Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 49.303
Filtrar
1.
PLoS One ; 19(3): e0299571, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38466744

RESUMO

Phosphatases can dephosphorylate phosphorylated kinases, leading to their inactivation, and ferroptosis is a type of cell death. Therefore, our aim is to identify phosphatases associated with ferroptosis by analyzing the differentially expressed genes (DEGs) of the Luminal A Breast Cancer (LumABC) cohort from the Cancer Genome Atlas (TCGA). An analysis of 260 phosphatase genes from the GeneCard database revealed that out of the 28 DEGs with high expression, only the expression of pyruvate dehydrogenase phosphatase 2 (PDP2) had a significant correlation with patient survival. In addition, an analysis of DEGs using gene ontology, Kyoto Encyclopedia of Genes and Genomes and gene set enrichment analysis revealed a significant variation in the expression of ferroptosis-related genes. To further investigate this, we analyzed 34 ferroptosis-related genes from the TCGA-LumABC cohort. The expression of long-chain acyl-CoA synthetase 4 (ACSL4) was found to have the highest correlation with the expression of PDP2, and its expression was also inversely proportional to the survival rate of patients. Western blot experiments using the MCF-7 cell line showed that the phosphorylation level of ACSL4 was significantly lower in cells transfected with the HA-PDP2 plasmid, and ferroptosis was correspondingly reduced (p < 0.001), as indicated by data from flow cytometry detection of membrane-permeability cell death stained with 7-aminoactinomycin, lipid peroxidation, and Fe2+. Immunoprecipitation experiments further revealed that the phosphorylation level of ACSL4 was only significantly reduced in cells where PDP2 and ACSL4 co-precipitated. These findings suggest that PDP2 may act as a phosphatase to dephosphorylate and inhibit the activity of ACSL4, which had been phosphorylated and activated in LumABC cells. Further experiments are needed to confirm the molecular mechanism of PDP2 inhibiting ferroptosis.


Assuntos
Neoplasias da Mama , Ferroptose , Feminino , Humanos , Neoplasias da Mama/genética , Coenzima A Ligases/genética , Ferroptose/genética , Peroxidação de Lipídeos , Monoéster Fosfórico Hidrolases , Fosforilação , Piruvato Desidrogenase (Lipoamida)-Fosfatase/metabolismo
2.
Int J Nanomedicine ; 19: 2091-2112, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38476278

RESUMO

Currently, cancer remains one of the most significant threats to human health. Treatment of most cancers remains challenging, despite the implementation of diverse therapies in clinical practice. In recent years, research on the mechanism of ferroptosis has presented novel perspectives for cancer treatment. Ferroptosis is a regulated cell death process caused by lipid peroxidation of membrane unsaturated fatty acids catalyzed by iron ions. The rapid development of bio-nanotechnology has generated considerable interest in exploiting iron-induced cell death as a new therapeutic target against cancer. This article provides a comprehensive overview of recent advancements at the intersection of iron-induced cell death and bionanotechnology. In this respect, the mechanism of iron-induced cell death and its relation to cancer are summarized. Furthermore, the feasibility of a nano-drug delivery system based on iron-induced cell death for cancer treatment is introduced and analyzed. Secondly, strategies for inducing iron-induced cell death using nanodrug delivery technology are discussed, including promoting Fenton reactions, inhibiting glutathione peroxidase 4, reducing low glutathione levels, and inhibiting system Xc-. Additionally, the article explores the potential of combined treatment strategies involving iron-induced cell death and bionanotechnology. Finally, the application prospects and challenges of iron-induced nanoagents for cancer treatment are discussed.


Assuntos
Ferroptose , Neoplasias , Humanos , Terapia Combinada , Morte Celular , Ferro , Peroxidação de Lipídeos
3.
Molecules ; 29(5)2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38474528

RESUMO

Amides containing methyl esters of γ-aminobutyric acid (GABA), L-proline and L-tyrosine, and esters containing 3-(pyridin-3-yl)propan-1-ol were synthesized by conjugation with 3,5-di-tert-butyl-4-hydroxybenzoic, an NSAID (tolfenamic acid), or 3-phenylacrylic (cinnamic, (E)-3-(3,4-dimethoxyphenyl)acrylic and caffeic) acids. The rationale for the conjugation of such moieties was based on the design of structures with two or more molecular characteristics. The novel compounds were tested for their antioxidant, anti-inflammatory and hypolipidemic properties. Several compounds were potent antioxidants, comparable to the well-known antioxidant, Trolox. In addition, the radical scavenging activity of compound 6 reached levels that were slightly better than that of Trolox. All the tested compounds demonstrated remarkable activity in the reduction in carrageenan-induced rat paw edema, up to 59% (compound 2, a dual antioxidant and anti-inflammatory molecule, with almost 2.5-times higher activity in this experiment than the parent NSAID). Additionally, the compounds caused a significant decrease in the plasma lipidemic indices in Triton-induced hyperlipidemic rats. Compound 2 decreased total cholesterol by 75.1% and compound 3 decreased triglycerides by 79.3% at 150 µmol/kg (i.p.). The hypocholesterolemic effect of the compounds was comparable to that of simvastatin, a well-known hypocholesterolemic drug. Additionally, all compounds lowered blood triglycerides. The synthesized compounds with multiple activities, as designed, may be useful as potential candidates for conditions involving inflammation, lipidemic deregulation and oxygen toxicity.


Assuntos
Anti-Inflamatórios não Esteroides , Antioxidantes , Ratos , Animais , Anti-Inflamatórios não Esteroides/química , Antioxidantes/química , Peroxidação de Lipídeos , Anti-Inflamatórios/farmacologia , Triglicerídeos , Edema/tratamento farmacológico , Carragenina/efeitos adversos
4.
Molecules ; 29(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38474625

RESUMO

This study aimed to characterize a Sideritis scardica extract (SidTea+TM) and investigate its effect on the physiological profile, metabolic health and redox status in healthy individuals. The chemical profile and antioxidant potential of the SidTea+TM extract were evaluated by UPLC-HRMS analysis and in vitro cell-free methods. Twenty-eight healthy adults participated in this randomized, double-blind, placebo-controlled study. Participants consumed 1500 mg/day of SidTea+TM or a placebo for 4 weeks. At baseline and post-supplementation, participants were assessed for their anthropometric and physiological profile and provided a resting blood sample. SidTea+TM decreased (p < 0.05) systolic blood pressure (-10.8 mmHg), mean arterial pressure (-4.5 mmHg), resting heart rate (-3.1 bpm) and handgrip strength of the non-dominant limb (-0.8 kg) whereas the placebo decreased (p < 0.05) handgrip strength of the dominant (-5.8 kg) and non-dominant (-3.2 kg) limb. SidTea+TM also resulted in an increase (p < 0.05) in estimated VO2max (+1.1 mL/kg/min) and a reduction (p < 0.05) in γ-GT and SGPT enzymatic activity in serum (-3.7 and -3.3 U/L, respectively). Finally, SidTea+TM increased (p < 0.001) total antioxidant capacity and decreased (p < 0.05) lipid peroxidation levels in plasma. These results indicate that SidTea+TM is a potent and safe to use antioxidant that can elicit positive changes in indices of blood pressure, cardiorespiratory capacity, liver metabolism, and redox status in healthy adults over a 4-week supplementation period.


Assuntos
Antioxidantes , Sideritis , Adulto , Humanos , Antioxidantes/farmacologia , Estresse Oxidativo , Sideritis/química , Força da Mão , Biomarcadores , Peroxidação de Lipídeos , Metaboloma , Método Duplo-Cego , Suplementos Nutricionais
5.
Molecules ; 29(5)2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38474637

RESUMO

Based on the reported research, hydroxyl radicals can be rapidly transformed into carbonate radicals in the carbonate-bicarbonate buffering system in vivo. Many of the processes considered to be initiated by hydroxyl radicals may be caused by carbonate radicals, which indicates that lipid peroxidation initiated by hydroxyl radicals can also be caused by carbonate radicals. To date, theoretical research on reactions of hydrogen abstraction from and radical addition to polyunsaturated fatty acids (PUFAs) of carbonate radicals has not been carried out systematically. This paper employs (3Z,6Z)-nona-3,6-diene (NDE) as a model for polyunsaturated fatty acids (PUFAs). Density functional theory (DFT) with the CAM-B3LYP method at the 6-311+g(d,p) level was used to calculate the differences in reactivity of carbonate radicals abstracting hydrogen from different positions of NDE and their addition to the double bonds of NDE under lipid solvent conditions with a dielectric constant of 4.0 (CPCM model). Grimme's empirical dispersion correction was taken into account through the D3 scheme. The energy barrier, reaction rate constants, internal energy, enthalpy and Gibbs free energy changes in these reactions were calculated With zero-point vibrational energy (ZPVE) corrections. The results indicated that carbonate radicals initiate lipid peroxidation primarily through hydrogen abstraction from diallyl carbon atoms. The reaction of hydrogen abstraction from diallyl carbon atoms exhibits the highest reaction rate, with a reaction rate constant approximately 43-fold greater than the second-ranked hydrogen abstraction from allyl carbon atoms. This process has the lowest energy barrier, internal energy, enthalpy, and Gibbs free energy changes, indicating that it is also the most spontaneous process.


Assuntos
Ácidos Graxos Insaturados , Hidrogênio , Peroxidação de Lipídeos , Hidrogênio/química , Ácidos Graxos Insaturados/química , Carbonatos , Radical Hidroxila/química , Carbono , Radicais Livres/química
6.
Cell Death Dis ; 15(3): 196, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459004

RESUMO

Cancer metabolism mainly includes carbohydrate, amino acid and lipid metabolism, each of which can be reprogrammed. These processes interact with each other to adapt to the complicated microenvironment. Ferroptosis is a regulated cell death induced by iron-dependent lipid peroxidation, which is morphologically different from apoptosis, necrosis, necroptosis, pyroptosis, autophagy-dependent cell death and cuprotosis. Cancer metabolism plays opposite roles in ferroptosis. On the one hand, carbohydrate metabolism can produce NADPH to maintain GPX4 and FSP1 function, and amino acid metabolism can provide substrates for synthesizing GPX4; on the other hand, lipid metabolism might synthesize PUFAs to trigger ferroptosis. The mechanisms through which cancer metabolism affects ferroptosis have been investigated extensively for a long time; however, some mechanisms have not yet been elucidated. In this review, we summarize the interaction between cancer metabolism and ferroptosis. Importantly, we were most concerned with how these targets can be utilized in cancer therapy.


Assuntos
Ferroptose , Neoplasias , Humanos , Neoplasias/genética , Apoptose , Necrose , Peroxidação de Lipídeos , Aminoácidos , Microambiente Tumoral
7.
Vestn Otorinolaringol ; 89(1): 16-20, 2024.
Artigo em Russo | MEDLINE | ID: mdl-38506020

RESUMO

The problem of chronic rhinitis (CR) remains unresolved in the world, while it has a negative impact on the quality of life of patients. Chronic forms of rhinitis suffer from 10-20% of the population, and its symptoms in epidemiological studies are noted in 40% of respondents. One of the leading mechanisms of disease occurrence is oxidative stress. OBJECTIVE: To study the state of the processes of lipid peroxidation and antioxidant protection in various types of chronic rhinitis. MATERIAL AND METHODS: The study included 50 patients with CR, of which 21 were with chronic allergic rhinitis (CALR), 20 with chronic vasomotor rhinitis (CVR), 9 with chronic atrophic rhinitis (CAR). The control group was represented by 50 practically healthy volunteers with no otorhinolaryngological complaints. The indicators of the LPO-AOD system in erythrocytes were evaluated by spectrophotometric methods. Statistical data processing was carried out using the Statistica 7.0 software package (StatSoft, USA). RESULTS: In all patients with CR in the blood erythrocytes, an increase in the level of malondialdehyde (MDA), a decrease in the activity of superoxide dismutase (SOD), catalase (CAT) relative to the control group was found. With CAR, the most pronounced changes are determined, with CVR - minimal. In patients with CR, lipid peroxidation is activated, MDA increases by 1.29 times, by 1.37 times with CAR, and by 1.31 times with CALR relative to normal values. The activity of the antioxidant system decreases, which reflects the classical variant of inhibition of antioxidant enzymes: SOD is reduced by 1.08 times in CAR, by 1.07 times in CALR, and 1.04 times in CVR, CAT in CAR is reduced by 1.02 times; CALR by 1.02 times, with CVR by 1.01 times. The coefficient of oxidative stress with CVR is 1.36, with CAR is 1.5, with CALR is 1.42. CONCLUSION: In CR, the predominance of pro-oxidant processes over antioxidant ones is revealed, a slight oxidative stress is detected, probably due to the presence of hypoxia and intoxication syndrome. An in-depth study of lipid peroxidation processes and factors of the antioxidant defense system, depending on the CR phenotype, can be used to correct therapy and prevent exacerbations, as well as markers of progression and prognosis of chronic rhinitis.


Assuntos
Antioxidantes , Rinite Alérgica , Humanos , Peroxidação de Lipídeos/fisiologia , Qualidade de Vida , Glutationa Peroxidase/metabolismo , Catalase/metabolismo , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismo , Rinite Alérgica/diagnóstico , Malondialdeído
8.
ACS Nano ; 18(11): 7945-7958, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38452275

RESUMO

Ferroptosis is a form of regulated cell death accompanied by lipid reactive oxygen species (ROS) accumulation in an iron-dependent manner. However, the efficiency of tumorous ferroptosis was seriously restricted by intracellular ferroptosis defense systems, the glutathione peroxidase 4 (GPX4) system, and the ubiquinol (CoQH2) system. Inspired by the crucial role of mitochondria in the ferroptosis process, we reported a prodrug nanoassembly capable of unleashing potent mitochondrial lipid peroxidation and ferroptotic cell death. Dihydroorotate dehydrogenase (DHODH) inhibitor (QA) was combined with triphenylphosphonium moiety through a disulfide-containing linker to engineer well-defined nanoassemblies (QSSP) within a single-molecular framework. After being trapped in cancer cells, the acidic condition provoked the structural disassembly of QSSP to liberate free prodrug molecules. The mitochondrial membrane-potential-driven accumulation of the lipophilic cation prodrug was delivered explicitly into the mitochondria. Afterward, the thiol-disulfide exchange would occur accompanied by downregulation of reduced glutathione levels, thus resulting in mitochondria-localized GPX4 inactivation for ferroptosis. Simultaneously, the released QA from the hydrolysis reaction of the adjacent ester bond could further devastate mitochondrial defense and evoke robust ferroptosis via the DHODH-CoQH2 system. This subcellular targeted nanoassembly provides a reference for designing ferroptosis-based strategy for efficient cancer therapy through interfering antiferroptosis systems.


Assuntos
Ferroptose , Compostos Organofosforados , Pró-Fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/metabolismo , Di-Hidro-Orotato Desidrogenase , Peroxidação de Lipídeos , Espécies Reativas de Oxigênio/metabolismo , Mitocôndrias/metabolismo , Dissulfetos/metabolismo
9.
J Cell Mol Med ; 28(7): e18212, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38516826

RESUMO

SBFI26, an inhibitor of FABP5, has been shown to suppress the proliferation and metastasis of tumour cells. However, the underlying mechanism by which SBFI26 induces ferroptosis in breast cancer cells remains largely unknown. Three breast cancer cell lines were treated with SBFI26 and CCK-8 assessed cytotoxicity. Transcriptome was performed on the Illumina platform and verified by qPCR. Western blot evaluated protein levels. Malondialdehyde (MDA), total superoxide dismutase (T-SOD), Fe, glutathione (GSH) and oxidized glutathione (GSSG) were measured. SBFI26 induced cell death time- and dose-dependent, with a more significant inhibitory effect on MDA-MB-231 cells. Fer-1, GSH and Vitamin C attenuated the effects but not erastin. RNA-Seq analysis revealed that SBFI26 treatment significantly enriched differentially expressed genes related to ferroptosis. Furthermore, SBFI26 increased intracellular MDA, iron ion, and GSSG levels while decreasing T-SOD, total glutathione (T-GSH), and GSH levels.SBFI26 dose-dependently up-regulates the expression of HMOX1 and ALOX12 at both gene and protein levels, promoting ferroptosis. Similarly, it significantly increases the expression of SAT1, ALOX5, ALOX15, ALOXE3 and CHAC1 that, promoting ferroptosis while downregulating the NFE2L2 gene and protein that inhibit ferroptosis. SBFI26 leads to cellular accumulation of fatty acids, which triggers excess ferrous ions and subsequent lipid peroxidation for inducing ferroptosis.


Assuntos
Ferroptose , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Dissulfeto de Glutationa , Ferroptose/genética , Peroxidação de Lipídeos , Glutationa , Ferro , Superóxido Dismutase/genética , Espécies Reativas de Oxigênio , Proteínas de Ligação a Ácido Graxo
10.
Anim Biotechnol ; 35(1): 2331179, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-38519440

RESUMO

Despite the significant threat of heat stress to livestock animals, only a few studies have considered the potential relationship between broiler chickens and their microbiota. Therefore, this study examined microbial modifications, transcriptional changes and host-microbiome interactions using a predicted metabolome data-based approach to understand the impact of heat stress on poultry. After the analysis, the host functional enrichment analysis revealed that pathways related to lipid and protein metabolism were elevated under heat stress conditions. In contrast, pathways related to the cell cycle were suppressed under normal environmental temperatures. In line with the transcriptome analysis, the microbial analysis results indicate that taxonomic changes affect lipid degradation. Heat stress engendered statistically significant difference in the abundance of 11 microorganisms, including Bacteroides and Peptostreptococcacea. Together, integrative approach analysis suggests that microbiota-induced metabolites affect host fatty acid peroxidation metabolism, which is correlated with the gene families of Acyl-CoA dehydrogenase long chain (ACADL), Acyl-CoA Oxidase (ACOX) and Acetyl-CoA Acyltransferase (ACAA). This integrated approach provides novel insights into heat stress problems and identifies potential biomarkers associated with heat stress.


Assuntos
Aves Domésticas , Transcriptoma , Animais , Aves Domésticas/genética , Aves Domésticas/metabolismo , Peroxidação de Lipídeos/genética , Jejuno/metabolismo , Galinhas/genética , Galinhas/metabolismo , Perfilação da Expressão Gênica , Resposta ao Choque Térmico/genética , Lipídeos , Aminoácidos/genética , Aminoácidos/metabolismo
11.
Pol J Vet Sci ; 27(1): 43-52, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38511595

RESUMO

Cystic endometrial hyperplasia-pyometra complex (CEH-P) is a common disease in sexually mature bitches. Disease progression leads to oxidative stress, resulting in the depletion of uterine antioxidants and lipid peroxidation of associated cells, which further aggravates the condition. The concentration of antioxidant enzymes, the level of lipid peroxidation within the uterine tissue, and its reflection in the serum and urine need to be elucidated. The aim of this study was to analyze the concentration of antioxidants such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), and the lipid peroxidation marker malonaldehyde (MDA) in three types of samples, i.e., serum, urine, and uterine tissue. For this purpose, 58 pyometra-affected and 44 healthy bitches were included in the present study. All animals underwent ovariohysterectomy (OVH). Our data indicated highly significant difference (p<0.01) in the antioxidant concentrations of uterine, serum and urine samples. Furthermore, there was a highly significant (p<0.01) difference in the serum levels of ferric reducing antioxidant power (FRAP) and free radical scavenging activity (FRSA) indicated poor capacity to overcome oxidative stress in the CEH-Pyometra condition. We showed that CEH-P induces oxidative stress, which further depletes the antioxidant enzyme reserves in the uterus. Thus, the weak antioxidant defence predisposes to uterine damage and disease progression. The simultaneous depletion of antioxidants and an increase in lipid peroxidation in the serum and urine may also act as early indicators of uterine pathology.


Assuntos
Doenças do Cão , Hiperplasia Endometrial , Piometra , Cães , Feminino , Animais , Hiperplasia Endometrial/veterinária , Hiperplasia Endometrial/metabolismo , Hiperplasia Endometrial/patologia , Piometra/veterinária , Piometra/metabolismo , Antioxidantes/metabolismo , Útero/metabolismo , Glutationa/metabolismo , Progressão da Doença , Peroxidação de Lipídeos
12.
Mol Med ; 30(1): 24, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321393

RESUMO

BACKGROUND: Lipid peroxidation is a characteristic metabolic manifestation of diabetic retinopathy (DR) that causes inflammation, eventually leading to severe retinal vascular abnormalities. Selenium (Se) can directly or indirectly scavenge intracellular free radicals. Due to the narrow distinction between Se's effective and toxic doses, porous Se@SiO2 nanospheres have been developed to control the release of Se. They exert strong antioxidant and anti-inflammatory effects. METHODS: The effect of anti-lipid peroxidation and anti-inflammatory effects of porous Se@SiO2 nanospheres on diabetic mice were assessed by detecting the level of Malondialdehyde (MDA), glutathione peroxidase 4 (GPX4), decreased reduced/oxidized glutathione (GSH/GSSG) ratio, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, and interleukin (IL) -1ß of the retina. To further examine the protective effect of porous Se@SiO2 nanospheres on the retinal vasculopathy of diabetic mice, retinal acellular capillary, the expression of tight junction proteins, and blood-retinal barrier destruction was observed. Finally, we validated the GPX4 as the target of porous Se@SiO2 nanospheres via decreased expression of GPX4 and detected the level of MDA, GSH/GSSG, TNF-α, IFN-γ, IL -1ß, wound healing assay, and tube formation in high glucose (HG) cultured Human retinal microvascular endothelial cells (HRMECs). RESULTS: The porous Se@SiO2 nanospheres reduced the level of MDA, TNF-α, IFN-γ, and IL -1ß, while increasing the level of GPX4 and GSH/GSSG in diabetic mice. Therefore, porous Se@SiO2 nanospheres reduced the number of retinal acellular capillaries, depletion of tight junction proteins, and vascular leakage in diabetic mice. Further, we identified GPX4 as the target of porous Se@SiO2 nanospheres as GPX4 inhibition reduced the repression effect of anti-lipid peroxidation, anti-inflammatory, and protective effects of endothelial cell dysfunction of porous Se@SiO2 nanospheres in HG-cultured HRMECs. CONCLUSION: Porous Se@SiO2 nanospheres effectively attenuated retinal vasculopathy in diabetic mice via inhibiting excess lipid peroxidation and inflammation by target GPX4, suggesting their potential as therapeutic agents for DR.


Assuntos
Diabetes Mellitus Experimental , Retinopatia Diabética , Nanosferas , Selênio , Humanos , Camundongos , Animais , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Selênio/metabolismo , Selênio/farmacologia , Selênio/uso terapêutico , Dióxido de Silício/metabolismo , Dióxido de Silício/farmacologia , Dióxido de Silício/uso terapêutico , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/metabolismo , Peroxidação de Lipídeos , Porosidade , Fator de Necrose Tumoral alfa/metabolismo , Dissulfeto de Glutationa/metabolismo , Dissulfeto de Glutationa/farmacologia , Dissulfeto de Glutationa/uso terapêutico , Inflamação/metabolismo , Anti-Inflamatórios/uso terapêutico , Proteínas de Junções Íntimas/metabolismo
13.
Biomed Pharmacother ; 172: 116270, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38364737

RESUMO

Iron homeostasisis is integral to normal physiological and biochemical processes of lungs. The maintenance of iron homeostasis involves the process of intake, storage and output, dependening on iron-regulated protein/iron response element system to operate tightly metabolism-related genes, including TFR1, DMT1, Fth, and FPN. Dysregulation of iron can lead to iron overload, which increases the virulence of microbial colonisers and the occurrence of oxidative stress, causing alveolar epithelial cells to undergo necrosis and apoptosis, and form extracellular matrix. Accumulated iron drive iron-dependent ferroptosis to exacerbated pulmonary fibrosis. Notably, the iron chelator deferoxamine and the lipophilic antioxidant ferritin-1 have been shown to attenuate ferroptosis and inhibit lipid peroxidation in pulmonary fibrosis. The paper summarises the regulatory mechanisms of dysregulated iron metabolism and ferroptosis in the development of pulmonary fibrosis. Targeting iron metabolism may be a potential therapeutic strategy for the prevention and treatment of pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Humanos , Fibrose Pulmonar/tratamento farmacológico , Peroxidação de Lipídeos , Estresse Oxidativo , Células Epiteliais Alveolares , Ferro
14.
Environ Sci Pollut Res Int ; 31(13): 20461-20476, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38376785

RESUMO

In the last few decades, there has been a growing interest in understanding the behavior of personal care products (PCPs) in the aquatic environment. In this regard, the aim of this study is to estimate the accumulation and effects of four PCPs within the clam Ruditapes philippinarum. The PCPs selected were triclosan, OTNE, benzophenone-3, and octocrylene. A progressive uptake was observed and maximum concentrations in tissues were reached at the end of the exposure phase, up to levels of 0.68 µg g-1, 24 µg g-1, 0.81 µg g-1, and 1.52 µg g-1 for OTNE, BP-3, OC, and TCS, respectively. After the PCP post-exposure period, the removal percentages were higher than 65%. The estimated logarithm bioconcentration factor ranged from 3.34 to 2.93, in concordance with the lipophobicity of each substance. No lethal effects were found although significant changes were observed for ethoxyresorufin O-demethylase activity, glutathione S-transferase activity, lipid peroxidation, and DNA damage.


Assuntos
Bivalves , Cosméticos , Poluentes Químicos da Água , Animais , Peroxidação de Lipídeos , Dano ao DNA , Alimentos Marinhos , Poluentes Químicos da Água/análise
15.
ACS Nano ; 18(9): 7011-7023, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38390865

RESUMO

Ferroptotic cancer therapy has been extensively investigated since the genesis of the ferroptosis concept. However, the therapeutic efficacy of ferroptosis induction in heterogeneous and plastic melanoma has been compromised, because the melanocytic and transitory cell subpopulation is resistant to iron-dependent oxidative stress. Here, we report a phenotype-altering liposomal nanomedicine to enable the ferroptosis-resistant subtypes of melanoma cells vulnerable to lipid peroxidation via senescence induction. The strategy involves the ratiometric coencapsulation of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor (palbociclib) and a ferroptosis inducer (auranofin) within cRGD peptide-modified targeted liposomes. The two drugs showed a synergistic anticancer effect in the model B16F10 melanoma cells, as evidenced by the combination index analysis (<1). The liposomes could efficiently deliver both drugs into B16F10 cells in a targeted manner. Afterward, the liposomes potently induced the intracellular redox imbalance and lipid peroxidation. Palbociclib significantly provoked cell cycle arrest at the G0/G1 phase, which sensitized auranofin-caused ferroptosis through senescence induction. Meanwhile, palbociclib depleted intracellular glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), further boosting ferroptosis. The proof-of-concept was also demonstrated in the B16F10 tumor-bearing mice model. The current work offers a promising ferroptosis-targeting strategy for effectively treating heterogeneous melanoma by manipulating the cellular plasticity.


Assuntos
Ferroptose , Melanoma , Animais , Camundongos , Melanoma/tratamento farmacológico , Lipossomos/farmacologia , Coenzimas/farmacologia , Auranofina/farmacologia , Peroxidação de Lipídeos
16.
J Ethnopharmacol ; 326: 117963, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38387680

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is a serious complication of liver disease characterized by excessive collagen deposition, without effective therapeutic agents in the clinic. Fu-Gan-Wan (FGW) is an empirical formula used for the clinical treatment of hepatitis and cirrhosis. It has been shown to reverse experimental liver fibrosis. However, its corresponding mechanisms remain unclear. AIM OF THE REVIEW: This study aimed to elucidate the key pathways and target genes of FGW in attenuating liver fibrosis. MATERIALS AND METHODS: The therapeutic effects of different doses of FGW on liver fibrosis were investigated using a 2 mL/kg 15% CCl4-induced mouse model. Then, RNA-seq combined with network pharmacology was used to analyze the key biological processes and signaling pathways underlying the anti-liver fibrosis exertion of FGW. These findings were validated in a TGF-ß1-induced model of activation and proliferation of mouse hepatic stellate cell line JS-1. Finally, the key signaling pathways and molecular targets were validated using animal tissues, and the effect of FGW on tissue lipid peroxidation was additionally observed. RESULTS: We found that 19.5 g/kg FGW significantly down-regulated CCl4-induced elevation of hepatic ALT and AST, decreased collagen deposition, and inhibited the expression of pro-fibrotic factors α-SMA, COL1α1, CTGF, TIMP-1, as well as pro-inflammatory factor TGF-ß1. Additionally, FGW at doses of 62.5, 125, and 250 µg/mL dose-dependently blocked JS-1 proliferation, migration, and activation. Furthermore, RNA-seq identified the NF-κB signaling pathway as a key target molecular pathway for FGW against liver fibrosis, and network pharmacology combined with RNA-seq focused on 11 key genes. Significant changes were identified in CCL2 and HMOX1 by tissue RT-PCR, Western blot, and immunohistochemistry. We further demonstrated that FGW significantly attenuated CCl4-induced increases in p-p65, CCL2, CCR2, and HMOX1, while significantly elevating Nrf2. Finally, FGW significantly suppressed the accumulation of lipid peroxidation products MDA and 4-HNE and reconfigured the oxidation-reduction balance, including promoting the increase of antioxidants GPx, GSH, and SOD, and the decrease of peroxidation products ROS and GSSG. CONCLUSIONS: This study demonstrated that FGW exhibits potential in mitigating CCl4-induced hepatic fibrosis, lipid peroxidation, and iron metabolism disorders in mice. This effect may be mediated through the NF-κB/CCL2/CCR2 and Nrf2/HMOX1 pathways.


Assuntos
NF-kappa B , Fator de Crescimento Transformador beta1 , Camundongos , Animais , NF-kappa B/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Peroxidação de Lipídeos , Farmacologia em Rede , RNA-Seq , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Transdução de Sinais , Fígado , Colágeno/metabolismo , Tetracloreto de Carbono/farmacologia , Células Estreladas do Fígado
17.
Int J Mol Sci ; 25(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38396896

RESUMO

Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.


Assuntos
Ascite , Cardiotoxicidade , Ratos , Animais , Carvedilol/farmacologia , NADP/metabolismo , Cardiotoxicidade/metabolismo , Ascite/patologia , Doxorrubicina/uso terapêutico , Miocárdio/metabolismo , Antibióticos Antineoplásicos/uso terapêutico , Ferro/metabolismo , Peroxidação de Lipídeos , Fígado/metabolismo , Transferrina/metabolismo , Peso Corporal
18.
Chemosphere ; 352: 141512, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38387655

RESUMO

This study aimed to assess the impact of acute exposure (96 h) to Cd in gills, digestive gland and muscle of the Tehuelche scallop Aequipecten tehuelchus from San José gulf in Patagonia, Argentina. Scallops were exposed to Cd concentrations of 0, 25, 50, 100, 150, 204, 275, 371, and 500 µg/L, and mortality rates were recorded after 96 h of exposure. Surviving organisms were analyzed for the biochemical response through reactive oxygen and nitrogen species (RONS), activities of catalase (CAT) and glutathione-S-transferase (GST), metallothioneins (MT), lipid peroxidation (LPO) and liposoluble antioxidants α-tocopherol (α-T) and ß-carotene (ß-C). The mean lethal concentration (LC50) was 155.8 µg Cd/L, a lower value than other scallops' species, showing that A. tehuelchus has a particular sensitivity to Cd. In the three tissues, at all exposure concentrations, there was no significant response in RONS levels, GST activity or LPO. Nevertheless, CAT activity and α-T levels decreased in the gills but increased in the digestive gland, with no significant response in the muscle. Two-way ANOVA revealed a significant interaction between Cd concentration and tissue on MT, which increased significantly in gills, decreased in digestive gland with 100 compared to 50 µg Cd/L; whereas in muscle a significant increase was observed with 25 µg Cd/L compared to control. The results show a significant effect of Cd in scallop's gills on CAT activity and α-T levels, highlighting this tissue as the primary target against relevant concentrations of metal in seawater. The effect on digestive gland and muscle was minimal. The overall results suggest that Cd toxicity is tissue-specific. This study will help reduce the existence knowledge gap regarding potential impacts of acute exposure to Cd in a bivalve species with high ecological and commercial importance, as well as identifying the most responsive biomarkers associated with Cd stress for monitoring assessment.


Assuntos
Pectinidae , Poluentes Químicos da Água , Animais , Antioxidantes/metabolismo , Cádmio/análise , Estresse Oxidativo , Catalase/metabolismo , Pectinidae/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Brânquias/metabolismo , Poluentes Químicos da Água/análise , Peroxidação de Lipídeos , Biomarcadores/metabolismo
19.
Mol Biol Rep ; 51(1): 314, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38376557

RESUMO

Kidney stone is a common and highly recurrent disease in urology, and its pathogenesis is associated with various factors. However, its precise pathogenesis is still unknown. Ferroptosis describes a form of regulated cell death that is driven by unrestricted lipid peroxidation, which does not require the activation of caspase and can be suppressed by iron chelators, lipophilic antioxidants, inhibitors of lipid peroxidation, and depletion of polyunsaturated fatty acids. Recent studies have shown that ferroptosis plays a crucial role in kidney stone formation. An increasing number of studies have shown that calcium oxalate, urate, phosphate, and selenium deficiency induce ferroptosis and promote kidney stone formation through mechanisms such as oxidative stress, endoplasmic reticulum stress, and autophagy. We also offered a new direction for the downstream mechanism of ferroptosis in kidney stone formation based on the "death wave" phenomenon. We reviewed the emerging role of ferroptosis in kidney stone formation and provided new ideas for the future treatment and prevention of kidney stones.


Assuntos
Ferroptose , Cálculos Renais , Humanos , Peroxidação de Lipídeos , Estresse Oxidativo , Antioxidantes
20.
J Pak Med Assoc ; 74(1 (Supple-2)): S63-S67, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38385474

RESUMO

OBJECTIVE: To examine the therapeutic effects of Olea europaea L. leaves extract on carbon tetrachloride-induced liver injury in rats. Methods: The experimental study was conducted at the Department of Physiology, University of Karachi, Karachi, in July 2021, and comprised Albino Wistar male rats weighing 180-220gm. The animals were divided into control group I, carbon tetrachloride group II, Olea europaea L. + carbon tetrachloride group III and Olea europaea L. group IV. In Vitro model of hepatic toxicity was developed by carbon tetrachloride. A daily dose of 50mg/kg of aqueous extract of olive leaves was administered orally and 0.8ml/kg of carbon tetrachloride was administered twice a week subcutaneously for 28 days. On the 29th day, the animals were sacrificed, and tested for hepatic enzymes, lipid peroxidation markers and histopathology. Data was analysed using SPSS 20. RESULTS: Of the 24 rats, 6(25%) were in each of the 4 groups. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin levels were significantly reduced (p<0.05) in group II whereas, 4- hydroxynonenal, isoprostane and malondialdehyde levels were significantly increased (p<0.05). However, total antioxidant level increased significantly (p<0.05) in group III compared to group II. Histopathology showed severe liver damage in group II and mild damage in group III. Conclusion: Olea europaea L. leaves extract was found to have profound hepatoprotective effects.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Olea , Ratos , Masculino , Animais , Tetracloreto de Carbono/toxicidade , Tetracloreto de Carbono/metabolismo , Olea/metabolismo , Fitoterapia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fígado/patologia , Ratos Wistar , Aspartato Aminotransferases , Alanina Transaminase/metabolismo , Peroxidação de Lipídeos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...