Search Results (1,296)

Zearalenone (ZEA) is a common contaminant in crops and animal feed. However, research on the effects of ZEA on animal mammary tissue is relatively limited. Sulforaphane (SFN) is a naturally active compound mainly derived from cruciferous vegetables (such as broccoli), with significant antioxidant and cytoprotective effects. The purpose of this study is the effect of SFN on ZEA-induced toxicity in bovine mammary epithelial cells (MAC-T). By treating MAC-T cells with different concentrations of ZEA and SFN for 24 h, the results showed that different concentrations of ZEA (10, 20, 40, 60, 80, or 100 μM) could inhibit MAC-T cell viability. Treatment with SFN at concentrations of 1, 2.5, and 5 μM had no significant effect on cell viability. The results of combined treatment with 10 μM ZEA and 1, 2.5, or 5 μM SFN showed that SFN could significantly reverse the decrease in cell viability caused by ZEA; reduce the increase in lactate dehydrogenase (LDH) release, reactive oxygen species (ROS), and malondialdehyde (MDA) content induced by ZEA; and increase the levels of glutathione (GSH), superoxide dismutase (SOD), and mitochondrial membrane potential that were decreased by ZEA. SFN can significantly inhibit the upregulation of interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and interleukin 1 beta (IL-1β) induced by ZEA exposure and markedly reverse the increase in cell apoptosis rate caused by ZEA. Compared with the control group, the expression of genes nuclear factor erythroid 2–related factor 2 (Nrf2), heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase modifier subunit (GCLM), and glutathione peroxidase 1 (GPX1) was significantly reduced in the ZEA group, while the addition of SFN effectively increased the expression levels of these genes. Corresponding protein detection results were consistent with the trends in gene expression. This study demonstrated that SFN alleviates ZEA-induced damage to MAC-T cells by activating the Nrf2 pathway, providing a theoretical basis for the subsequent application of SFN in dairy farming to prevent and control breast health risks related to mycotoxins. Full article

Citrus flavonoid intake is associated with beneficial effects on endothelial function. Our previous randomized control trial demonstrated that the concentration of Hesperetin-7-O-glucuronide (H7G) was positively correlated with the improvement in endothelial function in overweight and obese participants following blood orange juice consumption. To explore the underlying mechanism by which H7G improves endothelial function, we investigated the regulation of H7G on endothelial function in a permanent human endothelial cell line (EA. hy926 cells) under normal and oxidative conditions treated with high-oxidation low-density lipoprotein. The results indicated that H7G improved the expression of nitric oxide synthase 3 (NOS3), heme oxygenase 1 (HMOX1) ad glutamate cysteine ligase catalytic (GCLC), and inhibited the expression of endothelin-1 (EDN1), through the upregulation of miR-660-5p and inhibition of miR-21-5p. In summary, H7G improves endothelial cell function via the upregulation of miR-660-5p and the inhibition of miR-21-5p. Full article

Heme metabolism in the liver has traditionally been described as a linear pathway that supports oxygen utilization, redox balance, and detoxification. Here, we synthesize recent evidence and propose a framework in which heme functions as a system-level regulator, the “queen” of metabolism, whereas its upstream intermediate protoporphyrin IX (PPIX) represents a chemically reactive “dark twin” that emerges when metabolic flux fails to resolve. In this view, metabolic state is defined not only by end products but also by the behavior of pathway intermediates. This system is spatially organized. Hepatocytes dominate heme synthesis and utilization. In contrast, liver stromal compartments, particularly Kupffer cells, play a central role in heme degradation through heme oxygenase-1 (HMOX1), linking heme turnover to iron recycling and stress adaptation. The metabolic state of the liver therefore reflects not only pathway flux but also the degree of coupling between these cellular compartments. We propose a state model of hepatic heme metabolism. In the resolution state, most evident during inflammation, coordinated hepatocyte–macrophage activity maintains flux and limits intermediate accumulation. In contrast, the expansion state, exemplified in cancer, is defined by impaired flux completion, leading to PPIX accumulation, metabolic heterogeneity, and oxidative stress. This framework reframes liver disease through intermediate behavior rather than pathway presence: porphyrias reflect direct overload, metabolic liver diseases partial expansion, and hepatocellular carcinoma a fully developed expansion state. By focusing on the “intermediate space,” this model links biochemistry, spatial organization, and disease pathogenesis, while suggesting new opportunities for diagnosis and therapy based on metabolic state. Full article

Migraines are a common neurological disorder that significantly reduces quality of life. The sensitization of trigeminal afferents is a key factor in the development of the pain syndrome associated with migraine. Carbon monoxide (CO) is produced endogenously by heme oxygenase (HO), widely expressed in structures involved in pain processing. In our study, the role of CO in an acute and chronic nitroglycerin (NTG)-induced rat migraine model was investigated using behavioral, electrophysiological, biochemical and histological methods. The repeated administration of a CO donor (CORM-2) or an HO-1 inducer (CoPP) decreased mechanical hypersensitivity and photophobia of rats in the NTG-induced migraine model. Additionally, CORM-2 and CoPP prevented an increase in trigeminal afferent excitability, which was evaluated by the frequency of action potentials in response to KCl application. Preliminary CORM-2 or CoPP injections promoted mast cell stability in the meninges and prevented NTG-induced CGRP elevation in blood plasma. Our results suggest that exogenously or endogenously produced CO has a protective potential in preventing inflammation and the sensitization of peripheral trigeminal afferents, the activity of which underlies the occurrence of pain in migraine. This could contribute to the development of new approaches for migraine prevention. Full article

Ultraviolet (UV) radiation is a main environmental factor responsible for skin damage, leading to oxidative stress, inflammation, and impairment of the skin barrier function. Furthermore, many components in sunscreen may accumulate in aquatic systems, causing environmental pollution. Therefore, the identification of novel natural bioactives that counteract these effects and can be useful as effective adjuvants in sunscreen formulations is of particular interest. Morin (1), a natural flavonoid, represents an attractive scaffold for modifications to enhance its biological activity. Herein, we aimed to investigate the effects of combining the flavonoid 1 and its derivative, morin semicarbazone (2), with the carotenoid fucoxanthin (FX) on UVB-exposed HaCaT keratinocytes. All compounds exhibited higher radical scavenging activity compared to Trolox. In this cell model, the phenolic–carotenoid combinations provided greater photoprotection than individual compounds, significantly enhancing cell viability and reducing necrosis, FX-2 emerged as the most potent combination, as evidenced by a marked reduction in reactive oxygen species (ROS) and malondialdehyde (MDA) levels, likely mediated through the activation of the nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 (Nrf2/HO-1) signaling pathway. Furthermore, the tested treatments exerted enhanced anti-inflammatory effects by significantly reducing interleukin-6 (IL-6), cyclooxygenase 2 (COX-2), and matrix metalloproteinase-9 (MMP-9) mediators, with FX-2 being the most active combination. In conclusion, our findings highlight the protective effects of the combinations of these phenolics with the carotenoid FX against UVB radiation and support their potential application as natural active ingredients in sunscreen formulations. Full article

Neurological disorders, particularly Parkinson’s disease (PD), represent a pressing global health challenge with limited disease-modifying therapies. While Achyranthes bidentata exhibits neuroprotective potential, its bioactive constituents against PD remain poorly characterized. This study integrated phytochemical isolation and in silico target prediction to identify eight compounds from A. bidentata, followed by neuroprotective evaluation in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-challenged SH-SY5Y cells. Among these, 25R-inokosterone significantly downregulated Monoamine oxidase B (MAOB) and Glycogen synthase kinase-3β (GSK-3β) expression and showed superior neuroprotection compared to β-ecdysterone. It markedly restored mitochondrial membrane potential, suppressed Bcl-2-associated X protein (Bax)/Cysteinyl aspartate specific proteinase 3 (caspase-3) apoptotic signaling, and alleviated oxidative stress. Mechanistically, Nuclear factor erythroid 2-related factor 2 (Nrf2)/Heme oxygenase 1 (HO-1) activation was the dominant and indispensable mechanism for neuroprotection, while MAOB/GSK-3β expression downregulation served as an upstream synergistic regulatory event, as evidenced by the abolition of neuroprotection following Nrf2 knockdown in SH-SY5Y cells. These findings identify 25R-inokosterone as a promising multi-target natural lead for PD, which exerts antioxidant and anti-apoptotic effects predominantly by activating Nrf2, accompanied by the upstream modulation of MAOB/GSK-3β expression. Full article

Dry eye disease (DED) is a common ocular surface disorder characterized by instability of the tear film, inflammatory responses, and epithelial damage, and therapeutic interventions directed at these fundamental pathogenetic processes are still insufficient. This research aimed to evaluate the medicinal efficacy of glycyrrhizic acid (GA) and to unravel the underlying molecular pathways through which it exerts its protective role in DED. A benzalkonium chloride-induced mouse model and a hyperosmolarity-induced human corneal epithelial cell model were established. Corneal epithelial injury, tear secretion, and goblet cell density were evaluated in vivo, while cellular responses and related signaling pathways were examined using RT-qPCR, Western blotting, flow cytometry, and immunofluorescence. GA treatment alleviated corneal epithelial damage, increased tear secretion, and improved goblet cell density in mice. In vitro, GA reduced inflammatory responses, as evidenced by decreased tumor necrosis factor-α (TNF-α) expression, and helped preserve epithelial barrier integrity, accompanied by reduced matrix metalloprotease 9 (MMP9) levels. Further analysis suggested that GA suppressed pyroptosis through regulation of the high mobility group box 1 (HMGB1)/lysosomal membrane permeabilization (LMP)/cathepsin B (CTSB) pathway and attenuated oxidative stress via activation of the nuclear factor erythroid 2–related factor 2 (Nrf2)/heme oxygenase-1 (HO-1)/NAD (P)H:quinone oxidoreductase 1 (NQO1) axis. In addition, GA improved mitochondrial function, as indicated by decreased reactive oxygen species levels, restored membrane potential, and enhanced adenosine triphosphate (ATP) production. Taken together, these findings indicate that GA may alleviate hyperosmolarity-induced DED by modulating inflammation, oxidative stress, mitochondrial dysfunction, and epithelial barrier damage, underscoring its viability as a remedial candidate. Full article

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening vascular disease lacking therapies that target underlying cell death pathways. Ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, has emerged as a key mechanism in vascular remodeling. We investigated whether exogenous ketosis induced by ketone ester (KE) supplementation can suppress ferroptosis and prevent TAAD. TAAD was induced in C57BL/6 mice using β-aminopropionitrile (BAPN). A subset of these mice received KE [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate, 20 g/L] in their drinking water starting on day 15 of the BAPN treatment. Human aortic smooth muscle cells (HASMCs) were treated with the GPX4 inhibitor Ras-Selective Lethal 3 (RSL3) and β-hydroxybutyrate (β-OHB) to investigate ferroptotic markers, lipid peroxidation, and labile iron levels. KE supplementation significantly reduced TAAD incidence (69% → 43%) and improved survival rate (52% → 73%), while preserving aortic structure and reducing elastic fiber fragmentation. Transcriptomic analyses of human TAAD datasets (GSE153434 and GSE52093) and single-cell RNA sequencing data (GSE155468) revealed ferroptosis signatures characterized by decreased GPX4 and increased expression of iron metabolism genes. Mechanistically, KE suppressed BAPN-induced iron accumulation and lipid peroxidation in vivo. In HASMCs, β-OHB inhibited ferroptosis induced by GPX4 inhibition, decreasing lipid peroxidation and labile iron levels. KE restored GPX4 and SLC7A11 expression while suppressing HO-1 in vivo, with effects dependent on Nrf2 signaling in vitro. In summary, ketone ester supplementation protects against TAAD by inhibiting VSMC ferroptosis via GPX4 induction and HO-1 suppression, highlighting a potential therapeutic strategy for aortic disease. Full article

Recently, Quzhou Aurantii Fructus Extract (QAFE) was reported to exert anti-inflammatory effects on different types of respiratory diseases; however, it is yet to be determined whether it is effective in patients with idiopathic pulmonary fibrosis (IPF). The purpose of this study is to explore the capacity of QAFE to fight fibrotic disease, in particular how it works in relation to the regulation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway. QAFE was made with Quzhou Fructus Aurantii (QAF), and the content of four flavonoids in the samples prepared was analyzed by high-performance liquid chromatography (HPLC). The therapeutic effect of QAFE was experimented by establishing IPF models in mice and in cells. Identification of the mechanism of QAFE in IPF through knockout or knockdown of the Nrf2 gene. The experiments suggest that QAFE has the potential to prevent IPF-induced inflammation, collagen deposition, oxidative stress, and apoptosis of cells. Silencing Nrf2 by knockdown or knockout is enough to prevent the capacity of QAFE to inhibit the process of inflammation, oxidative stress, and collagen deposition to cause more serious lung injury and HO-1 expression downregulation. QAFE is a potential new antifibrotic drug in IPF with an effect on the Nrf2/HO-1 pathway that reduces inflammation and oxidative stress. Full article

Alcohol-related liver disease (ALD) and ALD-related mortality are associated with hemolysis, increased erythrophagocytosis, and disturbed iron homeostasis. While macrophage-mediated erythrophagocytosis is well established, we investigated the contribution of liver sinusoidal endothelial cells (LSECs) to handling oxidatively damaged or ethanol-primed red blood cells (RBCs) in ALD. Live-cell imaging demonstrated that damaged RBCs were rapidly taken up by SK-HEP1 cells, an endothelial cell line with LSEC-like characteristics, and RBC uptake was associated with induction of heme oxygenase-1 (HO-1) and activation of its upstream regulator Nrf2. siRNA-mediated knockdown of the scavenger receptor Stabilin-1 attenuated RBC-induced HO-1 expression, supporting a role for Stabilin-1 in efferocytic signaling. Exposure of RBCs to ethanol concentrations as low as 25 mM induced phosphatidylserine externalization and rendered erythrocytes efferocytosis-competent. Lysed RBCs and free hemin elicited comparable oxidative stress responses. In murine models of hemolysis and chronic ethanol feeding, hemoglobin-derived signals were detected within sinusoidal structures showing a diffuse CD206-positive distribution pattern consistent with the sinusoidal scavenger compartment. Similar signals were observed in sinusoidal endothelial regions in human heavy drinkers with clinical signs of hemolysis. Together, these data suggest that LSECs may represent an additional component of RBC clearance in ALD, alongside macrophages and hepatocytes, with implications for hepatic iron handling. Full article

T-2 toxin, a mycotoxin produced by the genus Fusarium, is widely prevalent in agricultural products and livestock feed, posing substantial health risks to livestock and humans. This toxin induces oxidative stress in testicular Sertoli cells, disrupts testicular architecture, and compromises spermatogenesis. Despite its widespread presence in contaminated feeds, effective therapeutic strategies to counteract T-2 toxin-induced reproductive toxicity in Sertoli cells remain elusive. This study evaluated the protective efficacy and molecular mechanisms of proanthocyanidins (PCs), a phytochemical with antioxidant properties, against T-2 toxin-induced damage in yak (Bos grunniens) Sertoli cells. The findings revealed that T-2 toxin markedly reduced the viability of yak Sertoli cells and stimulated the production of reactive oxygen species (ROS). Treatment with 10 μg/mL PCs significantly enhanced cell viability, decreased apoptosis, and preserved cellular functions. Furthermore, PCs reduced ROS levels in yak Sertoli cells exposed to T-2 toxin and improved antioxidant capacity by upregulating the nuclear factor erythroid derived 2-like (NRF2)/heme oxygenase-1 (HO-1) signaling pathway. Additionally, PCs inhibited mitochondria-mediated apoptosis, diminished the occurrence of malformed mitochondria, and enhanced the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) signaling pathway associated with mitochondrial biogenesis in yak Sertoli cells exposed to T-2 toxin. This study provides novel insights into the prevention and treatment of T-2 toxin-induced reproductive damage in yaks and underscores the potential application of PCs in this context. Full article

Dysregulated iron handling—including catalytic iron and ferroptosis, hepcidin–ferroportin signaling, ferritin dynamics, and neutrophil gelatinase-associated lipocalin (NGAL)-mediated siderophore transport—has been implicated in the initiation and propagation of acute kidney injury (AKI) across ischemia–reperfusion, sepsis, and nephrotoxic contexts. To provide a SANRA-aligned narrative synthesis of mechanistic and translational evidence on iron biology in AKI, clarifying biomarker readiness and therapeutic prospects while explicitly separating preclinical from human findings. PubMed, Scopus, and Web of Science (1 January 2000 to 30 September 2025), plus appraised grey literature (guidelines/registries) using predefined criteria (authority, update recency, and methodological transparency). Narrative review with comprehensive database searches, single-reviewer screening/extraction (acknowledged as a limitation), and qualitative synthesis. Evidence is organized by pathway (catalytic iron/ferroptosis, transferrin (Tf)/transferrin receptor (/TfR), ferritin/ferritin heavy chain (FtH), hepcidin–ferroportin and NGAL) and translational domain (biomarkers and therapeutics). Statements are tagged as [Preclinical] or [Human]. [Preclinical] Robust signals support roles for catalytic iron and ferroptosis, protection by iron chelation, hepcidin modulation, heme oxygenase 1 (HO-1)/FtH induction, and apotransferrin/NGAL-based strategies. [Human] Biomarkers such as NGAL show clinical utility for kidney injury detection, whereas catalytic iron assays (labile plasma iron [LPI]/bleomycin-detectable iron [BDI]) remain investigational with limited standardization. Observational links between iron-regulatory pathways and AKI risk exist, but interventional trials are sparse; dose, timing, and safety of iron-targeted strategies in defined AKI settings remain to be established. Iron-handling pathways are compelling targets for AKI prevention/mitigation, yet high-quality human trials are limited. Priorities include standardized catalytic-iron assays, biomarker-guided enrichment, and pragmatic trials of tractable interventions (e.g., peri-contrast or cardiopulmonary bypass settings). Until such evidence accumulates, recommendations beyond standard care should be avoided. Full article

Bilirubin, historically recognized solely as a waste product of heme catabolism, has recently gained attention for its potential protective role in the cardiovascular system. Experimental and clinical studies suggest that bilirubin exhibits potent antioxidant, anti-inflammatory, anti-apoptotic, and cytoprotective properties that may protect the heart against oxidative stress, ischemia–reperfusion injury, and the progression of cardiovascular diseases, such as heart failure. As an endogenous hormone, bilirubin activates peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor that controls energy balance and lipid metabolism. Moderately elevated circulating bilirubin levels have been associated with a reduced risk of coronary artery disease, heart failure, and myocardial infarction; however, the mechanisms underlying bilirubin’s protective effects remain incompletely understood. Conversely, the gut microbiota’s metabolism of bilirubin to urobilin is detrimental, given urobilin’s association with cardiometabolic dysfunction. The therapeutic potential of bilirubin in the management of cardiovascular disease is becoming increasingly apparent, supported by preclinical research and emerging technologies that enhance bilirubin delivery via nanoparticles and methods to elevate plasma bilirubin levels. Collectively, these scientific advancements position bilirubin as a promising, biologically plausible endogenous therapeutic for the prevention and treatment of heart disease. Full article

Chronic Obstructive Pulmonary Disease (COPD) is characterized by persistent inflammation and structural alterations in the lung triggered mainly by oxidative stress. Colonization by the opportunistic fungus Pneumocystis has been associated with worse clinical outcomes in COPD, yet its role in airway remodeling remains unclear. To this end, an elastase-induced COPD model was established, followed by colonization with Pneumocystis. Lung tissue was analyzed histologically and molecularly to assess epithelial thickness, alveolar morphometric parameters (mean linear intercept [MLI], D₀, D₁, D₂), inflammation, collagen deposition, and the expression of remodeling and oxidative stress markers. Emphysematous damage parameters MLI, D₀, D₁, and D₂ were markedly elevated in co-exposed animals, indicating enhanced alveolar enlargement. Animals with COPD and Pneumocystis colonization showed a significant increase in airway inflammation compared with control, COPD, and Pneumocystis groups. Airway epithelial thickness, mucus metaplasia, and collagen deposition exhibited a summative increase in the COPD/Pneumocystis group. Redox-responsive markers, such as superoxide dismutase (SOD) and catalase, were upregulated. Moreover, protein and mRNA levels of nuclear factor erythroid 2–related factor 2 (Nrf2) and its downstream gene heme oxygenase-1 (Hmox1) were significantly increased, with the strongest activation observed in co-exposed animals. Integrative correlation analysis showed that Pneumocystis burden positively correlated with lung damage, inflammation, and epithelial remodeling. These structural alterations were accompanied by coordinated activation of the antioxidant pathway Nrf2. Taken together, Pneumocystis colonization is associated with enhanced pulmonary remodeling and modulation of antioxidant signaling in experimental COPD, promoting structural and molecular changes that may contribute to disease progression. These findings suggest that Pneumocystis acts as an amplifying factor in COPD-associated lung damage. Full article

Basal blood pressure (BP) is partly determined by systemic vascular resistance, which is modulated by vasoactive pathways, including gaseous messengers. Carbon monoxide (CO), continuously generated by the constitutive enzyme heme oxygenase-2 (HO-2) encoded by HMOX2, promotes vascular smooth muscle relaxation and may contribute to interindividual variability in resting BP. The functional single-nucleotide polymorphism rs4786504_T>C has been associated with higher HMOX2 expression in C-allele carriers, providing a plausible biological link between genetic variation in the HO-2/CO pathway and vascular redox signaling. We investigated this association in forty young, healthy, normotensive adults studied under controlled laboratory conditions during a 4-day sleep deprivation protocol, with repeated standardized daytime BP measurements (478 observations). Linear mixed-effects models were adjusted for major physiological and behavioral covariates. T-allele carriers (C/T + T/T) exhibited higher diastolic BP (β = +6.08 mmHg, 95%CI [1.32–10.84], p = 0.017) and mean arterial pressure (β = +5.28 mmHg, 95%CI [0.28–10.29], p = 0.046) than C/C homozygotes, with no effect on systolic BP or heart rate. The association remained consistent across sensitivity and additive genetic models. This hypothesis-generating study provides preliminary evidence in humans, albeit limited by sample size, of a link between a functional HMOX2 variant and resting BP, consistent with a possible contribution of constitutive HO-2 activity to BP regulation. Full article