Natural flavonoids from herbs and nutraceuticals as ferroptosis inhibitors in central nervous system diseases: current preclinical evidence and future perspectives

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Март 24, 2025

Flavonoids are a class of important polyphenolic compounds, renowned for their antioxidant properties. However, recent studies have uncovered an additional function these natural flavonoids: ability to inhibit ferroptosis. Ferroptosis is key mechanism driving cell death in central nervous system (CNS) diseases, including both acute injuries and chronic neurodegenerative disorders, characterized by iron overload-induced lipid peroxidation dysfunction the defense system. This review discusses therapeutic potential flavonoids from herbs nutraceuticals as ferroptosis inhibitors CNS focusing on molecular mechanisms, summarizing findings preclinical animal models, providing insights clinical translation. We specifically highlight such Baicalin, Baicalein, Chrysin, Vitexin, Galangin, Quercetin, Isoquercetin, Eriodictyol, Proanthocyanidin, (−)-epigallocatechin-3-gallate, Dihydromyricetin, Soybean Isoflavones, Calycosin, Icariside II, Safflower Yellow, which shown promising results models injuries, ischemic stroke, cerebral ischemia-reperfusion injury, intracerebral hemorrhage, subarachnoid traumatic brain spinal cord injury. Among these, Baicalin its precursor Baicalein stand out due extensive research favorable outcomes injury models. Mechanistically, not only regulate Nrf2/ARE pathway activate GPX4/GSH-related pathways but also modulate metabolism proteins, thereby alleviating overload inhibiting While show promise especially settings, further needed evaluate efficacy, safety, pharmacokinetics, blood-brain barrier penetration application.

Язык: Английский

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Scutellarein ameliorates pulmonary arterial hypertension via sirtuin 1 mediated deacetylation of nicotinamide nucleotide transhydrogenase

Biochemical Pharmacology, Год журнала: 2025, Номер 237, С. 116932 - 116932

Опубликована: Апрель 6, 2025

Язык: Английский

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Sevoflurane exposure triggers ferroptosis of neuronal cells initiated by the activation of ATM/p53 in the neonatal mouse brain via JNK/p38 MAPK-mediated oxidative DNA damage

International Immunopharmacology, Год журнала: 2025, Номер 158, С. 114866 - 114866

Опубликована: Май 15, 2025

Neuronal death has long been regarded as a pivotal pathological factor in the developmental neurotoxicity caused by volatile anesthetic sevoflurane neonatal brain, but detailed mechanism remains controversial. Ferroptosis is novel type of regulated cell driven excess lipid peroxidation secondary to intracellular iron overload, and it implicated pathogenesis various neurological disorders. Acting messenger, p53 primarily activated ATM during DNA damage mediates forms death, including apoptosis, autophagy, ferroptosis. JNK/p38 MAPK are important stress-responsive pathways that can exacerbate ROS production, thereby linking many conditions such neurodegeneration ischemic injury. In our present study, we demonstrated exposure-induced neuronal was correlated with overload HT22 cells, primary hippocampal neurons, hippocampi mice, consistent hallmarks Furthermore, found sevoflurane-induced ferroptosis associated ATM/p53 activation response damage. Additionally, exposure followed accumulation, ultimately leading Mechanistically, contributed via two pathways: (1) enhancing uptake (upregulating TFR downregulating FPN) (2) promoting through NOX4, ALOX12, ALOX15 SLC7A11 suppression. Collectively, these findings induced cells triggered MAPK-mediated accumulation subsequent

Язык: Английский

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Interleukin-2/anti-interleukin-2 complex attenuates inflammation in a mouse COPD model by expanding CD4+ CD25+ Foxp3+ regulatory T cells

International Immunopharmacology, Год журнала: 2024, Номер 131, С. 111849 - 111849

Опубликована: Март 18, 2024

Язык: Английский

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Ferroptosis in chronic obstructive pulmonary disease: From cellular mechanisms to therapeutic applications

Chinese Medical Journal, Год журнала: 2024, Номер 137(10), С. 1237 - 1239

Опубликована: Апрель 9, 2024

To the Editor: Chronic obstructive pulmonary disease (COPD) is a global public health challenge without effective treatment currently available, affecting >300 million individuals worldwide. Comprehensively understanding pathogenesis of this required. Recently, ferroptosis, form cell death driven by iron-dependent lipid peroxidation, has been associated with COPD.[1] Multiple signaling pathways, such as glutathione peroxidase 4 (GPX4), ferroptosis suppressor protein 1 (FSP1), and tetrahydrobiopterin-dependent well iron metabolism, are involved in regulating ferroptosis[2,3] [Figure 1A]. Here, we provide comprehensive overview recent advances role COPD, highlighting potential therapeutic strategies targeting for treating disease.Figure 1: (A) Signaling pathways ferroptosis. (B–D) Ferroptosis BECs (B), macrophages (C), ECs (D) contributes to COPD. (E) Targeting various cells mitigate ACSL4: Acyl-CoA synthetase long-chain family member 4; ALOX15: Arachidonate 15-lipoxygenase; ALOX5: 5-lipoxygenase; BECs: Bronchial epithelial cells; COPD: disease; circSAV1: Circular RNA SAV1; DHFR: Dihydrofolate reductase; ECs: Endothelial FSP1: 1; FTH: Ferritin heavy chain; FTL: light GPX4: Glutathione GSH: Glutathione; GSS: synthetase; GSSG: Oxidized glutathione; GSR: Glutathione-disulfide HMOX-1: Heme oxygenase-1; iNOS: Inducible nitric oxide synthase; IREB2: Iron-responsive element binding 2; LOX: Lipoxygenase; LTB4: Leukotriene B4; MFG-E8: Milk fat globule-EGF factor 8; MMP9: Matrix metalloproteinase 9; MMP12: 12; NCOA4: Nuclear receptor coactivator Nrf2: erythroid 2-related PGE2: Prostaglandin E PLOO•: Lipid peroxyl radicals; PLOOH: Phospholipid hydroperoxides; PRMT7: Arginine methyltransferase 7; PTGS2: synthase PUFAs: Polyunsaturated fatty acids; PUFA-PLs: PUFA containing phospholipids; RAP1A: Ras-related 1A; SIRT3: Sirtuin 3; SLC40A1: Solute carrier 40A1; STEAP3: Six-transmembrane antigen prostate TF: Transferrin; TFRC: Transferrin receptor; TXNRD1: Thioredoxin reductase USP14: Ubiquitin-dpecific protease 14; YTHDF1: YTH N6-methyladenosine 1.Ferroptosis bronchial (BECs) Excessive deposition cigarette smoke (CS)-exposed leads increased ferritin expression. This process activates ferritinophagy mediated nuclear (NCOA4). Notably, knockdown NCOA4 mice reduces CS-induced ferroptosis.[4] In downregulated 2 (Nrf2) expression Nrf2 promoter hypermethylation. Conversely, enhances GPX4 levels, inhibits BECs, mitigates COPD.[5] Moreover, CS extract (CSE)-induced peroxidation sirtuin3 inactivation promoting inducible (iNOS) levels potentially triggering COPD.[6] globule epidermal growth 8 (MFG-E8) identified mitigator CSE-induced ubiquitin specific peptidase 14 (USP14) stabilizes MFG-E8 protein, suppressing ferroptosis.[7] m6A-modified circular SAV1 (circSAV1) forms an RNA–protein complex that promotes translation iron-responsive (IREB2) mRNA. Increased IREB2 disrupt homeostasis, resulting accumulation labile pool contributing cells. circSAV1 reversed suggesting its crucial regulatory process.[8] Overall, COPD 1B]. ferroptosis-sensitive M2-like macrophages.[9] Protein arginine 7 (PRMT7) regulated kappa B (NF-κB)/RelA activation also lung injury severity Pro-inflammatory PRMT7 stimulate arachidonate 5-lipoxygenase leukotriene B4 release, inducing acetyl coenzyme A (acyl-CoA) (ACSL4) rendering them more susceptible COPD.[1,10] M2 matrix (MMP) 9 MMP12 were observed CS-exposed co-cultured CSE-treated BECs.[11] exposure led elevated overload peroxidation-induced may contribute macrophage polarization 1C]. endothelial (ECs) interaction between exacerbating Wang Xia[12] exposed CSE homocysteine, characterized reduced FSP1 ACSL4 suggests disruption microvascular barrier Yu et al[13] discovered normal release exosomes micro (miR)-26a-5p, which can be transported into BECs. Within miR-26a-5p targets prostaglandin-endoperoxide (PTGS2) mRNA, inhibiting These findings suggest beneficial 1D]. Dihydroquercetin Nrf2-mediated inhibit COPD.[14] Curcumin attenuates inflammation BECs.[15] Scutellarein potent inhibitor through chelating Fe2+ reducing intracellular but antiferroptotic effects hindered 15-lipoxygenase overexpression.[16] addition these natural compounds, deferoxamine, ferrostatin-1, liproxstatin-1 BECs.[4,8] Sodium pyruvate GPX4/Nrf2 pathway BECs.[17] Hydrogen sulfide (H2S) peroxisome proliferator-activated receptor-γ NCOA4-mediated autophagy.[18] hydrosulfide (NaHS), H2S donor, Furthermore, gene therapy using lentiviral system (si_ACSL4) showing promise strategy COPD.[12] 1E]. study induce found M1 resistant whereas susceptible.[9] exhibited higher heme oxygenase-1 (HMOX1) than macrophages. Inhibiting HMOX1 zinc protoporphyrin (ZnPP) effectively prevented induced CSE. ZnPP, deferoxamine bronchoalveolar lavage fluid from treatments protected against COPD.[9] exacerbates dyslipidemia, atherosclerotic plaque formation, induces function decline, causes pathological damage, disrupts function, triggers fed high-fat diet. By mitigating preserving Tongxinluo prevent complicated atherosclerosis.[19] highlight approach summary, comprehensively analyze macrophages, treatment. However, several important questions remain addressed. First, future studies should use integrative omics approaches elucidate underlying mechanisms Second, further investigation required understand inhibitors on other types Finally, it determine whether occurs during entire development or mainly manifests advanced stages. Funding work was supported National Natural Science Foundation China (No. 82200084), Sichuan Province 2023NSFSC1456), Postdoctoral funded project TB2023047), Fundamental Research Funds Central Universities, University Interdisciplinary Innovation Fund 0020404153020). Conflicts interest None.

Язык: Английский

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Scutellarein alleviates osteoarthritis progression through the PI3K/Akt/NF‐kappaB signaling pathway: In vitro and in vivo studies

Phytotherapy Research, Год журнала: 2024, Номер 38(7), С. 3509 - 3524

Опубликована: Май 2, 2024

Abstract Osteoarthritis (OA), a joint disease that is associated with inflammatory processes involved in destruction. Scutellarein (Scu), component of the medicinal herbs Scutellaria barbata D. Don and Erigeron breviscapus (vant) Hand Mass , has anti‐inflammatory effects. We explored role Scu development OA underlying mechanisms. CCK‐8 assays, Calcein‐AM/PI EdU staining were used to determine chondrocyte viability after exposure. Western blot, qPCR, as well ELISA utilized measure extracellular matrix (ECM) degradation inflammation. Immunofluorescence (IF), western blot luciferase assays examine NF‐kappaB (NF‐κB) pathway. interacting proteins predicted using network pharmacology analysis molecular docking. X‐ray, H&E, Safranin O‐Fast Green(S‐O), toluidine blue, immunohistochemistry therapeutic effects destabilization medial meniscus (DMM) models. demonstrated inhibitory on ECM pro‐inflammatory factor levels chondrocytes treated IL‐1β. Mechanistically, inhibited IL‐1β‐induced activation PI3K/Akt/ NF‐κB signaling pathway cascades. Furthermore, been shown have significant binding capacities PI3K. Additionally, ameliorated progression DMM Our findings suggest may contribute amelioration by targeting PI3K/Akt/NF‐κB pathway, implying possesses promising potential for treatment OA.

Язык: Английский

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Recent advances in the potential effects of natural products from traditional Chinese medicine against respiratory diseases targeting ferroptosis

Chinese Medicine, Год журнала: 2024, Номер 19(1)

Опубликована: Март 22, 2024

Abstract Respiratory diseases, marked by structural changes in the airways and lung tissues, can lead to reduced respiratory function and, severe cases, failure. The side effects of current treatments, such as hormone therapy, drugs, radiotherapy, highlight need for new therapeutic strategies. Traditional Chinese Medicine (TCM) offers a promising alternative, leveraging its ability target multiple pathways mechanisms. Active compounds from herbs other natural sources exhibit anti-inflammatory, antioxidant, antitumor, immunomodulatory effects, making them valuable preventing treating conditions. Ferroptosis, unique form programmed cell death (PCD) distinct apoptosis, necrosis, others, has emerged key area interest. However, comprehensive reviews on how products influence ferroptosis diseases are lacking. This review will explore potential mechanisms TCM modulating like acute injury (ALI), asthma, pulmonary fibrosis (PF), chronic obstructive disease (COPD), ischemia–reperfusion (LIRI), hypertension (PH), cancer, aiming provide insights research clinical application health.

Язык: Английский

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Sea buckthorn extract mitigates chronic obstructive pulmonary disease by suppression of ferroptosis via scavenging ROS and blocking p53/MAPK pathways

Journal of Ethnopharmacology, Год журнала: 2024, Номер 336, С. 118726 - 118726

Опубликована: Авг. 23, 2024

Язык: Английский

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Nuclear factor erythroid 2-related factor-mediated signaling alleviates ferroptosis during cerebral ischemia-reperfusion injury

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 180, С. 117513 - 117513

Опубликована: Сен. 27, 2024

Язык: Английский

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In vitro and in vivo activities of scutellarein, a novel polyphosphate kinase 1 inhibitor against Acinetobacter baumannii infection

Microbial Cell Factories, Год журнала: 2024, Номер 23(1)

Опубликована: Окт. 8, 2024

Inorganic polyphosphate (polyP)-targeted kinase 1 (PPK1) has attracted much attention by virtue of its importance in bacterial pathogenicity and persistence, as well exclusive presence microorganisms. However, only very few drugs have been found to be efficacious inhibiting the Acinetobacter baumannii (A. baumannii) PPK1 protein.

Язык: Английский

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