlings are essential. In other tree s...
Silver maple is a fast-growing, adaptable tree that often frequents wet places and thus can play an important ecological role in replanting schemes. For this, robust, high-quality seedlings are essential. In other tree species, improved seedling quality has been achieved by treating with a combination of humic substances (HSs) and bacterial strains capable of synthesizing auxin phytohormone; the benefit being attributed, without clear supporting evidence, to changes in phytohormone concentrations in the plant. To clarify the uncertainty, we conducted assays of hormones in silver maple seedlings treated with HSs and appropriate bacteria. We hypothesized that any positive additive effects between HSs and bacteria may be due to the ability of HSs to bind phytohormones. This hypothesis was tested and confirmed by using optical absorption spectra of auxins, humic acids, and their combination, as well as by modeling their interactions. The combination of humic substances and bacteria resulted in an approximately 1.5-fold increase in auxin content in roots, accompanied by a marked increase in root weight and length. We suggest this is likely the outcome of HSs binding to bacterial auxins and delivering them to plant roots. Concentrations of cytokinins and abscisic acid also changed under these treatments, which may help explain observed increases in photosynthesis and improved water balance.
Metformin Enhances 2-Aminoethyl Dihydrogen Phosphate-Induced Mitochondrial Dysfunction and Apoptosis in Melanoma Cells.
Oliveira TAD, Almeida GHDR, Chammas SM … +12 more , Laiso RAN, Sousa YEM, Matos ÍGTP, Rodriguez VS, Queiroz BCB, Oliveira ACA, de Lima S, Arruda LAM, Rabelo DDC, Rici REG, Mathias PCF, Maria DA
Int J Mol Sci · 2026 Jun · PMID 42353208 · Full text
Melanoma exhibits pronounced metabolic plasticity and mitochondrial dependency, contributing to therapeutic resistance and tumor progression. Targeting mitochondrial function therefore represents a promising anticancer s...
Melanoma exhibits pronounced metabolic plasticity and mitochondrial dependency, contributing to therapeutic resistance and tumor progression. Targeting mitochondrial function therefore represents a promising anticancer strategy. 2-Aminoethyl dihydrogen phosphate (2-AEHP), a bioactive phosphomonoester, has demonstrated antiproliferative potential, while metformin, a clinically established antidiabetic drug, acts as a mitochondrial complex I inhibitor and metabolic modulator. This study investigated the cytotoxic and mechanistic effects of 2-AEHP and metformin hydrochloride, individually and in combination, in human (SK-MEL-28) and murine (B16-F10) melanoma models, using non-tumorigenic fibroblasts (FN1 and L929) as controls. Cell viability, proliferation dynamics, cell-cycle distribution, mitochondrial membrane potential (ΔΨm), and apoptosis-associated markers were evaluated by flow cytometry. 2-AEHP reduced melanoma cell viability and proliferation while inducing G2/M accumulation, DNA fragmentation, mitochondrial depolarization, increased cytochrome c release, caspase-3 and caspase-8 activation, upregulation of p53 and Bad, and downregulation of Bcl-2. Metformin alone exerted moderate cytotoxic and pro-apoptotic effects. Notably, combined treatment markedly potentiated mitochondrial depolarization and intrinsic apoptotic signaling in melanoma cells, significantly lowering IC values and enhancing caspase activation and cytochrome c release. Bliss independence analysis demonstrated synergistic interaction in SK-MEL-28 and B16-F10 cells. Although interaction scores indicated synergy in one fibroblast model, absolute cytotoxicity remained lower than in melanoma cells. These findings demonstrate that metabolic co-targeting with metformin enhances mitochondrial dysfunction-associated apoptotic signaling in melanoma cells, supporting a drug repositioning strategy aimed at exploiting mitochondrial vulnerability in metabolically adaptable tumors.
Solution Structure of Nucleoprotein Domain 1 from the Emerging Yezo Virus.
Gladysheva AV, Yanshin AO, Radchenko NS … +3 more , Osinkina IA, Ukladov EO, Agafonov AP
Int J Mol Sci · 2026 Jun · PMID 42353207 · Full text
The Yezo virus (YEZV) is a recently discovered tick-borne orthonairovirus with pathogenic potential, causing acute febrile illness in humans. Viral nucleoproteins (N) play a key role in genome packaging, replication, and...
The Yezo virus (YEZV) is a recently discovered tick-borne orthonairovirus with pathogenic potential, causing acute febrile illness in humans. Viral nucleoproteins (N) play a key role in genome packaging, replication, and modulation of host immune responses, making their structural characterization essential for understanding viral pathogenesis and developing targeted countermeasures. However, the absence of structural data for YEZV proteins significantly hinders these efforts. This study presents the first solution structure of the YEZV N domain 1 (D1). A highly purified, soluble, tag-free recombinant YEZV N D1 was produced from the native sequence of the clinical YEZV isolate. The native-state conformation was resolved through an integrated approach combining size-exclusion chromatography coupled with small-angle X-ray scattering (SEC-SAXS), AlphaFold 3 structure prediction, and all-atom molecular dynamics simulations. The YEZV N D1 structure adopts a stable, predominantly α-helical globular fold that remains monomeric under near-physiological conditions. SEC-SAXS data show excellent agreement with computational models, revealing moderate conformational flexibility. The characterized recombinant YEZV N D1 and its first solution structure reported here providing essential insights into understanding of YEZV molecular architecture. These findings lay a foundation for rational serological assay development and structure-guided therapeutic design against this and other emerging orthonairoviruses.
Off-Target Binding of Miglustat to Glycogen Debranching Enzyme.
Barber D, Mishra N, Hegarty F … +1 more , Paz A
Int J Mol Sci · 2026 Jun · PMID 42353206 · Full text
The iminosugar N-butyldeoxynojirimycin (Miglustat) is clinically used for the inhibition of ceramide glucosyltransferase for treating Type 1 Gaucher and Niemann-Pick type C diseases. This drug also inhibits glycogen debr...
The iminosugar N-butyldeoxynojirimycin (Miglustat) is clinically used for the inhibition of ceramide glucosyltransferase for treating Type 1 Gaucher and Niemann-Pick type C diseases. This drug also inhibits glycogen debranching enzyme (GDE), the enzyme responsible for terminal glycogen catabolism via coordinated glucotransferase and amylo-α-1,6-glucosidase (GC) activities, although the structural basis for inhibition has been undefined. Here, we report the crystal structure of GDE in complex with Miglustat, revealing inhibitor engagement at the conserved GC domain in an area that was previously hypothesized to accommodate the α-1,6-linked glucose moiety of glycogen. Structure-guided mutagenesis demonstrates that alanine substitution of residues at the GC site abolishes Miglustat binding, functionally validating the pocket and defining the interaction hot spots. To assess the possible relevance of these observations to the human enzyme, in silico docking predicts that Miglustat binds to the human enzyme in a pose close, albeit not identical, to our structure. These findings provide an opportunity to determine the molecular basis of GDE-inhibitor recognition, rationalize reported off-target effects of Miglustat, and provide a template for designing iminosugar therapies with reduced off-target binding.
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