Search Results (13,869)

Phenolic compounds contribute significantly to the nutritional and functional properties of wheat, particularly due to their antioxidant activity. In this study, a genome-wide association study was conducted to elucidate the genetic basis of total phenolic content (TPC) and antioxidant activity (AA) in a panel of 144 tetraploid wheat accessions representing diverse subspecies. The panel was evaluated under two different environments, located in Chile and Italy, to assess the influence of genotype, environment, and their interaction. Significant variability was observed for both TPC and AA, with TPC ranging from 0.26 to 0.82 mg gallic acid equivalent (GAE)/g and AA from 0.04 to 0.99 µmol Trolox equivalent (TE)/g. Substantial phenotypic variation and high broad-sense heritability were observed for both traits, underscoring the predominant genetic control. The genome-wide association study, using a mixed linear model (MLM), and the Bayesian information and Linkage-disequilibrium Iteratively Nested Keyway (BLINK) approaches identified 17 significant marker–trait associations, including quantitative trait loci on chromosomes 2B, 3A, 4B, 5A, 5B, and 6B. Notably, QTLs on chromosome 5A were co-localized for both TPC and AA, suggesting potential pleiotropic loci. Candidate genes linked to these loci included flavonol 3-sulfotransferase and peptidylprolyl isomerase, which are involved in phenylpropanoid metabolism and oxidative stress response, respectively. These findings offer valuable insights into the genetic basis of wheat phenolic traits and provide molecular targets for the development of biofortified cultivars through marker-assisted selection. Full article

Targeted therapy with BRAFi has significantly improved outcomes for patients with BRAF-mutated metastatic melanoma. However, resistance mechanisms, particularly metabolic adaptations, such as increased glutaminolysis, present substantial clinical challenges. This study investigated the metabolic changes underlying BRAFi resistance in melanoma cells. Using pharmacological agents, including dabrafenib (BRAFi), pimasertib (MEKi), dasatinib (cKITi), and CB-839 (glutaminase inhibitor), we explored metabolic adaptations in melanoma cell lines harboring various mutations. Our methodologies included cell culture, qPCR, polysome profiling, animal studies in nude mice, and analyses of patient samples to evaluate the therapeutic potential of targeting glutaminolysis. Our findings confirmed that melanoma cells, with resistance to targeted therapies, exhibit metabolic adaptations, including enhanced glutaminolysis, increased mitochondrial content, and elevated antioxidative capacities. We evaluated the efficacy of CB-839 and demonstrated its ability to reduce the proliferation of resistant melanoma cells both in vitro and in vivo. Mechanistic studies revealed that CB-839 suppressed ATP production and TCA cycle intermediates in resistant cells while inducing oxidative stress in sensitive cells, thereby inhibiting their proliferation. High glutaminase expression in primary patient tumor samples was associated with poor prognosis. We identified a metabolic signature in tumors from patients responsive or unresponsive to BRAFi prior to treatment, which could serve as a predictive factor for BRAFi response. This study underscores the metabolic alterations driving resistance to BRAFi in melanoma cells and highlights the therapeutic potential of targeting glutaminolysis with CB-839. The identification of metabolic signatures in patient samples provides valuable insights for personalized treatment strategies, aiming to overcome resistance mechanisms and improve patient outcomes in melanoma management. Full article

Background and purpose: Vulvovaginal candidiasis (VVC), caused by Candida albicans (C. albicans), is exacerbated by oxidative stress and uncontrolled inflammation. Pathogens like C. albicans generate reactive oxygen species (ROS) to enhance virulence, while host immune responses further amplify oxidative damage. This study investigates the antioxidant and antifungal properties of Hyssopus cuspidatus Boriss volatile extract (SXC), a traditional Uyghur medicinal herb, against fluconazole-resistant VVC. We hypothesize that SXC’s bioactive volatiles counteract pathogen-induced oxidative stress while inhibiting fungal growth and inflammation. Methods: GC-MS identified SXC’s major bioactive components, while broth microdilution assays determined minimum inhibitory concentrations (MICs) against bacterial/fungal pathogens, and synergistic interactions with amphotericin B (AmB) or fluconazole (FLC) were assessed via time–kill kinetics. Anti-biofilm activity was quantified using crystal violet/XTT assays, and in vitro studies evaluated SXC’s effects on C. albicans-induced cytotoxicity (LDH release in A431 cells) and inflammatory responses (cytokine production in LPS-stimulated RAW264.7 macrophages). A murine VVC model, employing estrogen-mediated pathogenesis and intravaginal C. albicans challenge, confirmed SXC’s in vivo effects. Immune modulation was assessed using ELISA and RT-qPCR targeting inflammatory and antioxidative stress mediators, while UPLC-MS was employed to profile metabolic perturbations in C. albicans. Results: Gas chromatography-mass spectrometry identified 10 key volatile components contributing to SXC’s activity. SXC exhibited broad-spectrum antimicrobial activity with MIC values ranging from 0.125–16 μL/mL against bacterial and fungal pathogens, including fluconazole-resistant Candida strains. Time–kill assays revealed that combinations of AmB-SXC and FLC-SXC achieved sustained synergistic bactericidal activity across all tested strains. Mechanistic studies revealed SXC’s dual antifungal actions: inhibition of C. albicans hyphal development and biofilm formation through downregulation of the Ras1-cAMP-Efg1 signaling pathway, and attenuation of riboflavin-mediated energy metabolism crucial for fungal proliferation. In the VVC model, SXC reduced vaginal fungal burden, alleviated clinical symptoms, and preserved vaginal epithelial integrity. Mechanistically, SXC modulated host immune responses by suppressing oxidative stress and pyroptosis through TLR4/NF-κB/NLRP3 pathway inhibition, evidenced by reduced caspase-1 activation and decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Conclusions: SXC shows promise as a broad-spectrum natural antimicrobial against fungal pathogens. It inhibited C. albicans hyphal growth, adhesion, biofilm formation, and invasion in vitro, while reducing oxidative and preserving vaginal mucosal integrity in vivo. By disrupting fungal metabolic pathways and modulating host immune responses, SXC offers a novel approach to treating recurrent, drug-resistant VVC. Full article

Background: The Space Omics and Medical Atlas (SOMA) is an extensive database containing gene expression information from samples collected during the short-duration Inspiration4 spaceflight mission in 2021. Given our prior understanding of the genetic basis for cardiovascular diseases in spaceflight, including orthostatic intolerance and cardiac deconditioning, we aimed to characterize changes in differential gene expression among astronauts using SOMA-derived data and curated cardiovascular pathways. Methods: Using the KEGG 2021 database, we curated a list of genes related to cardiovascular adaptations in spaceflight, focusing on pathways such as fluid shear stress and atherosclerosis, lipid metabolism, arrhythmogenic ventricular hypertrophy, and cardiac muscle contraction. Genes were cross-matched to spaceflight-relevant datasets from the Open Science Data Repository (OSDR). Differential expression analysis was performed using DESeq2 (v1.40.2, R) with normalization by median-of-ratios, paired pre-/post-flight covariates, and log2 fold change shrinkage using apeglm. Differentially expressed genes (DEGs) were defined as |log2FC| ≥ 1 and FDR < 0.05 (Benjamini–Hochberg correction). Module score analyses were conducted across SOMA cell types to confirm conserved cardiac adaptation genes. Results: A total of 185 spaceflight-relevant genes were analyzed. Statistically significant changes were observed in immune-related cardiovascular pathways, particularly within monocytes and T cells. Persistent upregulation of arrhythmogenic genes such as GJA1 was noted at post-flight day 82. WikiPathways enrichment revealed additional pathways, including focal adhesion, insulin signaling, and heart development. Conclusions: Short-duration spaceflight induces significant gene expression changes that are relevant to cardiovascular disease risk. These changes are mediated largely through immune signaling and transcriptional regulation in peripheral blood mononuclear cells. Findings highlight the need for tailored countermeasures and longitudinal monitoring in future long-duration missions. Full article

Gestational complications, such as preeclampsia and gestational diabetes mellitus (GDM), pose significant risks to maternal and fetal health and increase long-term cardiovascular disease risk in offspring. This review aims to synthesize current knowledge on the roles of ferroptosis and neutrophil extracellular trap formation (NETosis)—two regulated cell death pathways—in these pregnancy-related conditions. We performed a comprehensive analysis of preclinical and clinical studies that investigate the involvement of dysregulated iron metabolism, oxidative stress, inflammation, and endothelial dysfunction mediated by ferroptosis and NETosis in gestational pathologies. Evidence indicates that disturbances in maternal iron homeostasis and enhanced formation of lipid peroxides and NETs contribute to placental dysfunction and systemic inflammation, exacerbating disease severity. Therapeutic strategies targeting these pathways are emerging but require further validation. Our review also identifies key gaps in mechanistic understanding, biomarker development, and translational research needs. We conclude that modulation of ferroptosis and NETosis offers promising avenues for improving diagnosis and treatment of pregnancy complications, though carefully designed clinical studies are essential to confirm their clinical utility and safety. Full article

Poultry production exposes birds to diverse environmental and physiological stressors that disrupt redox balance, impair gut–liver axis function, and undermine health and productivity. This study investigated the hepatoprotective and antioxidative effects of mangosteen pericarp extract (MPE) in an experimental model of diquat-induced oxidative stress in laying hens. A total of 270 Hy-Line White laying hens were randomly assigned to three groups: control group (CON), diquat-challenged group (DQ), and MEP intervention with diquat-challenged group (MQ), with six replicates of 15 birds each. The results showed that MPE supplementation effectively mitigated the hepatic oxidative damage caused by diquat, as evidenced by the increased ALT and AST activity, improved lipid metabolism, and reduced hepatic fibrosis. Mechanistically, MPE activated the NRF2/HO-1 antioxidant pathway, thus enhancing the liver’s ability to counteract ROS-induced damage and reducing lipid droplet accumulation in liver tissue. MPE supplementation restored intestinal barrier integrity by upregulating tight junction protein expression (Occludin-1 and ZO-1), enhancing MUC-2 expression, and thereby decreasing gut microbiota-derived LPS transferring from the intestine. Additionally, MPE also modulated gut microbiota composition by enriching beneficial bacterial genera such as Lactobacillus and Ruminococcus while suppressing the growth of potentially harmful taxa (e.g., Bacteroidales and UCG-010). Fecal microbiota transplantation (FMT) from MPE-treated donors into diquat-exposed recipients reproduced these beneficial effects, further highlighting the role of gut microbiota modulation in mediating MPE’s systemic protective actions. Together, these findings demonstrated that MPE alleviated DQ-induced liver injury and oxidative stress through a combination of antioxidant activity, protection of intestinal barrier function, and modulation of gut microbiota, positioning MPE as a promising natural strategy for mitigating oxidative stress-related liver damage by regulating the gut microbiota and gut–liver axis in poultry. Full article

This study aimed to evaluate the effects of controlled atmosphere (CA) treatment on the postharvest quality of strawberries harvested at different 50% and 80% maturity under export shipping conditions. The strawberries were subjected to CA and refrigerated container (Reefer) environments at 10 °C, and their quality attributes were then analyzed. Metabolomic profiling revealed significant variations in primary and secondary metabolites and volatile organic compounds (VOCs). A pathway analysis revealed that CA conditions altered metabolic pathways related to sugar, amino acid, and energy metabolism during storage. CA treatment effectively delayed the accumulation of anthocyanins and enhanced the levels of specific amino acids and VOCs essential for the flavor and aroma of strawberries. Bioluminescence imaging revealed that CA treatment effectively reduced lipid peroxidation. A correlation analysis showed that certain VOCs and secondary metabolites significantly correlated with lipid peroxidation, indicating their role in enhancing antioxidant activity and reducing oxidative stress. These results suggest that CA conditions are associated with significantly reduced weight loss, the maintenance of firmness, and lower respiration rates in strawberries, particularly in those harvested at 80% maturity, extending the shelf life and improving the sensory quality of strawberries. Therefore, CA treatment is an effective method for long-term export. Full article

Ammonia is a common toxic pollutant in aquaculture environments that poses significant threats to the health, growth, and survival of aquatic organisms. This study investigates the physiological and molecular responses of triploid Crassostrea gigas to ammonia exposure, focusing on the activation and regulation of oxidative stress and immune-related pathways. By integrating histological observations, biochemical assays, and transcriptomic analysis, we systematically revealed the oxidative stress and immune regulatory mechanisms in the hepatopancreas of triploid C. gigas under ammonia exposure. Results showed significant tissue damage in the hepatopancreas, disrupted activities of key antioxidant enzymes including SOD, CAT, and GSH-Px, along with elevated MDA levels, indicating oxidative damage to cellular membrane lipids. Transcriptomic data further indicated significant activation of the glutathione metabolism pathway, with antioxidant genes such as GPX5 and GPX7 displaying a dynamic pattern of initial upregulation followed by downregulation, suggesting their critical roles in modulating oxidative stress responses and maintaining cellular homeostasis. Immunologically, ammonia exposure significantly activated lysosomal and phagosomal pathways, as well as multiple signaling cascades including FOXO, mTOR, and PI3K-Akt. Several key immune regulatory genes exhibited dynamic expression changes, reflecting coordinated regulation of apoptosis, autophagy, and energy metabolism to maintain immune defense and cellular homeostasis. Notably, dynamic expression of the GADD45 gene family in the FOXO signaling pathway underscores the important role of triploid C. gigas in mounting stress responses and adaptive immune regulation under ammonia toxicity. This study provides in-depth molecular insights into the integrated response mechanisms of triploid oysters to ammonia exposure, offering a molecular foundation for understanding bivalve adaptation to ammonia and revealing novel perspectives on molluscan ammonia tolerance. Full article

Neurodegenerative diseases such as Alzheimer’s disease (AD) are closely linked to oxidative stress and advanced glycation end products (AGEs), two interrelated processes that exacerbate neuronal damage through mitochondrial dysfunction, protein aggregation, and chronic inflammation. This narrative review explores the metabolic interplay between reactive oxygen species (ROS) and AGEs, with a focus on the AGE-RAGE (receptor for advanced glycation end products) signaling axis as a driver of neurodegeneration. Evidence from preclinical and clinical studies highlights their combined role in disease progression and underscores potential therapeutic targets. Strategies including mitochondria-targeted antioxidants, AGE inhibitors, RAGE antagonists, and metabolic interventions are discussed, along with future directions for biomarker development and personalized treatments. This review integrates current molecular insights into a unified metabolic–inflammatory model of AD, highlighting translational therapeutic opportunities. Full article

Chlorophyll biosynthesis is essential for photosynthesis and plant development. Disruptions in this pathway often manifest as pigment-deficient phenotypes. This study characterizes the morphological, anatomical, and physiological consequences of a chlorophyll-deficient rice mutant (yellow seedling, YS) caused by a loss-of-function mutation in the OsCHLI gene, which encodes the ATPase subunit of magnesium chelatase. Comparative analyses between YSs and wild-type green seedlings (GSs) revealed that YSs exhibited severe growth retardation, altered mesophyll structure, reduced xylem and bulliform cell areas, and higher stomatal and papillae density. These phenotypes were strongly light-dependent, indicating that OsCHLI plays a crucial role in light-mediated chloroplast development and growth. Transcriptome analysis further revealed global down-regulation of photosynthesis-, TCA cycle-, and cell wall-related genes, alongside selective up-regulation of redox-related pathways. These results suggest that chlorophyll deficiency induces systemic metabolic reprogramming, prioritizing stress responses over growth. This study highlights the multifaceted role of OsCHLI in plastid maturation, retrograde signaling, and developmental regulation, providing new insights for improving photosynthetic efficiency and stress resilience in rice. Full article

Biomolecular condensates (BCs), formed through liquid–liquid phase separation (LLPS), are membraneless compartments that dynamically regulate key cellular processes. Beyond their canonical roles in energy metabolism and apoptosis, Mitochondria harbor distinct BCs, including mitochondrial RNA granules (MRGs), nucleoids, and degradasomes, that coordinate RNA processing, genome maintenance, and protein homeostasis. These structures rely heavily on proteins with intrinsically disordered regions (IDRs), which facilitate the transient and multivalent interactions necessary for LLPS. In this review, we explore the composition and function of mitochondrial BCs and their emerging involvement in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, and Huntington’s disease. We provide computational evidence identifying IDR-containing proteins within the mitochondrial proteome and demonstrate their enrichment in BC-related functions. Many of these proteins are also implicated in mitochondrial stress responses, apoptosis, and pathways associated with neurodegeneration. Moreover, the evolutionary conservation of phase-separating proteins from bacteria to mitochondria underscores the ancient origin of LLPS-mediated compartmentalization. Comparative analysis reveals functional parallels between mitochondrial and prokaryotic IDPs, supporting the use of bacterial models to study mitochondrial condensates. Overall, this review underscores the critical role of mitochondrial BCs in health and disease and highlights the potential of targeting LLPS mechanisms in the development of therapeutic strategies. Full article

Background: Mitochondrial substrate switching plays an important role in aging. The substrate metabolic rate is closely related to mitochondrial activity, as mitochondria are the primary site for substrate oxidation and ATP production. Different substrates (glucose, amino acids, and fatty acids) enter the mitochondria through distinct pathways and are metabolized at different rates, depending on the energy demand and cellular conditions. However, it remains unclear how the mitochondrial metabolic rate of these substrates affects auditory cellular function. This study aimed to characterize the substrate-dependent mitochondrial respiratory responses of cochlear cells under varying energy supply conditions and metabolic stress, focusing on glucose, amino acids, and fatty acids as representative energy sources. Methods: The oxygen consumption rate (OCR) was measured after substrate addition using an Agilent Seahorse XF24 Flux Analyzer In-House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, and the maximum OCR (MOCR) was determined as part of the mitochondrial stress test. Statistical analyses were performed using analysis of variance (ANOVA). Results: The OCR increased significantly after glutamine (L-Gln) or palmitate addition. The MOCR after L-Gln addition was significantly higher than that after glutamic acid, glycine, and phenylalanine addition. The MOCR after pyruvate addition was significantly higher than that after glucose addition. However, there was no significant increase in the MOCR after fatty acid addition. Conclusions: Glucose is essential for basal metabolism but cannot rapidly meet sudden energy demands. Pyruvate and L-Gln serve as effective substrates for short-term, high-intensity energy demands. Fatty acids increase OCR through mitochondrial uncoupling effects, though their role may be limited in inner ear cells. These findings provide a foundation for exploring metabolic interventions to support cochlear function and hearing health. Full article

Heart failure (HF) remains a major global health challenge defined by the inability of the heart to adequately meet systemic metabolic requirements. While ventricular dysfunction has traditionally been the primary focus in both conceptual and clinical frameworks of HF, emerging evidence highlights atrial myopathy—covering structural, functional, electrical, metabolic, and neurohormonal remodeling—as a central yet often overlooked contributor to disease progression across the HF spectrum. This review offers a comprehensive overview of the molecular and cellular mechanisms underlying atrial remodeling, with a focus on inflammation and innate immune activation as key pathogenic mediators. Among pattern recognition receptors, Toll-like receptors (TLRs) and NOD-like receptors (NLRs) play crucial roles in translating myocardial stress into pro-inflammatory, profibrotic, and pro-arrhythmic signals that exacerbate HF. By combining experimental and clinical evidence, we emphasize atrial myopathy as both a biomarker and an active driver of HF deterioration, advocating for the inclusion of atrial-targeted diagnostics and immunomodulatory therapies in future HF treatment approaches. Such a paradigm shift holds significant potential for improved risk stratification, arrhythmia prevention, attenuation of structural remodeling, and ultimately, better prognosis and clinical outcomes in this increasingly common syndrome. Full article

Saline–alkaline water resources are globally widespread, and their rational development offers significant potential to alleviate freshwater scarcity. Saline–alkaline water aquaculture farming not only affects fish growth and survival but also impairs reproductive and developmental functions. Largemouth bass (Micropterus salmoides), an economically important fish, has demonstrated excellent high tolerance to such environments, in order to investigate the effects of alkaline water aquaculture environments on its growth performance, sex hormone levels, gonadal development, and molecular adaptation mechanisms. In this study, largemouth bass were chronically exposed to freshwater (0.55 mmol/L), low alkalinity (10 mmol/L), or high alkalinity (25 mmol/L) and cultured for 80 days. Alkalinity exposure more severely impacted the growth rate of females. High alkalinity significantly increased the hepatosomatic index and decreased the gonadosomatic index in both sexes; moreover, it induced oxidative stress in both sexes, evidenced by reduced superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAOC) levels and elevated malondialdehyde (MDA) content. Furthermore, the levels of sex hormones Serum estradiol (E2), 11-ketotestosterone (11-KT), and testosterone were significantly reduced, accompanied by either an elevated ratio of primary oocytes and follicular atresia, or by reduced spermatogenesis. Apoptotic signals appeared in gonadal interstitial cells, with upregulated expression of genes P53, Bax, Casp3, and Casp8. Ultrastructural damage included fewer mitochondria and cristae blurring, further indicating tissue damage causing dysfunction. Transcriptome results showed that oxidative stress damage and energy metabolism imbalance caused by carbonate alkalinity were key to the delayed gonadal development, which was mainly manifested in enrichment of the ECM–receptor interaction and PI3K-Akt signaling pathways in females exposed to low alkalinity, and the GnRH secretion and chemokine signaling pathways in males. Glycosphingolipid biosynthesis and Ferroptosis pathway were enriched in females exposed to high alkalinity, and the Cortisol synthesis and secretion pathway were enriched in males. Overall, high-alkalinity exposure significantly delayed gonadal development in both sexes of largemouth bass, leading to reproductive impairment. Full article

Alcohol Use Disorder (AUD) poses global health challenges, and causes hematological alterations such as macrocytosis and oxidative stress. Disruption of protein structures by alcohol and/or its metabolites may exacerbate AUDs; proteomics can elucidate the underlying biological mechanisms. This study examined the proteins differentially expressed in the cytosol and membrane fractions of erythrocytes obtained from 30 male patients with AUD, comparing them to samples from 15 age- and BMI-matched social drinkers (SDs) and 15 non-drinkers (control). The analysis aimed to identify the molecular differences related to alcohol consumption. The AUD patient subgrouping was based on mean corpuscular volume (MCV), with 16 individuals classified as having a normal MCV and 14 having a high MCV. Proteins were separated via two-dimensional(2D)-gel electrophoresis, digested with trypsin, and identified via Matrix-Assisted Laser Desorption/Ionization Time-of-Flight (TOF) mass spectrometry (MALDI-TOF/TOF). Additionally, levels of malondialdehyde and 4-hydroxyalkenals (MDA + HAE), reduced glutathione (GSH), oxidized glutathione (GSSG), serum carbohydrate-deficient transferrin (%CDT), disialotransferrin (%DST), and sialic acid (SA) were analyzed. The results showed increased MDA + HAE and decreased total thiols in AUD patients, with GSSG elevated and the GSH/GSSG ratio reduced in the AUD MCV-high subgroup. Serum %CDT, %DST, and SA were significantly higher in AUD. Compared to the control profiles, the AUD group exhibited differential protein expression. Few proteins, such as bisphosphoglycerate mutase, were downregulated in AUD versus control and SD, as well as in the MCV-high AUD subgroup. Conversely, endoplasmin and gelsolin were upregulated in AUD relative to control. Cytoskeletal proteins, including spectrin-alpha chain, actin cytoplasmic 2, were overexpressed in the AUD group and MCV-high AUD subgroup. Several proteins, such as 14-3-3 isoforms, alpha-synuclein, translation initiation factors, heat shock proteins, and others, were upregulated in the MCV-high AUD subgroup. Under-expressed proteins in this subgroup include band 3 anion transport protein, bisphosphoglycerate mutase, tropomyosin alpha-3 chain, uroporphyrinogen decarboxylase, and WD repeat-containing protein 1. Our findings highlight the specific changes in protein expression associated with oxidative stress, cytoskeletal alterations, and metabolic dysregulation, specifically in AUD patients with an elevated MCV. Understanding these mechanisms is crucial for developing targeted interventions and identifying biomarkers of alcohol-induced cellular damage. The complex interplay between oxidative stress, membrane composition, and cellular function illustrates how chronic alcohol exposure affects cellular physiology. Full article