Search Results (2,318)

Background/Objectives: Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and remains associated with poor prognosis despite multimodal therapy. Metabolic reprogramming, particularly increased dependence on glutamine, supports GBM bioenergetic, biosynthetic, and redox demands. This study aimed to systematically identify glutamine-associated metabolic regulators with prognostic relevance and biological plausibility in GBM. Methods: Transcriptomic data from TCGA and GTEx were analyzed using GEPIA2, with survival validation performed using the CGGA. Functional pathway enrichment, protein expression assessment, protein–protein interaction network analysis, tumor microenvironment evaluation, epigenetic profiling, and single-cell RNA sequencing validation were integrated to contextualize candidate genes. Pharmacogenomic correlation analysis and structure-based molecular docking were applied as supportive validation layers. Results: Ceruloplasmin (CP), Solute Carrier Family 25 Member 13 (SLC25A13), and Solute Carrier Family 38 Member 2 (SLC38A2) were selectively dysregulated and associated with poor clinical outcomes in GBM. CP was linked to redox regulation and stress-adaptive survival programs, SLC25A13 to mitochondrial metabolite exchange and glutamine-coupled nucleotide biosynthesis, and SLC38A2 to glutamine uptake, nutrient sensing, and mTORC1-MYC-associated growth signaling. Conclusions: CP, SLC25A13, and SLC38A2 emerge as clinically relevant glutamine-associated metabolic regulators in GBM, linking redox regulation, mitochondrial metabolite exchange, and glutamine-driven growth signaling. These findings highlight transport- and exchange-centered metabolic nodes as potential biomarkers and candidates for future metabolic targeting in GBM. Full article

This study applied SBAS-InSAR to a dense Sentinel-1 Single Look Complex (SLC) archive (146 scenes) to monitor the 1915 Çanakkale Bridge between 2022 and 2024 (data up to 7 January 2025 were available and considered in the time-series reconstruction). The analysis produced LOS mean velocity maps and pointwise displacement time series, revealing localized displacement concentrated near the Lapseki approach. Extreme LOS values reached approximately −101 mm (min) and +77 mm (max) across the domain, while maximum cumulative LOS displacement near the Asian anchorage approached −90 mm. These satellite observations suggest that ground-related processes may contribute to the detected observed movement; however, LOS-only measurements and limited in situ validations preclude a definitive separation between structural and geotechnical drivers. We therefore recommend targeted GNSS/levelling campaigns, ascending (ASC)–descending (DSC) InSAR fusion, and formal uncertainty reporting to better constrain the deformation sources and magnitude. The study concluded that the SBAS-InSAR method is effective for long-term, contactless monitoring of bridges and similar mega structures. It was also determined that this method can be used to identify critical areas requiring ongoing monitoring. Full article

Proteins can be methylated at either of the two N atoms of the imidazole ring of histidine, yielding 1-methylhistidine (or pi-methylhistidine) or 3-methylhistidine (tau-methylhistidine). While protein histidine methylation in mammals was discovered more than 50 years ago, the first histidine methyltransferases were identified only recently. So far, four different human protein histidine methyltransferases have been uncovered, and one of these is METTL9, which is responsible for introducing 1-methylhistidine in a number of proteins. The minimal sequence motif that is required, though not always sufficient, for METTL9-mediated methylation is His-X-His (HxH), where X is preferentially a small uncharged residue. Many METTL9 substrates are methylated at stretches of alternating histidines, i.e., several adjoining HxH motifs, such as HxHxH. Histidines are frequently involved in binding metal ions, such as zinc. Accordingly, it has been shown for several sequences targeted by METTL9, for example, in the immunomodulatory and antibacterial protein S100A9 and the zinc transporter SLC39A7, that histidine methylation diminishes zinc binding and thereby modulates protein function. In this review, we present a detailed account of METTL9-mediated histidine methylation, regarding its discovery, biochemical mechanism, structural features, and biological significance. Full article

Background: Neuropsychiatric disorders such as Alzheimer’s disease (AD), bipolar disorder (BD), and depression exhibit shared glutamatergic abnormalities, although their upstream molecular mechanisms remain poorly defined. Magnesium (Mg²⁺) serves as a key regulator of N-methyl-D-aspartate (NMDA) receptor function; however, the role of Mg²⁺ transporters, particularly SLC41A1, has not been systematically investigated. As NMDA receptor dysregulation contributes to emotional and cognitive impairments, elucidating Mg²⁺-NMDA signaling may enable the development of novel therapeutic strategies. Methods: We integrated Mendelian randomization, locus colocalization, human brain transcriptomics, functional enrichment, and co-expression analyses to determine whether SLC41A1 functions as a cross-disorder molecular driver. In addition, in vitro electrophysiological experiments using field potential recordings in hippocampal Schaffer-CA1 synapses were conducted to validate its functional role in NMDA receptor-mediated synaptic transmission. Results: Genetically elevated SLC41A1 expression increased the risk of AD, BD, depression, and alcohol dependence, with strong colocalization analyses supporting shared causal variants. Transcriptomic profiling revealed SLC41A1 upregulation in AD and BD, with enrichment in magnesium transport, mitochondrial function, and synaptic signaling pathways. Co-expression networks across GTEx brain regions demonstrated strong correlations with NMDA-related genes (e.g., GRINA, CAMK2G, GRIN2C). Under NMDAR-selective recording conditions, both imipramine treatment and SLC41A1 knockdown significantly reduced NMDAR-mediated fEPSP amplitudes, supporting a role for SLC41A1 in regulating NMDA receptor-dependent synaptic responses. Conclusions: This study identifies SLC41A1 as a magnesium-centered, transdiagnostic therapeutic target that links Mg²⁺ homeostasis to NMDA-dependent synaptic dysfunction. These findings provide a mechanistic foundation for developing SLC41A1-modulating or magnesium-based therapeutic approaches for mood and cognitive disorders. Full article

Nervonic acid (NA), a very-long-chain monounsaturated fatty acid, is known for its benefits in treating neurological diseases and promoting brain health. In this study, we utilized two different receptors, Brassica juncea (B. juncea, rich in erucic acid, C22:1) and Brassica napus (B. napus, high in oleic acid, C18:1), to overproduce NA through systematic metabolic engineering. Two multi-gene vector constructs, Napin-3 and Napin-5 (CgKCS::SLC1-1::DGAT1; CgKCS::SLC1-1::BnFAE1::LdLPAAT::DGAT1), are driven by seed-specific napin promoters. In B. juncea, Napin-3 and Napin-5 expression elevated NA levels to 48.7% and 46.3% in seed oil, respectively, compared to 2.5% in wild types. In B. napus, Napin-3 and Napin-5 expression achieved NA levels of 45% and 39.6%, respectively, while NA is absent in wild types. To our knowledge, this represents the highest NA production in plants to date, with stable oil content and yield, enabling cost-effective NA production. In B. juncea, a significant increase in NA is observed alongside a decrease in C18:1, C20:1, and C22:1 levels; in B. napus, the rise in NA is accompanied by a decrease in C18:1, and an increase in C20:1 and C22:1. These patterns reflect the dynamic equilibrium of fatty acids following NA conversion, influenced by the Dynamic Substrate Tugging (DST) Mechanism, in the form of either an EA-tugging mode or C18:1-tugging mode mechanism, depending on the cellular context. NA is an elongation product derived from C18:1, catalyzed by CgKCS with broad substrate specificity, indicating that plants with high levels of C18:1, similarly to those rich in C22:1, serve as excellent candidates for NA production. This “green factory” for NA production provides strong support for its pharmaceutical, nutraceutical, and industrial applications. The exogenous and the endogenous enzymes coordinate function remodeling of the intra-seed fatty acid elongation flux through the DST strategy, thereby systematically enhancing the synthesis and accumulation efficiency of the target fatty acid. Full article

Boron compounds, classified as prohibited food additives due to their high toxicity, persist in pesticides and fertilisers, industrial processes, food supply chains, and consumer goods, perpetuating multisource exposure risks. Chronic ingestion may induce fatal hepatorenal injury; however, mechanistic insights and epidemiological surveillance remain critically lacking amidst sector-wide regulatory gaps. This study employed integrated cellular and organismal models to elucidate the relationship between boron-induced hepatotoxicity and ferroptosis. We demonstrate that dietary boron accumulation in chicken livers is associated with histopathological damage, mitochondrial cristae dissolution and atrophy (a hallmark of ferroptosis), and elevated serum biomarkers AST and ALT. Boron exacerbates oxidative damage in hepatocytes by elevating malondialdehyde (MDA) production while modulating the Nrf2/ARE antioxidant signaling pathway—specifically downregulating key genes (Nrf2, HO-1, GCLM, CAT). Concurrently, it inhibits critical antioxidant enzymes (SOD, T-AOC), thereby depleting cellular antioxidant defenses. Crucially, boron disrupts iron homeostasis and induces ferroptosis by dysregulating the SLC7A11-GPX4 pathway: upregulating pro-ferroptotic genes (ACSL4, TF, TFR) and downregulating cytoprotective genes (SLC7A11, GPX4, FTH1). Co-treatment with the ferroptosis inhibitor ferrostatin-1 (Fer-1) attenuated boron-induced oxidative damage, whereas the ferroptosis inducer Erastin potentiated toxicity. Collectively, we pioneer the dual-pathogenic mechanism of boron hepatotoxicity—oxidative stress and ferroptotic cell death—establishing the SLC7A11/GPX4 axis as a novel therapeutic target against boron toxicity. Full article

Mitochondrial dysfunction is an early driver of Alzheimer’s disease (AD), and the decline in sex hormones, including 17β-estradiol (E2), at menopause has been linked to AD risk in women. While E2 exerts potent neuroprotective and mitochondrial-regulatory effects, its clinical utility in estrogen replacement therapy (ERT) may be limited by thrombotic and oncologic risks. Estetrol (E4), a fetal estrogen with a selective safety profile, may represent a promising alternative. This study evaluated the impact of E4 on mitochondrial bioenergetics and neuronal morphology in human SH-SY5Y neuroblastoma cells, including models of AD-related amyloidopathy (amyloid precursor protein overexpression) and tauopathy (P301Ltau mutation overexpression). E4 significantly enhanced ATP levels, mitochondrial membrane potential, and oxidative respiration in all cell models, notably outperforming E2 in P301L cells. E4 also promoted significant neurite outgrowth, alleviating deficits observed in AD models. In addition, we demonstrated that the bioenergetic effects of E4 were mediated by the estrogen receptors ERα, ERβ, and GPER1. Furthermore, E4 modulated the expression of key mitochondrial genes, specifically upregulating the phosphate carrier SLC25A23 while downregulating the complex I subunit NDUFA1. In conclusion, E4 improves mitochondrial health and supports neuronal integrity via a multi-receptor mechanism, highlighting its potential as a safe neuroprotective therapy for AD. Full article

Globally, chronic kidney disease (CKD) affects over 800 million individuals and is characterized by significant genetic complexity. More than 600 genes are associated with hereditary kidney disease, which may manifest as isolated kidney issues or as part of a syndrome that also includes extrarenal manifestations. The aim of this study was to identify genetic variants in a group of ten patients who presented with clinical signs suggestive of genetic syndromes associated with CKD, or who were asymptomatic but had a positive family history of CKD. Extensive genetic testing (targeted gene panels and whole-exome sequencing—WES) identified a mutation in the PKD1 gene in 3 out of 10 cases. In one patient, a known mutation in the PKD2 gene was identified. Another four patients were diagnosed with Alport syndrome: three of these presented with de novo missense mutations in the COL4A5 gene, and one patient had a mutation in the COL4A3 gene. One patient was diagnosed with MODY5, caused by a known mutation in the HNF1B gene, and one patient was diagnosed with Bartter syndrome type 1, resulting from a known mutation in the SLC12A1 gene. We present genotype–phenotype correlations, highlighting the particularities of each patient within their family context. Our findings emphasize the importance of genotype–phenotype correlations in refining diagnosis, personalizing therapeutic management, and providing essential genetic counseling for at-risk relatives. Full article

Background/Objectives: Obesity and prediabetes are overlapping global epidemics. This systematic review synthesises evidence on gene-diet interactions in adults with obesity, prediabetes, or related cardiometabolic risks. It evaluates Mediterranean and DASH dietary patterns, macronutrient quality, and energy restriction across both single-variant and polygenic score approaches. Methods: PubMed was searched for English language papers published in the last 5 years (last run: 31 October 2025). Fewer than 200 studies were retained after excluding those lacking explicit statistical testing for gene-diet interactions or relevant endpoints. Results: Evidence supports restricting saturated fat and preserving carbohydrate quality as general baseline targets, with associations heterogeneous by genotype. Effect modification was observed: healthy dietary patterns were associated with lower risk in high polygenic-risk strata (OR~0.53) but little or no benefit in low-risk groups. TCF7L2 variants were associated with macronutrient thresholds (e.g., protein > 18%, carbohydrate < 48%) affecting visceral adiposity, while APOA2 variants showed genotype-dependent inflammation, including paradoxical increases in markers with higher dietary antioxidant capacity. Interpretation was limited by underpowered interaction tests, multiplicity, and uneven ancestry representation (e.g., unique SLC16A11 and CREBRF signals). Conclusions: While anti-inflammatory dietary substitutions improve biomarkers irrespective of some variants (e.g., TCF7L2), genotype-informed nutrition appears to yield the largest absolute risk reduction in high-risk populations. Clinical implementation should therefore combine baseline diet-quality guidance with targeted strategies for genotype-specific response patterns (e.g., APOA2 antioxidant heterogeneity and TCF7L2 carbohydrate thresholds), rather than rely on uniform recommendations alone. Future progress requires preregistered, genotype-stratified trials and locally trained polygenic scores to address ancestry-specific genetic architecture. Full article

Suicidal behavior is a multifactorial and highly heritable phenotype; however, data concerning its genetic determinants in disparate ethnic groups remain limited. Genes implicated in serotonergic neurotransmission and stress response regulation are regarded as primary candidates for elucidating biological vulnerability to suicide. The objective of this study is to investigate the relationship between suicide attempts and candidate gene polymorphisms in an ethnically homogeneous Kazakh population from Astana, Kazakhstan. The study’s sample population comprised 126 patients with a documented history of suicide attempts and 120 age- and gender-matched controls without a history of suicidal behavior. A comprehensive genotyping analysis was conducted, encompassing polymorphisms in genes associated with serotonergic signaling, stress response, and neuroplasticity (TPH1, TPH2, HTR2A, MAOA, SLC6A4, ANKK1, BDNF, COMT, CXCL8, SKA2, and FKBP5). The associations were assessed across several genetic models, using odds ratios with 95% confidence intervals. A substantial correlation was identified between the HTR2A rs6311 polymorphism and suicide attempts. The CC genotype exhibited a protective effect (p = 1.36 × 10⁻⁵), while the TT genotype was associated with an elevated risk (OR = 3.16; 95% CI: 1.72–5.81). The association remained robust after stratification by sex, with an even stronger effect observed in women (OR = 4.70; 95% CI: 2.08–10.64). A nominal sex-specific association was observed for the SKA2 rs7208505 variant, suggesting a potential role in stress-response mechanisms in women; however, this association was no longer statistically significant after adjustment for multiple comparisons. These results identify HTR2A rs6311 as a potential genetic marker of suicide risk in the Kazakh population and support the involvement of serotonergic receptor regulation in the biological mechanisms underlying suicidal behavior. The results underscore the significance of sex-specific genetic influences, thereby enhancing our understanding of the polygenic underpinnings of suicidality. Full article

Background: The Xinjiang Black pig is an excellent breed developed by the Xinjiang Production and Construction Corps in the 1990s; however, it has been endangered by the impact of commercial breeds. Methods: Whole genomes of 224 individuals from the Xinjiang Black pig conservation population were resequenced. Results: Genetic structure and diversity analyses revealed that Xinjiang Black pigs underwent severe inbreeding and were genetically closely linked to Landrace pigs. The genetic diversity of the F₂ generation was well preserved in the existing breeding scheme. A total of 686 significant selection regions and 406 candidate genes were identified using F_ST and θπ complementary methods, with Xinjiang Black pigs, Min pigs, and Laiwu pigs as ancestral populations, and F₂. Based on Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and quantitative trait loci annotations, potential germplasm candidate genes were identified. Among these, SOX5, HMG20A, and NEDD4 are associated with fat deposition; SPRY1, MNS1, DMXL2, and ALB are closely associated with male reproductive ability; ARPP19 and TLN2 are strongly associated with oestrous cycle regulation and oocyte maturation; and SLC4A4 and SLC12A1 are extremely important for osmotic regulation and foetal survival. Conclusions: These findings deepen our understanding of the genetic mechanisms of artificial selection in Xinjiang Black pigs and provide a theoretical basis for subsequent breeding and genetic research on this breed. Full article

Background/Objectives: Pediatric sleep-disordered breathing (SDB) is influenced by craniofacial morphology and host susceptibility. Evidence integrating cephalometric airway features with targeted genetic variation in symptomatic skeletal Class II children remains limited. We explored whether children with skeletal Class II mandibular retrognathia and SDB symptoms harbor selected genetic variants and whether carriers show distinct cephalometric airway characteristics. Methods: This cross-sectional study included 48 children with skeletal Class II malocclusion, mandibular retrognathia, and snoring/mouth-breathing symptoms. Craniofacial and airway parameters were assessed on lateral cephalograms. SDB burden was evaluated by a baseline home sleep study (respiratory event index, REI). Targeted sequencing screened TNFRSF1A, PSTPIP1, SLC6A4 (5HTT), ACE, APOE, IRS1, and additionally PHOX2B and PMP22. Exploratory group comparisons used Student’s t-test. Results: Variants were identified in 13/48 participants (27%) in TNFRSF1A, PSTPIP1, SLC6A4, ACE, APOE, and IRS1; none were detected in PHOX2B or PMP22. C3–H was higher in variant carriers (39.90 ± 6.40 vs. 36.48 ± 3.95 mm; p < 0.05). HH1 (perpendicular distance from the hyoid bone to the C3–RGN line) was higher but not significant (16.99 ± 7.58 vs. 14.61 ± 5.25 mm; p > 0.05). Conclusions: In this clinically screened pediatric skeletal Class II cohort with SDB symptoms, selected genetic variants co-occurred with specific hyoid–cervical cephalometric features. Given the cross-sectional design, absence of a control group, and small number of carriers, findings are exploratory and require replication in larger, controlled cohorts with standardized phenotyping. Full article

Aging is associated with complex physiological changes that influence drug pharmacokinetics, including alterations in mitochondrial function and gastrointestinal (GI) drug transporter activity. Mitochondrial dysfunction—characterized by reduced oxidative phosphorylation, mitochondrial DNA damage, and increased reactive oxygen species—is a hallmark of aging and may affect energy- and redox-dependent cellular processes in the gut. At the same time, aging can modulate the expression and function of key intestinal drug transporters from the ATP-binding cassette (ABC) and solute carrier (SLC) families, which play a central role in oral drug absorption and bioavailability. This review examines the molecular links between age-related mitochondrial dysfunction and regulation of GI drug transporters, with a focus on their pharmacokinetic consequences in older adults. We summarize evidence of mitochondrial decline in the aging intestine and discuss how mitochondrial signals—such as cellular energy status and oxidative stress—regulate transporter expression and activity via pathways including AMPK (AMP-Activated Protein Kinase), Sirtuin–FOXO (Forkhead box O transcription factors), Nrf2 (Nuclear factor erythroid 2-related factor 2), and NF-κB (Nuclear Factor kappa B). We highlight clinical examples of drugs showing age-related changes in bioavailability that may be attributable to transporter dysfunction. Finally, we discuss therapeutic implications for geriatric pharmacotherapy, including dose adjustment, management of transporter-mediated drug–drug interactions, and strategies aimed at preserving mitochondrial health. Full article

Nonsyndromic hearing loss (NSHL) is a highly prevalent, genetically heterogeneous condition, yet its molecular basis in the Singaporean population remains underexplored. We performed whole-exome sequencing and integrative bioinformatics analysis in 115 patients with NSHL to define population-specific genetic biomarkers. A molecular diagnosis was achieved in 57% of cases, with 76% of identified variants classified as pathogenic or likely pathogenic and 24% exhibiting high pathogenic potential. Common East Asian NSHL genes, including GJB2, SLC26A4, and OTOF, were frequently detected alongside less prevalent genes such as ACTG1, CEACAM16, COL11A2, DIAPH1, KCQN4, MYH14, MYO6, MYO7A, MYO15A, SLC17A8, SMPX, STRC, TJP2, TMC1, TMPRSS3, highlighting extensive genetic heterogeneity. Notably, multiple novel variants, including MYO6 c.554-2A>G, and TNC p.N750Y, were identified, expanding the known mutational spectrum of NSHL. Genotype–phenotype correlations revealed that GJB2 variants were primarily associated with mild to moderate hearing loss, whereas SLC26A4 variants correlated with severe to profound phenotypes in the Singaporean populations. Collectively, our study provides important insights into the genetic architecture of NSHL in Singapore’s population. In addition, it supports improved molecular diagnosis yield and informed clinical management decisions as well as the advancement of precision medicine approaches aimed at reducing the burden of hearing loss in the region. Full article

Iron overload, a key driver of ferroptosis, results from excessive iron accumulation in tissues and contributes to organ injury, including renal dysfunction. Increasing evidence indicates that ferroptosis plays an important role in the pathogenesis of kidney diseases. Natural antioxidants capable of regulating ferroptosis have therefore attracted growing attention. Quercetin (Que), a naturally occurring flavonoid, possesses well-documented antioxidant and anti-inflammatory properties and may provide protection against iron overload-induced renal injury. Present study aimed to clarify the molecular mechanisms underlying iron overload-induced nephrotoxicity and to evaluate the protective effects of Que through modulation of ferroptosis-related signaling pathways. Using in vivo and in vitro experimental approaches, we found that Que markedly reduced oxidative stress by regulating reactive oxygen species (ROS) levels, intracellular iron homeostasis, and the expression of ferroptosis-related proteins in renal tissues and HK-2 cells. The results demonstrate that iron overload induces renal injury primarily through activation of ferroptosis, characterized by iron-dependent lipid peroxidation and subsequent cellular damage. Importantly, Que significantly attenuated iron overload-induced renal injury by activating the NRF2/SLC7A11 (xCT)/GPX4 signaling pathway, thereby restoring antioxidant capacity and inhibiting ferroptotic cell death. In conclusion, Que protects against iron overload-induced renal injury by enhancing antioxidant defenses and maintaining iron homeostasis through inhibition of ferroptosis. These findings suggest that Que may represent a potential therapeutic strategy for kidney diseases associated with iron overload. Full article