Search Results (253)

Pulmonary hypertension (PH) causes morbidity and mortality in sickle cell disease (SCD). The release of heme during hemolysis triggers endothelial dysfunction and contributes to PH. Long non-coding RNAs (lncRNAs) may play a pivotal role in endothelial dysfunction and PH pathogenesis. This study assessed the regulatory role of the lncRNA–heme oxygenase-1 (HMOX1) axis in SCD-associated PH pathogenesis. Total RNAs were isolated from the lungs of 15–17-week-old sickle cell (SS) mice and littermate controls (AA) mice and subjected to lncRNA expression profiling using the Arrystar™ lncRNA array. Volcano plot filtering was used to screen for differentially expressed lncRNAs and mRNAs with statistical significance (fold change > 1.8, p < 0.05). A total of 3915 lncRNAs were upregulated and a total of 3545 lncRNAs were downregulated in the lungs of SS mice compared to AA mice. To validate differentially expressed lncRNAs, six upregulated lncRNAs and six downregulated lncRNAs were selected for quantitative PCR. MALAT1 expression was significantly upregulated in the lungs of SS mice and in hemin-treated human pulmonary artery endothelial cells (HPAECs), suggesting that hemolysis induces MALAT1. Functional studies revealed that MALAT1 depletion increased, while MALAT1 overexpression decreased, the endothelial dysfunction markers endothelin-1 (ET-1) and vascular cell adhesion molecule-1 (VCAM1), indicating a protective role of MALAT1 in maintaining endothelial homeostasis. In vivo, adenoviral MALAT1 overexpression attenuated PH, right ventricular hypertrophy (RVH), vascular remodeling, and reduced ET-1 and VCAM1 expression in SS mice. Given that HMOX1 protects endothelial cells during hemolysis, we observed that HMOX1 expression and activity were elevated in SS mouse lungs and hemin-treated HPAECs. HMOX1 knockdown enhanced ET-1 and VCAM1 expression, confirming its endothelial-protective function. Importantly, MALAT1 overexpression increased HMOX1 expression and activity, whereas MALAT1 knockdown reduced HMOX1 levels and mRNA stability. Collectively, these findings identify MALAT1 as a protective regulator that mitigates endothelial dysfunction, vascular remodeling, and PH in SCD, at least in part through the induction of HMOX1. These results suggest that SCD modulates the MALAT1–HMOX1 axis, and further characterization of MALAT1 function may provide new insights into SCD-associated endothelial dysfunction and PH pathogenesis, as well as identify novel therapeutic targets. Full article

Plastic pollution is acknowledged as a serious problem for ecosystems. Among these plastics, polystyrene nanoplastics (PS-NPs) are emerging environmental pollutants, and their biological effects on hepatotoxicity are the least explored. Therefore, the present work examined the effect of PS-NPs on the hepatic transcription of the antioxidant genes Hmox1 and Sod3 in mice (n = 6, treatment (PS-NPs) vs. vehicle group (Veh)), mediated by RORγ and epigenetic modifications. The results show that PS-NP mice had significantly reduced body weight; increased activity of adenosine triphosphate (ATP), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH), and Complexes I, III, and V in the liver; and increased Alanine Transaminase (ALT), Aspartate Transaminase (ASP), Alkaline Phosphatase (ALP), malondialdehyde (MDA) and reactive oxygen species (ROS) compared to the Veh group. Furthermore, PS-NPs resulted in considerably lower relative mRNA expression of Hmox1, Sod3, and RORγ in the liver than the Veh group. Likewise, when compared to Veh, PS-NPs significantly reduced the enrichment of RORγ, as well as the occupancies of the key components of the transcriptional activation pathway (P300, SRC1, Pol II, Ser5-Pol II, and Ser2-Pol II) at the loci of Hmox1 and Sod3. In comparison to Veh, PS-NPs showed downregulated occupancies of the histone active marks H3K9ac and H3K18ac, while H3K4me3 and H3K27me3 were higher at the target loci of Hmox1 and Sod3. In conclusion, the present study highlights that PS-NPs induce oxidative stress by modifying Hmox1 and Sod3 in mice’s livers through histone changes and nuclear receptor RORγ modulation. Full article

Sustainable extraction methods represent a key strategy in green chemistry and nutraceutical development, aiming to replace conventional solvent-based techniques while maintaining extract quality and safety. This study compared pistachio (Pistacia vera L.) extracts obtained by Ultrasound-Assisted Extraction (UAE) and a classical solvent-based protocol, focusing on compositional features and biological effects. Extracts were characterized for their chemical profiles, and their impact on HCT-116 colon-derived cells was evaluated through viability assays and gene expression analysis. The UAE-derived extract, richer in carbohydrates, promoted higher cell proliferation after 72 h, whereas the classical extract upregulated HMOX-1, suggesting activation of antioxidant defense pathways. Moreover, UAE treatment downregulated GLUT2 expression while modulating cytokinestranscripts, indicating a possible carbohydrate-driven immunometabolic response. Overall, these findings highlight both the advantages and limitations of green extraction approaches: while environmentally sustainable and efficient, ultrasound-assisted protocols may modify extract composition in ways that influence biological responses. Optimization of extraction parameters is therefore essential to ensure a balance between ecological sustainability, compositional integrity, and biological safety. Full article

Skin aging is driven largely by oxidative stress, chronic inflammation, and mitochondrial dysfunction, processes closely linked to cellular senescence and declining NRF2 activity. Numerous dietary phytochemicals—such as curcumin (from turmeric), resveratrol (from grapes), sulforaphane (from cruciferous vegetables), zerumbone, and salvianolic acid B—abundant in fruits, vegetables, herbs, and traditional food sources, exhibit potent antioxidant and anti-inflammatory properties. This review systematically elucidates the molecular mechanisms by which these compounds mitigate skin aging, primarily through modulating the NRF2 signaling pathway. We further integrate insights from clinical trials of NRF2-targeting agents to inform the translational potential of these dietary bioactives. Molecular docking analyses confirm that these food-derived compounds interact directly with the KEAP1-NRF2 complex, promoting NRF2 activation. Transcriptomic analyses of skin-related datasets (GSE35160, GSE71910, GSE185129) further validate the downregulation of key NRF2-regulated cytoprotective genes (e.g., FTH1, FTL, HMOX1, SLC7A11) involved in antioxidant defense and the suppression of pro-inflammatory mediators. Based on this mechanistic foundation, we discuss the translational potential of these food-derived bioactives and the rationale for their future incorporation into skin-health-promoting nutraceuticals. We highlight how these food-derived phenolics and other bioactives may be incorporated into functional foods or nutraceuticals to support skin health from within, offering a dietary strategy to delay aging. We acknowledge that key translational challenges, such as oral bioavailability and optimal formulation, require further investigation. Further research is warranted to bridge these mechanistic insights into effective human applications. Full article

Background: Non-alcoholic steatohepatitis (NASH) lacks approved pharmacotherapies despite affecting approximately 25% of the global population. Agrimonia pilosa, a traditional herb with anti-inflammatory and antioxidant properties, remains unexplored for NASH treatment. Objective: This study investigated the hepatoprotective effects and mechanisms of Agrimonia pilosa extract (APE) in NASH models. Methods: HepG2 cells were treated with free fatty acids (0.125 mM) and APE (+12.5–50 μg/mL). C57BL/6J mice received a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) for 12 weeks with APE (25–100 mg/kg/day), silymarin (100 mg/kg/day), or luteolin (20 mg/kg/day). Lipid accumulation, liver enzymes, histopathology, and molecular markers were assessed. Results: APE dose-dependently reduced lipid accumulation in FFA-treated cells, suppressed lipogenic factors (SREBF1, CEBPA, and PPARG), and upregulated fatty acid oxidation enzymes (CPT1A and PPARA) via AMPK/SIRT1 activation. In NASH mice, APE (100 mg/kg) significantly decreased serum ALT (160.0 ± 49.1 vs. 311.2 ± 66.7 U/L) and AST (96.0 ± 18.7 vs. 219.0 ± 55.7 U/L, p < 0.001), reduced hepatic macrophage infiltration by 68%, and substantially attenuated inflammatory markers (Ccl2, Tnf, and IL6), oxidative stress indicators (NRF2, HMOX1, and CYBB), and fibrogenic markers (ACTA2, COL1A1, and TGFB1) by 83–85% (p < 0.001). Collagen deposition decreased from 5.63 ± 0.39% to 1.54 ± 0.03% (p < 0.001). Conclusions: APE exerts potent hepatoprotective effects through multi-targeted modulation of lipid metabolism, inflammation, oxidative stress, and fibrosis via AMPK/SIRT1 pathway activation, supporting its potential as a natural therapeutic intervention for NASH. Full article

Multidrug resistance (MDR) remains a significant obstacle to effective cancer chemotherapy, primarily due to overexpression of P-glycoprotein (P-gp), which reduces intracellular accumulation of cytotoxic drugs. This study evaluated the pharmacological potential of the glycyrrhetinic acid derivative soloxolone N-3-(dimethylamino)propylamide (Sol-DMAP) as a biocompatible P-gp inhibitor with hepatoprotective properties. Using a murine model of P-gp-overexpressing RLS40 lymphosarcoma, we demonstrated that Sol-DMAP significantly enhanced the antitumor efficacy of doxorubicin (DOX) by increasing its intratumoral concentration 4.7-fold without enhancing systemic toxicity. Independently, Sol-DMAP exhibited direct antitumor activity, reducing tumor growth in vivo and inducing apoptosis and G1-phase arrest in RLS40 cells in vitro. In addition, Sol-DMAP mitigated DOX-induced hepatic injury by reducing necrotic and dystrophic changes in liver tissue and restoring heme oxygenase 1 (Hmox1) expression. Further studies in HepG2 cells confirmed that Sol-DMAP activated the NRF2-dependent antioxidant response, upregulating HMOX1, GCLC, GCLM, and NQO1 genes. Molecular docking revealed that Sol-DMAP can disrupt the KEAP1-NRF2 interaction, likely leading to NRF2 activation. Collectively, these findings demonstrate that Sol-DMAP effectively reverses P-gp-mediated MDR while protecting the liver from oxidative stress, highlighting its potential as a multifunctional scaffold for the development of safer and more effective chemotherapeutic adjuvants. Full article

The development of new approach methodologies that include human cells differentiated into organotypic formats is of high interest due to their structural and functional similarities to tissues in vivo, enabling mechanistic understanding and translation to adverse health outcomes in humans. However, these systems often fail to capture complex intercellular signaling required for processes such as pulmonary inflammation induced by polycyclic aromatic hydrocarbons (PAHs). To investigate airway epithelial–macrophage interactions in response to benzo[a]pyrene and a PAH mixture (Tox Mix), co-culture models utilizing primary human bronchial epithelial cells (HBECs) differentiated at the air–liquid interface were cultured with THP-1 macrophages either directly or indirectly, alongside HBECs alone. After 24 h of exposure, cytokine expression (IL1B, IL6, CXCL8, TNF) as well as PAH biomarkers previously identified for chemical metabolism (CYP1A1, CYP1B1), oxidative stress (ALDH3A1, HMOX1, NQO1), and barrier integrity (TJP2) were evaluated. Cytotoxicity and barrier integrity were also assessed. HBECs alone and direct co-cultures exhibited similar responses after PAH treatment, while indirect co-cultures showed lower sensitivity to induction of inflammatory cytokines and CYP1A1 and CYP1B1 biomarker expression following exposure to PAHs. The expression of other biomarkers, including ALDH3A1, HMOX1, and NQO1, remained largely consistent across all models after treatment. Overall, these findings suggest that direct co-culture systems may provide a more physiologically relevant platform for studies of PAH-induced toxicity and demonstrate that the configuration of co-culture systems can influence cellular responses to chemical exposure. Full article

Bilirubin, a metabolite derived from heme degradation, has traditionally been regarded as a waste product and a marker of liver injury. However, increasing evidence suggests that bilirubin also functions as a hormone, and reduced levels are associated with metabolic dysfunction. Studies have shown a strong association between low circulating bilirubin levels and an increased risk of metabolic disorders and cardiovascular disease. To advance bilirubin-based treatment strategies, it is essential to elucidate the mechanisms underlying bilirubin transport and metabolism. Therefore, we provide an in-depth discussion of bilirubin production and its subsequent fates, with a particular focus on the transport between the liver and the intestine. We describe the molecular players involved in heme degradation and biliverdin formation, leading to bilirubin production, followed by its transport from the bloodstream to hepatocytes and from the liver to the intestine. We discuss intestinal bilirubin catabolism, including the microbiome generation of urobilinogen, urobilin, and other metabolites. Finally, we discuss how bilirubin clearance and catabolism intersect with its metabolic effects, highlighting potential therapeutic targets. By integrating these aspects, this review provides a comprehensive understanding of bilirubin’s physiological importance, intestinal transport, and breakdown, as well as insights into novel strategies for treating hypobilirubinemia-associated disorders. Full article

The global demand for processed foods has increased reliance on synthetic phenolic antioxidants (SPAs), including tert-butylhydroquinone (TBHQ), a widely used additive to prevent lipid oxidation and extend shelf life. TBHQ is considered safe at present regulated levels; however, studies suggest potential adverse effects, including oxidative stress, genotoxicity, and impacts on immune function, raising concerns about human health and ecological risks. Herein, we investigated the immunomodulatory effects of TBHQ on RAW 264.7 murine macrophages pre-exposed to 0.1, 1, and 5 µM TBHQ and then stimulated with lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly I:C, PIC) to model bacterial and viral immune challenges. We then used functional assays and transcriptomic profiling to assess inflammatory responses and oxidative stress signaling. TBHQ reduced nitric oxide production and IL-10 secretion at the highest non-cytotoxic dose, and enhanced phagocytosis and IL-6 secretion at the lowest concentrations. Overall, transcriptomics revealed significant downregulation of proinflammatory pathways and induction of glutathione and xenobiotic metabolism. Pre-treatment with TBHQ increased gene transcript counts of key metabolic genes/transporters such as Cbr3, Adh7, Gstp1/3, Gsta3, Hmox1 and Gclm. Following treatment with LPS or PIC several genes for classical proinflammatory chemokines and cytokines such as Cxcl2, Ccl2, Ccl12, Acod1, Ptgs2, Nos2, and Il6 were downregulated. Genes involved in NF-κB signaling, such as Nfkbia, Nfkb1, and Ikbke were also downregulated. Our study suggests that the induction of Nrf2-related antioxidant pathways by TBHQ is the main driver for reduced inflammatory signaling in macrophages. Full article

Leprosy is a chronic infectious disease that targets the peripheral nervous system, leading to peripheral neuropathy. Mycobacterium leprae primarily infects Schwann cells, adipocytes, and macrophages, altering their metabolism and gene expression. This study investigates the metabolic interaction between M. leprae and Schwann cells, with a focus on indoleamine 2,3-dioxygenase (IDO), a key enzyme in tryptophan catabolism via the kynurenine pathway. We found that M. leprae induces IDO expression in Schwann cells, suggesting a role in immune modulation and neuropathy. Inhibition of IDO with 1-methyl-L-tryptophan (1-MT) reduced Schwann cell viability and metabolic activity in response to M. leprae. After 24 h of infection, M. leprae impaired mitochondrial membrane potential, although no significant changes in autophagy or mitochondrial ultrastructure were observed by electron microscopy. Interestingly, IDO1 inhibition upregulated the expression of antioxidant genes, including GPX4, NFE2L2, and HMOX1. In conclusion, these findings highlight a central role for IDO in shaping the metabolic and immunological response of Schwann cells to M. leprae infection. IDO induction contributes to immune regulation and cellular stress, while its inhibition disrupts cell viability and promotes antioxidant gene expression. These results position IDO as a potential therapeutic target for modulating host–pathogen interactions and mitigating nerve damage in leprosy. Full article

Pregnancy toxemia (PT) represents a significant metabolic disorder affecting small ruminants that causes substantial economic losses due to reduced productivity, reproductive failure, and high mortality. This study investigated the clinical, ultrasonographic, hematobiochemical, oxidative stress, and immunological profiles, as well as the gene expression and nucleotide sequence variations, associated with PT susceptibility in Shami goats. Fifty late-pregnant does (33 healthy and 17 PT-affected) were examined. Clinical evaluation, complete blood count, biochemical analysis, cytokine profiling, antioxidant assays, hepatic ultrasonography, quantitative real-time PCR of immune (IL6, IL8), antioxidant (SOD3, HMOX1), and lipogenic (ACACA, FASN) genes, and PCR-DNA sequencing were performed. PT does exhibit significant hypoglycemia, hyperketonemia, elevated liver and kidney function biomarkers, dyslipidemia, oxidative stress (↑ MDA, ↓ GSH, GPx, SOD, CAT), increased pro-inflammatory cytokines (IL1α, IL1β, IL6, TNFα), and reduced IL10. Gene expression analysis revealed upregulation of IL6 and IL8 and downregulation of SOD3, HMOX1, ACACA, and FASN in PT does. Sequencing identified multiple synonymous and non-synonymous SNPs significantly associated with PT. Ultrasonography indicated hepatic fatty infiltration. Discriminant analysis using SNPs achieved 100% classification accuracy between healthy and PT does. These findings suggested that combined clinical, biochemical, oxidative, immunological, and genetic markers could enhance early PT diagnosis and may provide a basis for future studies aimed at selective breeding for improved resistance. Full article

Background/Objectives: In the fight against ovarian cancer, various therapies have been employed, with a strong focus on developing novel derivatives of existing substances. Methods: In this study, we continue our research on novel xanthone derivatives in combination with mild hyperthermia, targeting ovarian cancer cell lines TOV-21G and SK-OV-3. Using qPCR arrays, we analyzed 84 cellular stress-related genes categorized into anti-oxidant and pro-oxidant enzymes, molecular chaperones, and xenobiotic metabolism including the cytochrome P450 group. Furthermore, we conducted in silico analyses to investigate the pathways of the most affected genes, gene set enrichment, and gene ontology. Results: The most significant changes were observed in SOD2, SOD3, CYP2F1, CYP1B1, and HMOX1. Additional changes related to drug toxicity and the postulated mechanism of action were also identified. Based on in silico analyses, we concluded that the primary node of hyperthermia-induced changes is HSPA1A. Heat-induced alterations predominantly revolve around misfolded proteins, monooxygenase activity, and ATPase activity. Conclusions: To summarize, the combined therapy of novel xanthone derivatives and mild hyperthermia shows promising results and warrants further investigation to fully elucidate the mechanisms of action underlying these effects. Full article

Background and Aims: Triple-negative breast cancer (TNBC) is a clinically aggressive malignancy marked by rapid disease progression, limited therapeutic avenues, and high recurrence risk. Ferroptosis an iron-dependent, lipid peroxidation-driven form of regulated cell death that has emerged as a promising therapeutic vulnerability in oncology. This study delineates the ferroptosis-associated molecular architecture of TNBC to identify key regulatory genes with prognostic and translational significance. Methods: Transcriptomic profiles from the GSE103091 dataset (130 TNBC and 30 normal breast tissue samples) were analyzed to identify ferroptosis-related differentially expressed genes (DEGs) using GEO2R. Protein–protein interaction (PPI) networks were constructed via STRING and GeneMANIA, with functional enrichment performed through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome analyses. Prognostic relevance was evaluated using GEPIA, BC-GenExMiner, and Kaplan–Meier Plotter survival analyses. Results: Six ferroptosis drivers (MAPK1, TLR4, IFNG, ATM, ULK2, and ATF3) and five suppressors (NFS1, GCLC, TP63, CD44, and SRC) were identified alongside HMOX1, a bifunctional regulator with context-dependent pro- and anti-ferroptotic activity. Enrichment analyses revealed significant associations with oxidative stress regulation, autophagy, immune modulation, and tumor progression pathways. Elevated IFNG expression was consistently linked to improve overall, disease-free, and distant metastasis-free survival, underscoring its dual function in antitumor immunity and ferroptosis sensitization. Conclusions: Ferroptosis represents a critical axis in TNBC pathophysiology, with IFNG emerging as both a prognostic biomarker and a viable therapeutic target. These insights provide a mechanistic foundation for integrating ferroptosis-inducing agents with immunotherapeutic modalities to enhance clinical outcomes and overcome therapeutic resistance in TNBC. Full article

Background: Robust evidence supports the role of tetrahydrobiopterin (BH4) metabolism in sustaining inflammation; however, the mechanisms underlying the persistent upregulation of the BH4 pathway remain incompletely understood. This study investigated the epigenetic regulation of BH4 metabolism following a single injection of lipopolysaccharide (LPS) in the mouse hippocampus. Methods: Male C57BL/6J mice received either saline or LPS (0.33 mg/kg, i.p.) and were sacrificed at 4 h or 24 h post injection. Behavioral assessments and analyses of hippocampal neurotransmitter metabolism, DNA methylation profile, oxidative stress, and inflammasome activation were performed. Neopterin levels, a marker of immune system activation, were measured in both the plasma and hippocampus. Results: LPS-treated mice exhibited sickness behavior, including reduced locomotor and exploratory activity at both 4 and 24 h. While exploratory behavior showed partial recovery by 24 h, locomotor activity remained impaired. Neopterin levels increased in both the plasma and hippocampus following LPS administration but returned to baseline in the hippocampus by 24 h. Despite the normalization of neopterin, a persistent pro-inflammatory state in the hippocampus was evident at 24 h, as shown by increased expression of Ikbkb and components of the NLRP3 inflammasome, along with elevated oxidative stress markers. Upregulation of Nrf-2 and Hmox1 suggested activation of a protective antioxidant response. Dopaminergic metabolism was disrupted, indicating impaired BH4-dependent dopamine turnover. Epigenetic analysis revealed increased expression of DNA methyltransferases (Dnmt1, Dnmt3a, Dnmt3b) and Tet2, along with reduced expression of Tet1 and Tet3. Promoter hypomethylation of Gch1 and Ptps was observed, correlating with increased hippocampal expression and potentially elevated BH4 levels. Conclusions: Together, these findings show that a single LPS challenge was sufficient to induce the activation of the BH4 synthesis pathway during the late acute inflammatory phase, both systemically and in the hippocampus, potentially driven by epigenetic modifications such as promoter hypomethylation. This may contribute to the perpetuation of neuroinflammation. Full article

Geographic atrophy or late-stage dry age-related macular degeneration (AMD) is characterized by drusen deposition and progressive retinal pigment epithelium (RPE) degeneration, leading to irreversible vision loss. The formation of drusen leads to dyshomeostasis, oxidative stress, and irreversible damage to the RPE. In this study, we used an in vitro model of oxidized low-density lipoprotein (ox-LDL)-induced human RPE damage/death to investigate the mechanism through which a sterically hindered phenol antioxidant compound, PMC (2,2,5,7,8-pentamethyl-6-chromanol), protects the RPE against ox-LDL-induced damage. We show that PMC exerts its protective effect by preventing the upregulation of stress-responsive heme oxygenase-1 (HMOX1/HO-1) and NAD(P)H: quinone oxidoreductase (NQO1) at the mRNA and protein levels. This effect was due to PMC’s blockade of ROS generation, which in turn blocked nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor, ultimately preventing the upregulation of antioxidant response elements (AREs), including HMOX1 and NQO1. The key role of HO-1 was demonstrated when the protective effect of PMC was inhibited by the knockdown of HMOX1. Additionally, PMC treatment under different experimental conditions and at different time points revealed that the continuous presence of PMC is required for the optimal protection against ox-LDL-induced cytotoxicity, defining the cellular pharmacokinetics of this molecule. Our data demonstrate the involvement of a key antioxidant pathway through which PMC mitigates the oxidative stress induced by ox-LDL and provides a potential therapeutic strategy for suppressing RPE degeneration/damage during AMD progression. Full article