Search Results (476)

Background/Objectives: Chronic obstructive pulmonary disease (COPD) is increasingly viewed as a disorder of impaired cellular adaptation to chronic stress, involving oxidative injury, mitochondrial dysfunction, and accelerated cellular senescence. We investigated whether genetic variation in these pathways contributes to disease susceptibility, lung function impairment, and polygenic risk prediction. Methods: Thirty-three single-nucleotide variants were analysed in 747 patients with COPD and 703 controls. Associations with disease susceptibility and lung function parameters were assessed using regression models with correction for multiple testing. Weighted and unweighted polygenic scores were constructed from associated variants and evaluated using receiver operating characteristic and net reclassification improvement analyses. Results: Significant associations were identified in genes involved in antioxidant defence (NFE2L2, HMOX1, GSR), PI3K/AKT/mTOR signalling (PIK3R1, PTEN), mitochondrial function (TOMM40), cellular stress responses (FOXO3A), and long non-coding RNA regulation (MEG3, CDKN2B-AS1). The strongest association was observed for PIK3R1 rs831125 (OR = 2.31, p = 2.53 × 10⁻¹⁰). Variants in NFE2L2, PIK3R1, MEG3, MALAT1, and SIRT3 were additionally associated with pulmonary function parameters. The weighted polygenic score demonstrated good discriminative ability (AUC 68.8%, 95% CI 65.9–71.7%) and substantially improved prediction when combined with age, sex, and smoking exposure (AUC 88.1%, 95% CI 86.3–89.8%; NRI = 0.62, p = 2.21 × 10⁻²⁸). Conclusions: The identified loci converge on interconnected pathways involved in cellular stress adaptation, mitochondrial homeostasis, and senescence, supporting their contribution to chronic obstructive pulmonary disease susceptibility and functional decline. Full article

The potassium-rich mother liquor generated from the sulfuric acid process for lithium extraction from spodumene cannot be directly used for the production of battery-grade lithium salts, resulting in lithium resource loss. To address the issues of slow reaction rate and high seed crystal dosage in the traditional jarosite process for potassium removal, this paper systematically optimizes the type, dosage, and particle size of seed crystals based on the mechanisms of crystal nucleation and growth, ion occupancy competition, and interfacial crystallization-driven behavior. Results show that potassium jarosite seed offers high crystallographic compatibility, ease of preparation, and the best overall performance. Seed particle size must balance specific surface area and dispersibility; either too large or too small is detrimental to uniform crystal growth. Thermodynamic and kinetic analyses confirm that jarosite precipitation is strongly spontaneous and chemically controlled. Under the optimal process conditions (pH = 1.5, n(Fe³⁺)/n(K⁺) = 3.5:1, 1 g of potassium jarosite seed, 95 °C, 1 h), the potassium removal rate reaches (92.60 ± 0.48)%, and the lithium recovery rate is (95.20 ± 0.34)%. Lithium loss mainly arises from precipitate entrainment and insufficient washing; enhanced washing can further improve recovery. This study elucidates seed-mediated crystallization regulation and provides both theoretical guidance and technical reference for efficient potassium removal and high-value lithium recovery from potassium-rich mother liquor. Full article

Background: The fruits of Rosa laxa Retz. (FRL) is a traditional medicinal and edible fruit widely used in Xinjiang for its potential health benefits. Its chemical variations across geographical origins remain poorly understood, as do the molecular mechanisms underlying its anti-hyperlipidemic effects. This study aimed to characterize the chemical profile of FRL extract (FRLE) from different origins, identify its bioactive constituents and metabolites in vivo, and evaluate its efficacy and potential mechanisms against HLP. Methods: UPLC-QTOF-MS was employed for qualitative and quantitative profiling, combined with PCA to differentiate samples from five origins. An HLP mouse model was established to evaluate the pharmacodynamic effects, while acute and sub-chronic toxicity tests assessed safety. Serum pharmacochemistry was used to track absorbed constituents and metabolites. Finally, network pharmacology, molecular docking, and Western blot were integrated to elucidate the underlying mechanisms. Results: A total of 60 compounds were identified in FRLE, with 20 key components quantified via the TOF-MRM mode. PCA indicated that the Yamalike Mountain samples possessed the most diverse chemical profile and the highest response of active markers. Pharmacodynamic results showed that FRLE (extraction yield 24.19%) significantly improved TC, LDL-C, and corrected abnormal HDL-C levels in HLP mice, while H&E staining confirmed the alleviation of hepatic steatosis. Safety evaluations revealed no significant acute or cumulative toxicity at the maximum feasible dose of 16.6 g/kg. In rat plasma, 15 prototypes and 14 metabolites were identified. FRLE acted on the “Lipid and Atherosclerosis” pathway by modulating key targets, including NFE2L2, CYP1A1, NOS3, and MAPK1. Conclusions: Our findings demonstrate that FRLE is a safe and effective candidate for the management of hyperlipidemia. This study establishes a link between the material basis and biological mechanisms of FRL, thereby providing a scientific foundation for its further resource development and clinical application. Full article

Aging is a significant risk factor for cardiovascular diseases. The prevalence of heart failure increases with age, making it a leading cause of morbidity and mortality. We investigated age-associated changes in expression of Nuclear Factor (Erythroid-derived 2)-Like 2 (NFE2L2 or NRF2) in the myocardium of humans, rhesus monkeys, Fischer rats, and C57BL/6 mice. NRF2 is a transcription factor that orchestrates the expression of genes involved in antioxidant and detoxification responses. Analyses of RNA-seq data from the Genotype-Tissue Expression (GTEx) project, which contains left ventricular samples from 294 male donors, revealed a trend of age-associated declines in NRF2 transcripts and several of its downstream genes (SOD1, SOD2, CAT, GCLM, and AKR1B). Age-dependent decreases in NRF2 protein expression were observed in the myocardium of Rhesus monkeys and Fischer rats. To determine whether NRF2 loss contributes to myocardial aging, we evaluated cardiac function of NRF2 knockout mice (KO) at 19 and 24 months of age. At 19 months, the NRF2 KO mice exhibited diastolic dysfunction, characterized by an increased end-diastolic volume (EDV) and end-systolic volume (ESV), accompanied by a reduced ejection fraction (EF) and fractional shortening (FS), indicative of early onset of heart failure. The NRF2 KO mice displayed premature aging phenotypes and had reduced lifespans. Our findings support the trend of NRF2 signaling decline with age, and that loss of NRF2 accelerates the maladaptive cardiac remodeling and functional deterioration associated with aging. Full article

Non-coding RNAs are pivotal regulators of metabolic disease pathogenesis, yet the role of microRNA-27a (miR-27a) in obesity-associated hepatic steatosis remains incompletely characterized. This study examined the functional contribution and molecular mechanism of miR-27a in regulating hepatocyte mitochondrial homeostasis and lipid metabolism. Utilizing in vivo mouse models, including low-fat diet controls, high-fat diet (HFD)-induced obesity, and gain- and loss-of-function approaches, miR-27a was found to be markedly upregulated in the serum and liver of obese mice, correlating with disrupted glucose and lipid homeostasis as well as hepatic steatosis. Mechanistically, miR-27a overexpression recapitulated HFD-induced mitochondrial dysfunction, manifested by decreased mitochondrial biogenesis and elevated reactive oxygen species (ROS) production. Conversely, genetic silencing of miR-27a restored mitochondrial integrity and mitigated lipid accumulation. In vitro experiments using HepG2 cells confirmed that miR-27a directly suppresses nuclear factor erythroid 2-related factor 2 (NFE2L2), and NFE2L2 overexpression counteracted miR-27a-induced mitochondrial damage and steatosis. Collectively, these results demonstrate that miR-27a promotes hepatic steatosis by targeting NFE2L2, leading to mitochondrial impairment and oxidative stress, highlighting miR-27a as a potential biomarker and therapeutic target for obesity-associated liver metabolic disorders. Full article

Tamoxifen remains the standard treatment for estrogen receptor alpha (ER α) positive breast cancer (BC) cases. However, a significant proportion of patients develop chemoresistance, leading to disease recurrence. The Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2), coded by NFE2L2 gene, has emerged as a key player in chemoresistance and tumoral progression across multiple cancer types, including BC. This study aimed to analyze the role of Nrf2 in metastasis-related processes in a tamoxifen-metabolite-resistant BC cell variant (MCF-7^Var-H) and to assess the impact of Nrf2 modulation. We analyzed Nrf2 expression and nuclear localization and observed that both were increased in endocrine-chemoresistant MCF-7^Var-H cells compared with MCF-7 parental cells. Critically, we assessed the effects of Nrf2 on migration, invasion, and metalloproteinase secretion capacity using wound-healing assays, Boyden chamber assays, and zymography, respectively. Our results suggest that Nrf2 actively promotes metastatic behaviors in the resistant variant. To further explore its pharmacological relevance, we designed and synthesized small interfering RNAs (siRNAs) targeting NFE2L2 mRNA in its coding region by heterogeneous-phase chemical synthesis. Transfection with these siRNAs significantly inhibited metastasis-related functions such as migration in MCF-7^Var-H cells. Overall, siRNAs targeting Nrf2 may be promising tools for treating chemoresistant and metastatic breast cancer. Full article

Obesity contributes to an increase in the prevalence of metabolic dysfunction-associated fatty liver disease (MAFLD) and is diagnosed when hepatic steatosis is accompanied by at least one of the following factors: obesity or overweight, diabetes mellitus, or signs of metabolic abnormalities. MAFLD is a term that encompasses a wide range of liver disorders, ranging from simple steatosis to metabolic steatohepatitis, which can progress to cirrhosis and eventually, hepatocellular carcinoma (HCC). Lipotoxicity generated by a high-fat diet causes liver inflammation, therefore, blocking inflammatory pathways is considered a promising strategy to prevent MAFLD progression. Inflammatory responses and oxidative stress are linked to endoplasmic reticulum stress, thereby activating the unfolded protein response (UPR) pathway. Although drugs such as resmetirom and semaglutide have recently been approved for the treatment of MAFLD, there is still a need to identify complementary therapies with different mechanisms of action. In this context, the present study evaluated the hepatoprotective effect of ellagic acid through the modulation of mRNAs of proteins in the UPR-Perk pathway in a murine model fed a high-calorie diet. This study revealed that the high-calorie diet activated the UPR pathway in response to stress, increasing the expression of the Grp78, Eif2ak3, Eif2α, Ddit3, Atf4, and Nfe2l2 genes in the liver and epididymal adipose tissue. Ellagic acid modulated the pathway genes and reduced levels of glucose, total cholesterol, HDL and VLDL, triglycerides, insulin, and glycated hemoglobin, and could therefore be considered a hepatoprotective agent. Full article

Prostate adenocarcinoma (PRAD) poses a significant challenge due to therapy resistance and an immunosuppressive tumor microenvironment (TME). Ferroptosis has emerged as a therapeutic vulnerability, yet its immunomodulatory role in PRAD remains elusive. Here, we employed a multi-omics approach—integrating bulk RNA-seq (498 tumors), single-cell RNA-seq (68,322 cells), and spatial transcriptomics (19,483 spots)—to decode the ferroptosis-immune landscape. We derived a robust 16-gene ferroptosis signature that predicted biochemical recurrence (C-index = 0.76) and validated it in two independent cohorts. Crucially, high-risk tumors exhibited a “cold” immunosuppressive TME enriched in regulatory T cells and M2 macrophages, alongside elevated immune checkpoints (HAVCR2, CTLA4, PDCD1). Single-cell and virtual knockout analyses revealed that cancer epithelial cells evade ferroptosis via NFE2L2-associated antioxidant defenses, which strongly correlates with immune exclusion. Spatial transcriptomics further demonstrated spatially organized vulnerabilities, with ferroptosis-resistant tumor cores and immune-infiltrated invasive margins. To identify therapeutic interventions, we utilized drug response modeling and molecular docking, prioritizing RSL3, Atovaquone (targeting NOX4 (NADPH oxidase 4)/DHODH), and Sorafenib (targeting TrxR1 (thioredoxin reductase 1, encoded by TXNRD1)) as potent agents with potential ferroptosis-modulatory activity. Collectively, our findings demonstrate that NFE2L2-associated ferroptosis resistance shapes immune evasion in PRAD. Targeting ferroptosis regulators provides a compelling therapeutic rationale to remodel the TME and synergize with immune checkpoint blockade. Full article

Early diagnosis of AMI is crucial for improving patient outcomes, yet current clinical tools often lack the requisite sensitivity and specificity for reliable early detection. As neutrophils are the first innate immune responders mobilized following infarction, we employed an integrated multi-omics and machine learning approach to identify neutrophil-driven molecular signatures with diagnostic potential. By analyzing multiple peripheral blood transcriptomic datasets, we conducted differential expression and immune infiltration analyses, followed by machine learning-based feature selection to pinpoint key genes linked to neutrophil activity. Integration of these findings with single-cell transcriptomic data further clarified the neutrophil-specific expression patterns of candidate genes during AMI progression. Using a joint diagnostic model, we identified MCEMP1, NFE2, and AQP9 as the most informative predictors, with MCEMP1 emerging as the primary contributor. Experimental validation in a murine model of myocardial infarction (MI) confirmed rapid upregulation of MCEMP1 after injury, closely mirroring the kinetics of neutrophil infiltration. Collectively, these findings delineate a neutrophil-associated molecular profile of early AMI and highlight MCEMP1 as a promising noninvasive biomarker and a potential therapeutic target for modulating neutrophil-driven myocardial injury. Full article

Background and Objectives: Drug-induced liver injury (DILI) is increasingly associated with the use of herbal medicines. Ephedra sinica (ES) occasionally induces hepatocellular injury, yet therapeutic strategies for herb-induced liver injury are limited. This study investigated the potential mechanisms of a multicomponent pharmacopuncture formulation (VP) in ES-associated hepatotoxicity. Materials and Methods: Bioactive constituents of VP were collected from pharmacological databases and literature. The physicochemical properties were evaluated using SwissADME. Compound–target interactions were identified using the STITCH database and integrated with DILI–related genes retrieved from GeneCards (relevance score ≥ 5.0). Protein–protein interaction network analysis, Gene Ontology enrichment, and KEGG pathway analyses were performed. Results: A total of 22 overlapping targets were identified. A nine-gene module—comprising TNF, IL6, STAT3, CASP3, PINK1, PRKN, NFE2L2, HMOX1, and ABCB11—was associated with key biological processes, including inflammatory signaling, mitochondrial quality control, oxidative stress regulation, and hepatobiliary transport. Conclusions: These findings suggest that VP may modulate multiple biological processes relevant to hepatotoxic stress, including inflammatory signaling, mitochondrial quality control, and bile acid transport. These results provide a plausible mechanistic framework for further investigation, pending experimental validation. Full article

Background: Esophageal squamous cell carcinoma (ESCC) remains a highly lethal malignancy with limited therapeutic options, in part due to frequent activation of nuclear factor erythroid 2-related factor 2 (NFE2L2 or NRF2). Gain-of-function mutations in NRF2 disrupt its negative regulation by Kelch-like ECH-associated protein 1 (KEAP1), resulting in sustained NRF2 signaling that promotes tumor growth and resistance to chemotherapy and radiation. We previously identified the FDA-approved drug pyrimethamine (PYR) as an NRF2 inhibitor and demonstrated that inhibition of dihydrofolate reductase (DHFR) represents the primary mechanism underlying its NRF2-suppressive activity, supporting its advancement into a Phase I window-of-opportunity clinical trial (NCT 05678348). Meanwhile, in NRF2^W24C-KYSE70 and NRF2^D77V-KYSE180 cells, PYR promoted NRF2^Mut ubiquitination and proteasomal degradation and shortened its half-life. This study aims to explore additional modes of action by which PYR inhibits NRF2. Methods: Cell cycle analysis was performed by flow cytometry. Cell proliferation, apoptosis and chemosensitivity were assessed by Live-Cell Analysis System, while radiosensitivity was evaluated using X-ray irradiation and the CellTiter-Glo assay. Molecular interactions between NRF2 and KEAP1 were examined through Co-IP and PLA, and the direct binding of PYR to KEAP1 was quantified using ITC and SPR. Molecular docking and dynamic simulations were employed to predict potential PYR-binding pockets within the Kelch domain. Results: Using genetically defined isogenic ESCC cell models, we show that activation of mutant NRF2 (NRF2^Mut) or wild-type NRF2 (NRF2^WT) produces distinct, context-dependent effects on squamous differentiation, proliferation, and therapeutic response. We further demonstrate that PYR restores sensitivity to chemotherapy and ionizing radiation in NRF2^Mut ESCC cells. Mechanistically, short-term PYR treatment promotes KEAP1-dependent proteasome-mediated degradation of NRF2^W24C. Biochemical and biophysical assays indicate that PYR enhances the interaction between KEAP1 and NRF2^W24C in a manner associated with KEAP1-dependent proteasomal degradation. Computational modeling further suggests that PYR may engage a pocket within the Kelch domain to facilitate the NRF2^W24C-KEAP1 interaction. Conclusions: These findings show that PYR functionally restores KEAP1-mediated NRF2 degradation of select NRF2^Mut through a glue-like effect and overcomes therapy resistance in ESCC. Although the proposed glue-like mechanism remains hypothetical, this work supports further investigation into the NRF2–KEAP1 interaction and may inform the development of KEAP1-targeted strategies for NRF2^Mut cancers, including ESCC. Full article

The integration of rapidly renewable biomass into insect production systems has been proposed as a strategy to improve resource-use efficiency in insect production. This study evaluated the graded inclusion levels of dried watermeal (Wolffia globosa) in diets of two-spotted crickets (Gryllus bimaculatus) and assessed voluntary nutrient regulation under free-choice feeding. Four fixed-inclusion diets (0%, 25%, 35%, and 45% watermeal) and one self-selection treatment were tested over 28 days. Growth performance, feed conversion ratio (FCR), survival rate (Surv), production index (PI), and whole-body composition were determined. Repeated-measures analysis using linear mixed-effects models indicated that treatment, week, and their interaction were statistically significant (p ≤ 0.024). However, partial R² analysis showed that the independent contributions of treatment and week were negligible, whereas the treatment × week interaction explained measurable variance, indicating that dietary effects were primarily expressed through time-dependent responses. Segmented regression identified a breakpoint at 35% watermeal inclusion (95% CI: 24.93–45.07), indicating that PI was the highest within a moderate supplementation range under the present fixed-diet conditions rather than at a precise single optimum. Inclusion levels beyond this threshold reduced performance. Under free-choice conditions, crickets progressively increased watermeal intake with age and maintained stable nitrogen-free extract (NFE):crude protein (CP) and gross energy (GE):CP intake ratios, selecting an average of 25–35% watermeal over the experimental period. This supplementation range improved feed efficiency and protein deposition while limiting lipid accumulation, suggesting improved energy–protein balance and nutrient partitioning. The self-selection result is interpreted as evidence of behavioral intake regulation under choice conditions and not as direct validation of the segmented-regression breakpoint. Collectively, these findings provide complementary statistical and behavioral evidence supporting a biologically relevant moderate inclusion range (approximately 30–35%) of dried watermeal. Full article

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation and oxidative stress, increasingly implicated in cancer biology. However, its molecular regulation across breast cancer subtypes and its potential systemic manifestations remain incompletely understood. The aim of this study was to identify ferroptosis-associated molecular alterations that are largely shared across subtypes and to evaluate their systemic reflection following localized tissue injury. Tumor and matched normal breast tissues representing major molecular subtypes were analyzed. Global mRNA and miRNA expression profiling was performed using microarrays, followed by validation of selected genes using quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). Functional enrichment and protein–protein interaction analyses were conducted to characterize associated pathways. In addition, systemic responses were assessed in patients undergoing fibroadenoma cryoablation through longitudinal blood sampling. Six ferroptosis-related genes (SLC7A11, GPX4, FTH1, NQO1, NFE2L2, SQSTM1) demonstrated consistent upregulation across all breast cancer subtypes, with higher expression observed in more aggressive tumors. These genes are functionally linked to antioxidant defense, iron metabolism, and oxidative stress regulation, and their coordinated expression pattern is consistent with activation of NRF2-dependent cytoprotective pathways. Downregulation of selected miRNAs may contribute to this expression profile but likely represents a secondary regulatory mechanism. Survival analysis revealed heterogeneous and subtype-dependent associations, with limited and gene-specific prognostic relevance. Cryoablation induced transient increases in circulating levels of the analyzed proteins, reflecting systemic responses to localized tissue injury. In conclusion, breast cancer is characterized by a largely shared ferroptosis-associated molecular signature across subtypes; however, its clinical impact appears to be variable and context-dependent. Systemic detection of related molecular signals suggests potential utility as indicators of tissue stress responses, although their role as specific biomarkers of ferroptosis requires further validation. Full article

MYO16 has previously been identified as a candidate gene in studies of meat productivity in sheep, but its complete sequence and the potential impact of polymorphisms on the functional properties of the gene in sheep remain understudied. The aim of this study was to analyze genetic variation in the MYO16 gene region in sheep and to identify polymorphisms that, according to bioinformatic prediction, are capable of changing the amino acid sequence of the protein or are associated with allele-specific differences in transcription factor binding motifs potentially significant for gene regulation or protein structure. Whole-genome sequencing was performed for genomic DNA from Manych Merino rams (n = 30) on an Illumina NovaSeq 6000 platform. Variants within the MYO16 region were extracted and annotated. For each variant, ±30 bp reference and alternative sequences were scanned with FIMO using the JASPAR 2020 Vertebrates PWMs to detect allele-specific gain or loss of significant motif hits. TFLink (Mus musculus) was used to retain only TFs with MYO16 listed as a target. In the MYO16 gene region, 10,318 variants were detected. The coding region contained 54 SNPs, including 15 missense variants. In silico TFBS scanning identified 23 variants showing allele-specific gain or loss of significant motif hits, involving motifs for EBF1, CTCF, NRF1, SPI1, NFE2L2, JUN, and GFI1. We examined polymorphism in the ovine MYO16 gene region and identified candidate variants to be tested for association with productivity traits in future genotype–phenotype studies. Full article

Aims/hypothesis: Hypoxia and oxidative stress have been implicated in both metabolic syndrome and COVID-19-associated dysglycaemia, yet it remains unclear whether shared or distinct mechanisms underlie β-cell dysfunction across these conditions. We investigated hypoxia- and oxidative stress-related pathways in relation to β-cell function during acute COVID-19, post-COVID metabolic states, and COVID-negative metabolic syndrome. Methods: In this prospective observational study, 100 adults were stratified into three groups: active COVID-19 (n = 32), post-COVID with newly diagnosed carbohydrate metabolism disorders (n = 35), and COVID-negative individuals with metabolic syndrome (n = 33). Circulating markers of hypoxia (HIF-1α), oxidative stress (8-epi-prostaglandin F2α), and antioxidant response (NFE2L2) were measured alongside α- and β-cell functional markers, including C-peptide, proinsulin, glucagon, and derived indices of β-cell processing and secretory efficiency. Non-parametric statistical analyses were applied. Results: Circulating HIF-1α levels differed significantly across study groups (p < 0.001), with the highest concentrations observed during active COVID-19, intermediate levels in COVID-negative individuals with metabolic syndrome, and the lowest levels in the post-COVID group. In contrast, oxidative stress, assessed by 8-epi-prostaglandin F2α, differed significantly across groups (p < 0.001), increasing from acute COVID-19 to post-COVID and reaching the highest levels in metabolic syndrome; however, the difference between the post-COVID and metabolic syndrome groups did not remain significant after correction for multiple testing. NFE2L2 concentrations did not differ significantly between groups. Marked β-cell dysfunction was observed predominantly in COVID-negative individuals with metabolic syndrome, characterized by reduced C-peptide levels, elevated glucagon concentrations, increased proinsulin/C-peptide ratios, and reduced C-peptide/glucose ratios (all overall group comparisons p < 0.001). In contrast, β-cell secretory indices were relatively preserved during acute and post-COVID states despite pronounced alterations in hypoxia and oxidative stress markers. Conclusions/interpretation: Hypoxia- and oxidative stress-related pathways exhibit distinct, context-dependent patterns across acute COVID-19, post-COVID dysglycaemia, and metabolic syndrome. Acute COVID-19 is characterized by pronounced hypoxia signalling with relative preservation of β-cell function, whereas chronic metabolic syndrome is associated with sustained oxidative stress and impaired β-cell processing and secretory efficiency. These findings suggest that diabetes-related β-cell dysfunction is more closely associated with chronic oxidative and metabolic stress than with transient infection-related hypoxia during SARS-CoV-2 infection. Full article