Search Results (81,645)

Early diagnosis of glaucoma remains challenging due to its asymptomatic onset and multifactorial pathological mechanisms. Growing evidence indicates that metabolic disorders and systemic molecular alterations play significant roles in glaucoma pathogenesis. However, reliable biomarkers and corresponding specific mechanisms remain unclear. In this study, we employed a multi-omics approach that encompassed metabolomics, transcriptomics, and Mendelian randomization to investigate the association between glaucoma and 35 types of blood and urine biomarkers. Metabolic pathway analysis was conducted using pathway enrichment analysis of differentially expressed genes based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Our study indicated that glaucoma contributed to elevated calcium concentration (OR = 1.044, 95% CI: 1.002–1.088, p = 0.039) in blood and urine, mediated by cell membrane calcium channels and calcium release from intracellular storage. Conversely, glucose was found to contribute to high glaucoma risk (OR = 1.324, 95% CI: 1.143–1.533, p = 0.0002), mediated by increased aqueous humor production, elevated intraocular pressure, endoplasmic reticulum stress, and oxidative stress. Validation experiments showed that calcium levels in blood, urine, and retina were elevated in the glaucoma group, and elevated glucose levels significantly reduced the 661W cell viability and induced apoptosis. This study offers new insights into the specific mechanisms linking blood and urine biomarkers to glaucoma, contributing to its prevention and screening. Full article

Renal cell carcinoma (RCC) is the most common kidney cancer, with increasing global incidence. Despite advances with VEGF-targeted tyrosine kinase inhibitors (TKIs) and immunotherapies, therapeutic resistance remains frequent, limiting long-term benefits. This highlights the need for potential biomarkers of tumor aggressiveness and therapeutic candidates, such as glucose-6-phosphate dehydrogenase (G6PD), whose altered expression has been associated with several cancers. We evaluated G6PD gene and protein expression in 121 RCC samples through immunohistochemistry and assessed functional role in vitro approaches. 786-O and ACHN cells were treated with the inhibitor G6PDi-1 and the anti-VEGF cabozantinib/lenvatinib. G6PD mRNA levels were higher in tumors than in non-neoplastic tissues, indicating shorter overall survival in clear cell (ccRCC) and papillary (pRCC) subtypes. Immunolabeling confirmed a higher expression in pRCC and associations with pathological features. CRISPR and RNAi datasets revealed a stronger G6PD dependency in the ccRCC. A high gene expression was observed in lenvatinib non-responder cell lines, and DepMap dose–response curves indicated modest responses to VEGF inhibitors. In vitro, ACHN was more sensitive to VEGF inhibition, particularly cabozantinib, whereas G6PDi-1 had stronger effects in 786-O, impairing viability, migration, and clonogenic capacity. Our findings support G6PD as a biomarker of tumor aggressiveness and G6PDi-1 as a potential therapeutic in RCC models. Full article

Surgical navigation and augmented reality (AR) are widely used in neurosurgery, spinal surgery, and orthopedics. However, their use in minimally invasive abdominal and thoracic soft-tissue surgery is limited, as tracking deformable, mobile organs is challenging. Recent advances in AR may address these challenges to improve intraoperative navigation. This systematic review, registered in PROSPERO (2024) and based on PRISMA guidelines, analyzes literature from 2014 to 2024 about AR in minimally invasive abdominal and thoracic soft-tissue surgery. It identifies target organs, describes AR hardware and software, and evaluates accuracy levels, usability outcomes, clinical benefits, technical limitations, and research needs. Searches of PubMed, Web of Science, and Embase for English-language studies found 1297 records, of which only 28 (2%) met the inclusion criteria. Nearly half (n =12; 42%) focused on liver surgery; none on gynecologic surgery. The AR devices varied in tracking methods, image processing, visualization, and display. Overall, AR improved anatomical guidance and procedural planning, especially in complex surgeries. Integration with robotic systems may further boost visualization, precision, and workflow, though challenges remain in standardization, large-cohort validation, and workflow integration. Full article

Oxidative stress is a critical pathophysiological factor in sepsis. Ursodeoxycholic acid (UDCA), a bile acid with anti-inflammatory, antioxidant, and anti-apoptotic properties, may protect against lipopolysaccharide (LPS)-induced myocardial injury. In an experimental study, 32 male Wistar rats were randomly assigned to four groups: control, LPS, UDCA, and UDCA + LPS. UDCA was administered orally for 10 days prior to LPS-induced endotoxemia. Serum levels of high-sensitive troponin I (hsTnI), homocysteine, and oxidative stress markers were measured, and immunohistochemistry and immunofluorescence were used to assess inflammation (nuclear factor kappa B, NF-κB), apoptosis (caspase 3), and signaling pathways related to protein kinase B (Akt)/NF-κB and silent information regulator 1 (SIRT1)/nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1). UDCA pretreatment significantly reduced myocardial pathological changes, serum hsTnI, homocysteine, and total oxidative stress compared with LPS alone. It enhanced catalase (CAT) activity and glutathione (GSH) levels while lowering thiobarbituric acid reactive substances (TBARS) and nitrite concentrations in cardiac tissue. UDCA modulated cellular signaling by decreasing Akt phosphorylation and activating the SIRT1/Nrf2/HO-1 pathway. These results indicate that UDCA protects the heart from LPS-induced damage by reducing oxidative stress, inflammation, and apoptosis. UDCA modulates cellular signaling by decreasing pro-inflammatory pathways and activating anti-inflammatory pathways associated with SIRT1/Nrf2/HO-1 signaling, emphasizing its key role in myocardial protection during sepsis. Full article

NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) are rare autoinflammatory disorders caused by uncontrolled inflammasome activation. While IL-1β blockade is first-line therapy, many patients respond inadequately, highlighting a need for alternative strategies. Transcriptomic analysis was performed on immune cells from a patient with an NLRP3 L573W mutation. Functional validation of CD177 as a downstream effector of NLRP3 activation was conducted. A novel NLRP3 L573W knock-in mouse model was established. Correlation between CD177 expression, disease severity, neutrophilia, and tissue damage was assessed. Therapeutic efficacy of siRNA-mediated CD177 silencing was evaluated and compared with IL-1β blockade. CD177, a neutrophil-specific protein, was significantly upregulated in NLRP3-mutant cells and confirmed as a direct downstream effector of NLRP3 activation. The NLRP3 L573W knock-in mouse recapitulated human disease heterogeneity, from mild self-limited inflammation to severe multi-organ pathology. CD177 expression correlated with disease severity, neutrophilia, and tissue damage. siRNA-mediated CD177 silencing attenuated systemic inflammation, reduced neutrophil infiltration and cytokine levels (IL-1β, IL-6, TNFα), and ameliorated multi-organ damage, with effects comparable to or exceeding those of IL-1β blockade. CD177 is a non-canonical amplifier of NLRP3-driven inflammation. Targeting CD177 represents a superior therapeutic strategy for NLRP3-AIDs, including IL-1β-refractory cases. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming increasingly prevalent worldwide, particularly among individuals with obesity and type 2 diabetes (T2D). MASLD remains potentially reversible in the early phases but, without timely intervention, it can progress to metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis, which in turn may advance to cirrhosis and hepatocellular carcinoma over time. With no pharmacological treatments specifically indicated for MASLD, current therapeutic strategies include lifestyle modifications, including dietary modifications. Niacin and its molecular derivatives (collectively belonging to the vitamin B3 group) play a central role in metabolic processes, especially through their involvement in the biosynthesis of the oxidized form of nicotinamide adenine dinucleotide (NAD⁺). A growing body of preclinical evidence suggests that reduced NAD⁺ levels are a hallmark of MASLD, and that NAD⁺ precursors may help attenuate disease progression through multiple mechanisms, including sirtuin 1 (SIRT1)-mediated inhibition of hepatic lipogenesis. Although these findings from experimental models suggest a potential role for niacin and related molecular derivatives as a modulators of MASLD-related pathways, evidence from human studies remains limited and inconsistent. For instance, interventional studies evaluating niacin or molecular derivatives supplementation have reported variable findings, with several trials showing limited meaningful benefits on MASLD-related outcomes. Consequently, further well-designed, controlled trials are needed to clarify therapeutic efficacy, dose–response relationship, and the feasibility of integrating niacin derivatives into dietary or therapeutic strategies aimed at reducing liver fat and improving adverse metabolic outcomes. This review aims to (i) summarize mechanistic insights on the role of niacin as a source of NAD⁺ on experimental MASLD and (ii) critically evaluate the available human evidence on the effect of supplemental niacin and derivatives in the prevention of MASLD development and its progression to MASH and fibrosis. Full article

Background: Liquid biopsy using circulating tumor DNA (ctDNA) is rapidly reshaping gastrointestinal (GI) oncology. The highest-impact applications are molecular residual disease (mRD) detection after curative-intent therapy and early recognition of progression or resistance during systemic treatment. Methods: We performed a structured, clinically oriented narrative synthesis by using explicit search, eligibility, evidence prioritization, and clinical interpretation rules, integrating landmark prospective cohorts, randomized ctDNA-guided strategy trials where available, meta-analyses, key methodological research (e.g., pre-analytics, assay design, and clonal hematopoiesis (CH)/clonal hematopoiesis of indeterminate potential (CHIP)), and selected trial registries. Results: In resected colorectal cancer (CRC), postoperative ctDNA positivity is among the strongest known biomarkers of recurrence risk; large prospective studies demonstrate clear separation of disease-free survival (DFS)/overall survival (OS) between mRD+ and mRD− patients. In stage II colon cancer, randomized data (DYNAMIC) show that a ctDNA-guided strategy reduces adjuvant chemotherapy exposure without compromising long-term outcomes. In metastatic CRC, ctDNA supports early response monitoring and resistance tracking; ctDNA-selected anti-EGFR rechallenge provides a model of biomarker-driven actionability (CHRONOS). In gastroesophageal cancers, longitudinal ctDNA dynamics correlate with relapse risk and treatment efficacy, and in esophageal squamous cell carcinoma, ctDNA after neoadjuvant chemoradiotherapy informs residual disease risk and adjuvant stratification. In pancreatic ductal adenocarcinoma and hepatobiliary malignancies, sensitivity is constrained by low shedding and background cell-free DNA (cfDNA), yet ctDNA positivity remains clinically meaningful, and emerging data in resected extrahepatic cholangiocarcinoma (STAMP-linked analyses) show that ctDNA dynamics during adjuvant therapy predict recurrence. Conclusions: ctDNA is a clinically validated biomarker for mRD in CRC, whereas in other GI cancers, it remains a promising but methodologically heterogeneous tool whose clinical utility is tumor- and context-dependent. The next phase requires interventional trials demonstrating outcome improvement, harmonized sampling and reporting standards, and rigorous control of confounders (notably CH/CHIP). Full article

Clonal hematopoiesis (CH) is the expansion of clones from a single hematopoietic stem cell (HSC) in the bone marrow. Clonal hematopoiesis of indeterminate potential (CHIP) refers to CH defined by the presence of pre-leukemic driver mutations in at least 2% of alleles in sequenced peripheral blood. This phenomenon is, by definition, associated not only with the future development of acute myeloid leukemia but also with non-malignant conditions, including cardiovascular disease. However, the underlying molecular mechanisms for CH in non-malignant diseases, such as cardiovascular disease, are not fully explained. Certain subtypes of CHIP may give rise to proinflammatory immune cells, which, in turn, may promote atherosclerosis progression. Key subtypes of CHIP include mutations in genes encoding epigenetic regulators DNMT3A (DNA methyltransferase 3A), TET2 (ten-eleven translocation methylcytosine dioxygenase 2), and ASXL1 (associated sex combs-like 1), as well as mutations in the gene encoding hematopoietic cytokine signaling: JAK2 (Janus kinase 2). The aim of this review is to summarize the current knowledge of CHIP and its association with inflammation and cardiovascular risk factors. Full article

Background: Turner syndrome is a genotypic disorder in females characterized by the total or partial absence of an X chromosome. While cardiovascular issues and sensorineural hearing loss are well-documented, vestibular system involvement remains understudied. This study aims to examine vestibular system involvement in patients with Turner syndrome and assess if they exhibit a higher prevalence of peripheral vestibular pathology compared to the general population. Methods: A retrospective longitudinal study was conducted with 21 Turner syndrome patients and 21 age-matched controls. Evaluations included clinical history, otoscopy, pure tone audiometry, the Video Head Impulse Test (vHIT) to measure vestibulo-ocular reflex gain, and computerized dynamic posturography, specifically the Sensory Organization Test (SOT) and Stability Limits Analysis. Results: Turner syndrome patients showed significantly higher hearing thresholds across all frequencies compared to controls (p < 0.001). In the vHIT, 30% of the Turner group presented pathological results, with significant gain reductions in the right horizontal and left posterior semicircular canals. Posturography revealed a significant reduction in overall stability (p = 0.006) and a significantly lower vestibular index (p = 0.011) in the Turner group. Additionally, patients with Turner syndrome demonstrated significant impairments in directional control, reaction time, and excursion points during Stability Limits Analysis. Conclusions: Patients with Turner syndrome are more likely to experience vestibular disorders, a finding likely associated with estrogen deficiency and the loss of its protective effect on the inner ear. These results highlight the necessity of including vestibular and posturographic assessments in the routine clinical follow-up of these patients to facilitate early detection and rehabilitation, even in the absence of overt symptoms like vertigo. Full article

This study explored ultrastructural changes and the expression of oxidative stress-related genes and proteins in the laminar tissue of dairy cows with acute laminitis induced by oligofructose (OF) overload. Twelve clinically healthy, non-pregnant Chinese Holstein cows were randomly allocated into two groups: the OF-overload group (n = 6) and the control group (n = 6). 17 g/kg BW of oligofructose (OF) dissolved in 20 mL/kg BW of deionized water was provided to the OF-treated group, while the control group received 20 mL/kg BW of deionized water via a stomach tube. Laminar tissue samples were collected at 72 h post-OF administration. RT-qPCR revealed significantly increased Keap1 mRNA expression (p = 0.0097) and significantly decreased Nrf2 (p < 0.0001), Ho1 (p < 0.0001), and Nqo1 (p = 0.0101) mRNA expression in the OF group compared to the control group. Western blot analysis confirmed corresponding protein-level changes, with significantly increased Keap1 (p = 0.0062) and significantly decreased Nrf2 (p = 0.0008), Ho1 (p = 0.0297), and Nqo1 (p = 0.0004) in the OF group compared with the control group. Immunohistochemical analysis revealed significantly increased cytoplasmic Keap1 distribution (p = 0.0200) and significantly decreased nuclear Nrf2 localization (p = 0.0032) in the OF group than the control group. Ultrastructural examination revealed significant pathological changes in the OF group, including a reduced number of hemidesmosomes (p < 0.01), an increased distance from epidermal basal cells to the lamina densa (p < 0.01), thickened and damaged lamina densa with disorganized collagen fibers, and deformed basal cell nuclei with reduced chromatin relative to the control group. In conclusion, these findings demonstrate that OF-induced acute laminitis is associated with significant dysregulation of the Keap1-Nrf2 antioxidant pathway and severe ultrastructural damage to the dermal–epidermal interface, suggesting that oxidative stress contributes to laminar tissue injury in dairy cows. Full article

Vein graft disease remains a significant limitation to the long-term patency of venous conduits following coronary artery bypass grafting. Early oxidative stress, triggered by ischaemia–reperfusion injury and haemodynamic changes following the implantation of veins into the arterial circulation, disrupts endothelial integrity and initiates inflammation, apoptosis, and maladaptive remodelling. The KEAP1-NRF2 axis is a central regulator of cellular antioxidant responses; however, its role in the development of vein graft disease remains poorly defined. This narrative review aimed to summarise what is known about NRF2/KEAP1 signalling in modulating vein graft pathology. Methods: A systematic search of PubMed was conducted to identify original research studies examining the NRF2/KEAP1 pathway in human saphenous vein tissue in vivo or ex vivo. Narrative synthesis was performed due to limited evidential availability and study heterogeneity. Results: Only one study has directly evaluated NRF2 pathway activation directly in human saphenous vein tissue, and it demonstrated that Protandim (a herbal dietary supplement) treatment increased antioxidant enzyme activity and reduced oxidative stress markers, including superoxide and 4-hydroxynonenal, both known activators of MAPK-dependent smooth muscle proliferation. Adjacent studies in other cells and tissues reveal that NRF2 intersects with multiple pathways central to vein graft pathology: it suppresses NFκB-mediated inflammation, modulates eNOS-NO signalling, inhibits NADPH oxidase expression, regulates MAPK activation, and influences angiogenic responses. However, context-dependent activation of NRF2 under arterial cyclic stretch can paradoxically drive proliferation through p62-mediated KEAP1 sequestration and enhanced glutathione synthesis. Conclusions: The NRF2/KEAP1 pathway serves as a central integrator of oxidative stress responses that directly intersect with established mechanisms of intimal hyperplasia and pathological angiogenesis. Post-translational KEAP1 inhibition may offer a targeted intervention point to limit these processes. Critical gaps remain regarding our understanding of the role of NRF2 in human saphenous vein under physiological arterial conditions and sex-specific pathway regulation. Mechanistic studies in vein-specific models are essential for advancing our understanding and any potential therapeutic translation. Full article

Steroid-resistant nephrotic syndrome (SRNS) in childhood frequently reflects monogenic podocytopathies in which immunosuppression is ineffective. Biallelic variants in MYO1E, encoding the class I myosin Myo1E, cause a distinctive form of focal segmental glomerulosclerosis (FSGS) often accompanied by “Alport-like” multilamination of the glomerular basement membrane (GBM). Early recognition has therapeutic and prognostic implications. A previously healthy 4-year-old boy presented with generalized edema and nephrotic-range proteinuria. Glucocorticoids induced no remission; sequential calcineurin inhibition (cyclosporine, then tacrolimus) and a single dose of ofatumumab yielded only transient, partial reductions in proteinuria. A first biopsy elsewhere showed FSGS with nonspecific IgM/C3 trapping; electron microscopy (EM) was not performed. At age 10, repeat biopsy with EM revealed ~30% segmental foot-process effacement, focal GBM thickening (to 1740 nm), irregular lamina densa multilamination, and lamellar duplications without immune-complex deposits—features highly suggestive of hereditary GBM disease. Targeted sequencing identified compound-heterozygous MYO1E variants segregating in trans: a canonical splice-donor change (c.2785+1G>A) and a frameshift (c.3094_3097del; p.Thr1032Profs*73). Each parent was an unaffected heterozygous carrier; the sibling was negative. Supportive therapy with ramipril was continued. At last follow-up (January 2025), renal function was normal (serum creatinine 0.5 mg/dL; creatinine clearance 122 mL/min) with stable sub-nephrotic proteinuria (0.52 g/day; 16 mg/m² per hour) and normotension. This case broadens clinicopathologic recognition of MYO1E-associated nephropathy and highlights the teaching point that Alport-like GBM changes are not pathognomonic for type IV collagen disorders but may signal defects in podocyte cytoskeletal anchoring. Full article

Addressing principal challenges in common bean (Phaseolus vulgaris L.) breeding requires a holistic approach. A combined strategy was implemented to assess seven genotypes (landraces and commercial varieties) for yield potential, stability and resistance to bean common mosaic virus (BCMV) under Mediterranean low-input conditions. Pure-line selection and prognostic breeding together with SSR and CAPS-SCAR marker-assisted selection (MAS) formed the core methodology. Significant variation was detected across 24 morpho-agronomic descriptors, while SSR revealed 48.57% polymorphic loci and private alleles in specific landraces. High genetic coefficients of variation and high heritability were recorded for yield-related traits. Phenotypical evaluation showed diverse responses to BCMV, with mild symptoms predominating (52.14%). Entries G1 (45%) and G5 (35%) exhibited the highest frequency of the symptomless resistant phenotype. Molecular screening at I and bc-3/eIF4E loci confirmed G5’s robust dominant I gene profile, while G1 included individuals carrying both the dominant I gene and recessive bc-3, offering a valuable source for pyramiding resistance. Additionally, G1 (LI = 2.35; 100%) performed strongly in productivity, whereas G2 (SI = 3.1; 100%) and G7 (SI = 2.8; 89.7%) exhibited exceptional stability. Overall, the mixed-model approach highlighted the complementary characteristics of the tested genotypes and identified G1, G2, G5 and G7 as promising candidates for future breeding programs targeting high yield, low-input adaptability and resistance to BCMV. Full article

Nontyphoidal Salmonella (NTS) is a zoonotic pathogen that threatens public health worldwide. This study investigated the prevalence, serotype, virulence, and antimicrobial resistance of NTS isolated from chicken meat in Fukuoka, Japan. Of 50 samples, 64% were positive for Salmonella spp., and 32 NTS strains were isolated from positive samples. Serotyping identified three serotypes: S. enterica ser. Schwarzengrund (78.1%), S. enterica ser. Thompson (15.6%), and S. enterica ser. Oranienburg (6.3%). Multilocus sequence typing revealed three sequence types (STs), and MALDI-TOF MS analysis revealed six distinct clusters, reflecting heterogeneity in protein expression among isolates with the same STs. All isolates harbored the virulence genes hilA, spiC, and ssrB, but not spvC. Microplate assays showed that all S. enterica ser. Schwarzengrund and S. enterica ser. Thompson strains formed biofilms with varying strengths. Antimicrobial susceptibility tests demonstrated that S. enterica ser. Thompson and S. enterica ser. Oranienburg strains were sensitive to all the antimicrobials tested. However, S. enterica ser. Schwarzengrund strains showed resistance to multiple antibiotic classes, and 36% of the isolates were multidrug resistant. These findings suggest a potential public health concern, particularly from S. enterica ser. Schwarzengrund, and underscore the importance of continuous surveillance that integrates both genotypic and phenotypic methods. Full article

Hyperuricemia is associated with liver dysfunction, yet its molecular mechanisms remain unclear. This study investigated high uric acid (HUA)-induced hepatocyte injury using a hyperuricemia mouse model (HUM) and uric acid (UA)-treated L02 cells. HUM exhibited elevated aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and pathological liver changes. Transmission electron microscopy (TEM) confirmed ferroptotic hallmarks, including mitochondrial shrinkage and increased membrane density. UA exposure upregulated NADPH oxidase 4 (NOX4), increased reactive oxygen species (ROS), and promoted lipid peroxidation (LPO), accompanied by intracellular Fe²⁺ accumulation. Mechanistically, UA increased hypoxia-inducible factor-2α (HIF-2α) expression, subsequently upregulating iron transporters divalent metal transporter 1 (DMT1) and transferrin receptor (TFRC). Deferoxamine (DFO) treatment effectively reversed Fe²⁺ overload and alleviated oxidative stress. Notably, pharmacological inhibition or genetic knockdown of HIF-2α specifically suppressed DMT1 upregulation and restored iron homeostasis, while TFRC expression remained unaffected. Blocking the HIF-2α/DMT1 axis significantly reduced LPO and mitochondrial dysfunction. These findings demonstrate that HUA induces hepatocyte ferroptosis through HIF-2α-mediated DMT1 upregulation, leading to Fe²⁺ overload and mitochondrial impairment. This study identifies the HIF-2α/DMT1 pathway as a key driver of HUA-induced liver injury and a potential therapeutic target. Full article