Search Results (589)

Cardiovascular disease (CVD) and dementia may share common pathogenic factors such as atherosclerosis and hyperlipoproteinemia. Dyslipidemia-induced oxidative stress contributes to dementia comorbidity in CVD. Abelmoschus esculentus (AE, okra) potentiates in alleviating hyperlipidemia and diabetes-related cognitive impairment. This study evaluated the effects of AE in hyperlipidemic ApoE^−/− mice treated with streptozotocin (50 mg/kg) and fed a high-fat diet (17% lard oil, 1.2% cholesterol). AE fractions F1 or F2 (0.65 mg/kg) were administered for 8 weeks. AE significantly reduced serum LDL-C, HDL-C, triglycerides, and glucose, improved cognitive and memory function, and protected hippocampal neurons. AE also lowered oxidative stress markers (8-hydroxy-2′-deoxyguanosine, 8-OHdG) and modulated neuronal nuclei (NeuN) and doublecortin (DCX) expression. In vitro, AE promoted neurite outgrowth and neuronal differentiation in retinoic acid (RA)-differentiated human SH-SY5Y cells under metabolic stress (glucose and palmitate), alongside the upregulation of heme oxygenase-1 (HO-1), Nuclear factor-erythroid 2-related factor 2 (Nrf2), and brain-derived neurotrophic factor (BDNF). These findings suggest AE may counter cognitive decline via oxidative stress regulation and the enhancement of neuronal differentiation. Full article

Large-conductance, voltage- and calcium-activated potassium (BK) channels are crucial regulators of cellular excitability, influenced by various signaling molecules, including heme. The BK channel contains a heme-sensitive motif located at the sequence ⁶¹²CKACH⁶¹⁶, which is a conserved heme regulatory motif (HRM) found in the cytochrome c protein family. This motif is situated within a linker region of approximately 120 residues that connect the RCK1 and RCK2 domains, and it also includes terminal α-helices similar to those found in cytochrome c family proteins. However, much of this region has yet to be structurally defined. We conducted a sequence alignment of the BK linker region with mitochondrial cytochrome c and cytochrome c domains from various hemoproteins to better understand this functionally significant region. In addition to the HRM motif, we discovered that important structural and functional elements of cytochrome c proteins are conserved in the BK RCK1-RCK2 linker. Firstly, the part of the BK region that is resolved in available atomic structures shows similarities in secondary structural elements with cytochrome c domain proteins. Secondly, the Met80 residue in cytochrome c domains, which acts as the second axial ligand to the heme iron, aligns with the BK channel. Beyond its role in electron shuttling, cytochrome c domains exhibit various catalytic properties, including peroxidase activity—specifically, the oxidation of suitable substrates using peroxides. Our findings reveal that the linker region endows human BK channels with peroxidase activity, showing an apparent H₂O₂ affinity approximately 40-fold greater than that of mitochondrial cytochrome c under baseline conditions. This peroxidase activity was reduced when substitutions were made at ⁶¹²CKACH⁶¹⁶ and other relevant sites. These results indicate that the BK channel possesses a novel module similar to the cytochrome c domains of hemoproteins, which may give rise to unique physiological functions for these widespread ion channels. Full article

The regulation of oxidative stress is an effective strategy for treating cancers. Therapeutic strategies for modulating an undesirable redox balance against cancers have included the enhancement of oxidative components, reducing the action of antioxidant systems, and the combined application of radiation and redox-modulating drugs. A precise understanding of redox regulation is required to treat different kinds of cancer. This review focuses on the redox regulation and oxidative stress defense systems of lung cancers. Thus, we highlighted several enzymatic antioxidant components, such as superoxide dismutase, catalase, heme oxygenase-1, peroxiredoxin, glutaredoxin, thioredoxin, thioredoxin reductase, glutathione peroxidase, and antioxidant components, including glutathione, nuclear factor erythroid 2–related factor 2, 8-oxo-7,8-dihydro-2′-deoxyguanosine, and mitochondrial citrate carrier SLC25A1, based on PubMed and Scopus-indexed literature. Understanding the oxidative stress defense system in lung cancer would be beneficial for developing and expanding therapeutic strategies, such as drug development, drug design, and advanced delivery platforms. Full article

: Negative energy balance (NEB) in dairy cows induces excessive lipolysis, leading to elevated levels of β-hydroxybutyric acid (BHBA), which, when accumulated, can cause liver damage. Rutin (RT), a natural flavonoid with antioxidant and anti-inflammatory properties, has demonstrated potential hepatoprotective effects; however, its ability to mitigate BHBA-induced hepatocellular injury in calves remains unclear. This study first assessed the impact of various BHBA concentrations on oxidative stress in calf hepatocytes, then explored the protective effects and underlying mechanisms of RT, and finally employed untargeted metabolomics to further elucidate RT’s mode of action. The results showed that exposure to 1.2 mM BHBA significantly increased malondialdehyde (MDA), nitric oxide (NO) contents, and reactive oxygen species (ROS) levels, while markedly decreasing glutathione (GSH) content and catalase (CAT) activity compared with the blank control. Notably, pretreatment with 100 μg/mL RT resulted in the greatest increase in GSH contents (180%) compared to BHBA treatment alone, while 150 μg/mL RT led to the most pronounced reduction in MDA contents (220%). Furthermore, BHBA treatment significantly upregulated the expression of Kelch-like ECH-associated protein 1 (Keap1) and downregulated nuclear factor erythroid 2-related factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 (NQO1), and heme oxygenase-1 (HO-1) at both the mRNA and protein levels. These alterations were effectively reversed by pretreatment with 100 μg/mL RT. Non-targeted metabolomics identified 1525 metabolites in total. Based on OPLS-DA, metabolites with a variable importance in projection (VIP) > 1 and p < 0.05 were considered significantly altered. Compared with the blank control, BHBA treatment upregulated 47 metabolites—including 8-hydroxy-2′-deoxyguanosine, 3-hydroxyisovaleric acid, and N-palmitoyl-sphingosine—and downregulated 58 metabolites, such as betaine, linolenic acid, and arachidonic acid. In contrast, RT pretreatment upregulated 207 metabolites relative to the BHBA treatment, including linolenic acid, taurocholic acid, and 4-hydroxybenzoic acid, and downregulated 126 metabolites, including 3-hydroxyisovaleric acid, 8-hydroxy-2′-deoxyguanosine, and pyruvaldehyde. Pathway enrichment analysis indicated that RT alleviated BHBA-induced hepatocyte injury primarily by modulating the fatty acid degradation pathway. In summary, RT mitigated BHBA-induced oxidative stress in calf hepatocytes by regulating the Keap1/Nrf2 signaling pathway and further exerted protective effects through metabolic reprogramming. Full article

Serratia plymuthica, isolated from the midgut of Aedes aegypti, displays remarkable resilience to hemin, a toxic hemoglobin byproduct generated during blood digestion. This study explores its proteomic adaptations under oxidative stress induced by 5 mM hemin, mimicking midgut conditions. Growth assays demonstrated that S. plymuthica tolerated hemin concentrations ranging from 5 µM to 1 mM, reaching the stationary phase within approximately 10 h. Colonies exhibited morphological changes—darkened peripheries and translucent halos—suggesting heme accumulation and detoxification. Label-free quantitative proteomics identified 436 proteins, among which 28 were significantly upregulated—including universal stress proteins (USPs), ABC transporters, and flavodoxin—while 54 were downregulated, including superoxide dismutase and several ribosomal proteins. Upregulated proteins were associated with antioxidant defense, heme transport, and redox regulation, whereas downregulated proteins suggested metabolic reprogramming to conserve energy under stress. Functional enrichment analysis revealed significant alterations in transmembrane transport, oxidative stress response, and central metabolism. These findings suggest that S. plymuthica contributes to redox homeostasis in the mosquito gut by mitigating reactive oxygen species (ROS) and detoxifying excess heme, supporting its role as a beneficial symbiont. The observed stress tolerance mechanisms may influence mosquito physiology and vector competence, offering novel insights into mosquito–microbiota interactions and potential microbiota-based strategies for vector control. Full article

Background: Renal ischemia–reperfusion injury (IRI) is a frequent cause of kidney transplant failure. Recent studies have shown that the extent of injury is closely linked to ferroptosis, and the process of cellular ferroptosis is diurnal and regulated by circadian genes. NRF2, involved in iron–heme metabolism, may be related to ferroptosis. We hypothesize that the pathway plays a role in circadian regulation in ferroptosis in renal IRI. Methods: Using hematoxylin and eosin (H&E) staining, enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK8), flow cytometry, real-time quantitative reverse transcription PCR (qRT-PCR), and Western blotting, we analyzed renal tubular tissues in vivo and in vitro and compared the groups with IR injury treatment, inhibition of ferroptosis, and inhibition of BMAL1 gene expression at the ZT0 (zeitgeber time 0) and ZT12 (zeitgeber time 12) time points. Results: IR injury treatments caused exacerbation of injury, both in vivo and in vitro, and were more pronounced at the ZT12 time point, which correlates with circadian rhythms. The use of the ferroptosis inhibitor (Fer-I) attenuated IR injury, suggesting that IRI is associated with ferroptosis. In contrast, reduced BMAL1-gene expression exacerbated injury, and NRF2, which is elevated in IR injury, was suppressed. Conclusions: The circadian gene BMAL1 affects the circadian rhythm of ferroptosis in renal IRI through the regulation of NRF2 and its downstream pathway. In this study, renal injury is well ameliorated by the ferroptosis inhibitor, exhibiting potential as a therapeutic agent for use in renal transplantation. Full article

Background/Objectives: Hexaraphane, also known as 6-methylsulfinylhexyl isothiocyanate, derived from wasabi (Eutrema japonicum), increases heme oxygenase-1 (HO-1) and aldehyde dehydrogenase 2 (ALDH2) mRNA expression by activating nuclear factor erythroid 2-related factor 2 (Nrf2) in both HepG2 cells and the mouse liver. Given the presence of a peroxisome proliferator-activated receptor (PPAR) response element (PPRE) in the HO-1 and ALDH2 promoters, the present study aimed to determine the effects of hexaraphane on PPARα-associated genes, age-related weight gain, plasma triglyceride levels, and hepatic senescence. Methods: HepG2 cells were treated with hexaraphane to evaluate PPARα target gene expression and PPRE transcriptional activity. Male C57BL/6J young control, aged control, and aged mice administered with hexaraphane for 16 weeks were assessed for food and water intake, body and tissue weights, plasma parameters, and hepatic PPARα-related gene expression. Results: Hexaraphane increased HO-1 mRNA expression levels in HepG2 cells, which was inhibited by GW6471, a PPARα antagonist. It elevated PPRE transcriptional activity and increased carnitine palmitoyltransferase 1A (CPT1A) mRNA expression levels, indicating PPARα activation. In aged mice, hexaraphane intake reduced body weight gain by decreasing the adipose tissue weight. Increased CPT1A expression levels and a tendency toward increased acyl-CoA oxidase 1 (ACOX1) expression levels in the liver of aged mice administered hexaraphane were associated with reduced plasma triglyceride levels and body weight gain. Increased hepatic Sirt1 expression levels in aged mice administered hexaraphane was associated with lower plasma triglyceride levels. Increased hepatic PPARα mRNA expression levels in aged mice administered hexaraphane suggest a positive feedback loop between PPARα and Sirt1. The expression levels of hepatic p21 mRNA, a senescence marker regulated by Sirt1, were upregulated in aged mice but suppressed by hexaraphane intake. Conclusions: Hexaraphane may prevent age-related body weight gain, elevated plasma triglyceride levels, and hepatic senescence by activating PPARα, potentially contributing to longevity. Full article

Hepcidin is a key regulator of systemic iron homeostasis, which is essential for maintaining iron balance and cellular health. To investigate its role in zebrafish, we empolyed a hepcidin knockout model. Morphological and histological analyses revealed pale livers and significant iron accumulation in hep^−/− zebrafish, particularly in liver, skin, and egg tissues. RNA sequencing identified 1,424 differentially expressed genes (DEGs) between wild-type (WT) and hep^−/− zebrafish, with significant enrichment in pathways related to ferroptosis, fatty acid degradation, and heme binding. Western blot analysis showed reduced levels of key iron-related proteins, including GPX4, Fth1, and ferroportin (FPN), indicating impaired iron transport and increased oxidative stress. Gene Ontology (GO) and KEGG analyses highlighted disruptions in iron metabolism and lipid oxidation, linking iron overload to ferroptosis in the absence of hepcidin. These findings demonstrate that hepcidin deficiency leads to profound dysregulation of iron homeostasis, driving lipid peroxidation and ferroptosis in the zebrafish liver. Our study provides mechanistic insights into the molecular consequences of hepcidin loss, advancing our understanding of iron-related oxidative damage and its physiological impacts. Full article

Neonatal Meningitis-causing Escherichia coli (NMEC) is the leading cause of neonatal meningitis and exhibits remarkable adaptability to diverse host environments. Understanding its transcriptional responses across different host niches is crucial for deciphering pathogenesis and identifying potential therapeutic targets. We performed a comparative transcriptomic analysis of NMEC RS218, the prototype strain of NMEC, under four distinct host-mimicking conditions: colonic fluid (CF), serum (S), human brain endothelial cells (HBECs), and cerebrospinal fluid (CSF). Differential gene expression analysis was conducted to assess metabolic shifts, virulence factor regulation, and niche-specific adaptation strategies, in which RS218 demonstrated niche-specific transcriptional reprogramming. In CF, genes associated with biofilm formation, motility, efflux pumps, and cell division regulation were upregulated, aiding gut colonization. The serum environment triggered the expression of siderophore-mediated iron acquisition, enterobactin biosynthesis, and heme utilization genes, facilitating immune evasion and bacterial persistence. In HBECs, NMEC upregulated genes linked to nucleoside metabolism, membrane remodeling, pilus organization, and blood–brain barrier (BBB) traversal. In CSF, genes related to oxidative stress resistance, chemotaxis, DNA repair, biofilm formation, and amino acid biosynthesis were enriched, reflecting NMEC’s adaptive mechanisms for survival under nutrient-depleted conditions. Energy-intensive pathways were consistently downregulated across all niches, highlighting the need for an energy conservation strategy. This study provides novel insights into NMEC’s adaptive strategies across different host environments, emphasizing its metabolic flexibility, virulence regulation, and immune evasion mechanisms, offering potential targets for therapeutic intervention. Full article

Background/Objectives: Parkinson’s disease (PD) is a common neurodegenerative disease characterized by motor symptoms caused by the loss of dopaminergic neurons. While the pathophysiology of PD is still not fully understood, it is recognized that oxidative stress plays a major role in its progression. Previous studies have shown that the aerial parts of Artemisia iwayomogi Kitamura (AIK) possess medicinal properties, including antioxidant activity. This study aimed to investigate whether AIK can alleviate neuronal loss and motor symptoms in a PD model and to explore its therapeutic mechanisms. Methods: For the in vitro study, PC12 cells were treated with AIK and 1-methyl-4-phenylpyridinium (MPP⁺). For the in vivo study, C57BL/6J mice were orally administered AIK for 12 days; they received intraperitoneal injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 5 consecutive days, starting on the 8th day of AIK administration. Results: AIK treatment to PC12 cells in the presence of MPP⁺ enhanced the phosphorylation of the protein kinase B/glycogen synthase kinase-3β signaling pathway, which is a crucial regulator of nuclear factor erythroid 2-related factor 2 (Nrf2) translocation. Additionally, AIK treatment increased cell survival and induced an antioxidant response involving heme oxygenase-1, via increasing the level of Nrf2 in the nucleus. In an MPTP-induced mouse model of PD, AIK administration activated Nrf2 in dopaminergic neurons and prevented the loss of dopaminergic neurons in the brain, which in turn alleviated motor dysfunction. Conclusions: Collectively, these findings suggest that AIK is a potential botanical candidate for PD treatment by protecting dopaminergic neurons through antioxidant activity. Full article

Lung adenocarcinoma (LUAD) is a leading cause of cancer-related mortality, with heme metabolism playing a critical role in tumor progression and treatment resistance. This study investigates the clinical implications of heme metabolism in LUAD, focusing on its link to ferroptosis and drug sensitivity. Using multi-omics data from TCGA-LUAD, GEO databases, and a single-cell RNA-seq cohort, we identified two molecular subtypes based on heme metabolism-related genes. We further developed a prognostic panel, termed the heme metabolism risk score (HMRS), using LASSO and multivariate Cox regression analyses. The HMRS panel effectively stratified patients into high- and low-risk groups, with high-risk patients showing enhanced tumor proliferation, suppressed ferroptosis, and resistance to chemotherapy. Single-cell analysis revealed elevated heme metabolism risk in epithelial cells correlated with tumor progression. Drug sensitivity predictions were validated in platinum-based chemotherapy cohorts, confirming HMRS as a robust prognostic tool. ABCC2 was identified as a key regulator of ferroptosis and cisplatin resistance, with in vitro experiments demonstrating that ABCC2 knockdown enhanced cisplatin-induced ferroptosis. These findings highlight HMRS as a critical tool for patient stratification and ABCC2 as a promising therapeutic target to overcome cisplatin resistance. Full article

Ergosterol plays a dual role in fungal pathogenesis and azole resistance, driving key advancements in the understanding of its biosynthesis regulation. This review integrates the latest research progress on the regulation of fungal ergosterol biosynthesis and its role in drug resistance and pathogenicity. We comprehensively discuss the functions of key enzymes (such as Erg11p/Cyp51A, Erg6p, Erg3p, and Erg25p) in the mevalonate, late, and alternative pathways. Notably, we highlight the complex regulation of cyp51A expression by factors such as SrbA, AtrR, CBC, HapX, and NCT in Aspergillus fumigatus, and elucidate the distinctive roles of Upc2, Adr1, and Rpn4 in Candida species. Importantly, we summarize recent discoveries on the CprA-dependent regulation of Cyp51A/Erg11p and heme-mediated stability control. Based on these findings, we propose innovative antifungal strategies, including dual-target inhibition and multi-enzyme inhibition by natural products, which provide novel insights and potential directions for the development of next-generation antifungal therapies. Full article

OP, a systemic bone disorder marked by reduced bone mass and heightened fracture risk, poses a significant global health burden, particularly among aging populations. Current treatments, including bisphosphonates and calcium supplementation, are limited by adverse effects and incomplete efficacy. Emerging research highlights ferroptosis—an iron-dependent cell death driven by lipid peroxidation—as a critical contributor to OP pathogenesis, characterized by dysregulated iron metabolism, oxidative stress, and lipid peroxide accumulation, which disrupt bone remodeling by impairing osteoblast function and enhancing osteoclast activity. This review elucidates the mechanistic interplay between ferroptosis and OP subtypes (diabetic osteoporosis (DOP), glucocorticoid-induced (GIOP), and postmenopausal osteoporosis (PMOP)) and evaluates the efficacy of Chinese herbal interventions in mitigating ferroptosis-driven bone loss. Key findings reveal that excess iron exacerbates lipid peroxidation via the Fenton reaction, while glutathione peroxidase 4 (GPX4) inactivation and system Xc- inhibition amplify oxidative damage. In DIOP, hyperglycemia-induced ROS and advanced glycation end products suppress osteogenesis, countered by melatonin and naringenin via nuclear factor -related factor 2 (Nrf2)/GPX4 activation. GIOP involves dexamethasone-mediated GPX4 downregulation, mitigated by exosomes and melatonin through phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling. PMOP driven by estrogen deficiency-induced iron overload is alleviated by aconitine and icariin (ICA) via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways. Chinese herbs, including active compounds (quercetin, gastrodin, ICA, etc.) and formulations (Bugu Shengsui Capsule, Erxian Decoction (EXD), etc.), regulate iron metabolism, enhance antioxidant defenses (Nrf2/heme oxygenase 1(HO-1)), and inhibit lipid peroxidation, effectively restoring bone homeostasis. These findings underscore ferroptosis as a pivotal mechanism in OP progression and highlight the therapeutic promise of Chinese herbs in bridging traditional medicine with modern mechanistic insights. Future research should prioritize elucidating precise molecular targets, optimizing formulations, and validating clinical efficacy to address current therapeutic gaps. Full article

Background/Objectives: Enhancer RNAs (eRNAs) function in diverse modes and increasing studies have shown that they play important roles in normal development and disease. However, their role in erythropoiesis is not fully understood. Methods: We analyzed published RNA-seq and Promoter Capture Hi-C data from mouse E14.5 fetal liver cells to identify enhancer RNAs in erythroid cells with long-range interactions. Results: We discovered an erythroid-specific enhancer RNA (CpoxeRNA) transcribed from an enhancer region upstream of Cpox, an enzyme important for heme synthesis. CpoxeRNA is important for erythropoiesis, as the knockdown of CpoxeRNA by shRNA results in impaired enucleation and cell proliferation during terminal differentiation. CpoxeRNA interacts with cohesin and acts both in cis and trans to regulate erythroid genes. Conclusions: we have identified a trans-acting eRNA, CpoxeRNA, as a potential regulator of terminal erythropoiesis. Full article

Ferrochelatase is the terminal enzyme in heme biosynthesis. Bacillus thuringiensis (Bt) 97-27 contains two ferrochelatases, HemH1 and HemH2, but their regulatory mechanisms and functional differences under virous environmental stimuli remain unclear. This study confirmed that the iron uptake regulator protein (Fur) bound to the promoters of hemH1 and hemH2, with Fe²⁺ or Fe³⁺ enhancing this binding. Heterologous expression of HemH1 and HemH2 in Escherichia coli showed that pEH2/BL grew better than pEH1/BL under different 2,2′-Bipyridyl, Fe²⁺, and Fe³⁺ concentrations. Under iron limitation, the heme precursor ALA production decreased significantly in both strains. The heme production of pEH2/BL decreased sharply under iron-limited conditions, while that of pEH1/BL decreased significantly under iron-rich conditions. The H₂O₂ sensitivity experiment revealed that E. coli pEH1/BL was more tolerant to H₂O₂ than pEH2/BL. In Bt, ΔhemH2 was most sensitive to H₂O₂ stress, but complementation of hemH1 or hemH2 partially restored H₂O₂ resistance, with the overexpressed strain pHH2/Bt being most tolerant. β-galactosidase assays indicated that Fur positively regulated hemH1 and negatively regulated hemH2 under normal conditions, but this regulation reversed with 2.5 mM Fe³⁺. qRT-PCR showed upregulation of genes related to heme synthesis, oxidative stress, and ferrous iron transport. This study reveals the functional differentiation of HemH1 and HemH2 under the joint regulation of Fur and environmental factors, highlighting their synergistic roles in heme synthesis, heavy metal detoxification, and oxidative stress resistance to maintain bacterial physiological homeostasis. Full article