RÉSUMÉ
BACKGROUND: Ferroptosis is a newly recognized form of regulatory cell death characterized by severe lipid peroxidation triggered by iron overload and the production of reactive oxygen species (ROS). However, the role of ferroptosis in severe acute pancreatitis(SAP) has not been fully elucidated. METHODS: We established four severe acute pancreatitis models of rats including the sham control group, the SAP group, the Fer -1-treated SAP (SAP + Fer-1) group, the 3-MA-treated SAP (SAP + 3-MA) group. The SAP group was induced by retrograde injection of sodium taurocholate into the pancreatic duct. The other two groups were intraperitoneally injected with ferroptosis inhibitor (Fer-1) and autophagy inhibitor (3-MA), respectively. The model of severe acute pancreatitis with amylase crest-related inflammatory factors was successfully established. Then we detected ferroptosis (GPX4, SLC7A1 etc.) and autophagy-related factors (LC3II, p62 ect.) to further clarify the relationship between ferroptosis and autophagy. RESULTS: Our study found that ferroptosis occurs during the development of SAP, such as iron and lipid peroxidation in pancreatic tissues, decreased levels of reduced glutathione peroxidase 4 (GPX 4) and glutathione (GSH), and increased malondialdehyde(MDA) and significant mitochondrial damage. In addition, ferroptosis related proteins such as GPX4, solute carrier family 7 member 11(SLC7A11) and ferritin heavy chain 1(FTH1) were significantly decreased. Next, the pathogenesis of ferroptosis in SAP was studied. First, treatment with the ferroptosis inhibitor ferrostatin-1(Fer-1) significantly alleviated ferroptosis in SAP. Interestingly, autophagy occurs during the pathogenesis of SAP, and autophagy promotes the occurrence of ferroptosis in SAP. Moreover, 3-methyladenine (3-MA) inhibition of autophagy can significantly reduce iron overload and ferroptosis in SAP. CONCLUSIONS: Our results suggest that ferroptosis is a novel pathogenesis of SAP and is dependent on autophagy. This study provides a new theoretical basis for the study of SAP.
Sujet(s)
Autophagie , Modèles animaux de maladie humaine , Ferroptose , Peroxydation lipidique , Pancréatite , Rat Sprague-Dawley , Animaux , Pancréatite/métabolisme , Pancréatite/anatomopathologie , Rats , Mâle , Adénine/analogues et dérivés , Adénine/pharmacologie , Phospholipid hydroperoxide glutathione peroxidase/métabolisme , Acide taurocholique , Cyclohexylamines/pharmacologie , Pancréas/anatomopathologie , Pancréas/métabolisme , Phénylènediamines/pharmacologie , Malonaldéhyde/métabolisme , Espèces réactives de l'oxygène/métabolisme , Maladie aigüe , Glutathion/métabolisme , Fer/métabolismeRÉSUMÉ
The increasing rates of drug misuse highlight the urgency of identifying improved therapeutics for treatment. Most drug-seeking behaviours that can be modelled in rodents utilize the repeated intravenous self-administration (SA) of drugs. Recent studies examining the mesolimbic pathway suggest that Kv7/KCNQ channels may contribute to the transition from recreational to chronic drug use. However, to date, all such studies used noncontingent, experimenter-delivered drug model systems, and the extent to which this effect generalizes to rats trained to self-administer drugs is not known. Here, we tested the ability of retigabine (ezogabine), a Kv7 channel opener, to regulate instrumental behaviour in male Sprague Dawley rats. We first validated the ability of retigabine to target experimenter-delivered cocaine in a conditioned place preference (CPP) assay and found that retigabine reduced the acquisition of place preference. Next, we trained rats for cocaine-SA under a fixed-ratio or progressive-ratio reinforcement schedule and found that retigabine pretreatment attenuated the SA of low to moderate doses of cocaine. This was not observed in parallel experiments, with rats self-administering sucrose, a natural reward. Compared with sucrose-SA, cocaine-SA was associated with reductions in the expression of the Kv7.5 subunit in the nucleus accumbens, without alterations in Kv7.2 and Kv7.3. Therefore, these studies reveal a reward-specific reduction in SA behaviour and support the notion that Kv7 is a potential therapeutic target for human psychiatric diseases with dysfunctional reward circuitry.
Sujet(s)
Carbamates , Cocaïne , Phénylènediamines , Rat Sprague-Dawley , Autoadministration , Saccharose , Animaux , Phénylènediamines/pharmacologie , Phénylènediamines/administration et posologie , Carbamates/pharmacologie , Carbamates/administration et posologie , Cocaïne/pharmacologie , Cocaïne/administration et posologie , Mâle , Rats , Saccharose/administration et posologie , Saccharose/pharmacologie , Comportement de recherche de substances/effets des médicaments et des substances chimiques , Canaux potassiques KNCQ/effets des médicaments et des substances chimiques , Conditionnement opérant/effets des médicaments et des substances chimiques , Inhibiteurs de la capture de la dopamine/pharmacologie , Inhibiteurs de la capture de la dopamine/administration et posologieRÉSUMÉ
A dual-template molecularly imprinted electrochemical sensor was developed for the simultaneous detection of serotonin (5-HT) and glutamate (Glu). First, amino-functionalized reduced graphene oxide (NRGO) was used as the modification material of a GCE to increase its electrical conductivity and specific surface area, using Glu and 5-HT as dual-template molecules and o-phenylenediamine (OPD) with self-polymerization ability as functional monomers. Through self-assembly and electropolymerization, dual-template molecularly imprinted polymers were formed on the electrode. After removing the templates, the specific recognition binding sites were exposed. The amount of NRGO, polymerization parameters, and elution parameters were further optimized to construct a dual-template molecularly imprinted electrochemical sensor, which can specifically recognize double-target molecules Glu and 5-HT. The differential pulse voltammetry (DPV) technique was used to achieve simultaneous detection of Glu and 5-HT based on their distinct electrochemical activities under specific conditions. The sensor showed a good linear relationship for Glu and 5-HT in the range 1 ~ 100 µM, and the detection limits were 0.067 µM and 0.047 µM (S/N = 3), respectively. The sensor has good reproducibility, repeatability, and selectivity. It was successfully utilized to simultaneously detect Glu and 5-HT in mouse serum, offering a more dependable foundation for objectively diagnosing and early warning of depression. Additionally, the double signal sensing strategy also provides a new approach for the simultaneous detection of both electroactive and non-electroactive substances.
Sujet(s)
Techniques électrochimiques , Acide glutamique , Graphite , Limite de détection , Empreinte moléculaire , Phénylènediamines , Sérotonine , Sérotonine/sang , Sérotonine/analyse , Techniques électrochimiques/méthodes , Techniques électrochimiques/instrumentation , Animaux , Acide glutamique/analyse , Acide glutamique/sang , Acide glutamique/composition chimique , Graphite/composition chimique , Souris , Phénylènediamines/composition chimique , Dépression/diagnostic , Dépression/sang , Électrodes , Marqueurs biologiques/sang , Marqueurs biologiques/analyse , Reproductibilité des résultatsRÉSUMÉ
Abnormal shifts in global climate, leading to extreme weather, significantly threaten the safety of individuals involved in outdoor activities. Hypothermia-induced coma or death frequently occurs in clinical and forensic settings. Despite this, the precise mechanism of central nervous system injury due to hypothermia remains unclear, hindering the development of targeted clinical treatments and specific forensic diagnostic indicators. The GEO database was searched to identify datasets related to hypothermia. Post-bioinformatics analyses, DEGs, and ferroptosis-related DEGs (FerrDEGs) were intersected. GSEA was then conducted to elucidate the functions of the Ferr-related genes. Animal experiments conducted in this study demonstrated that hypothermia, compared to the control treatment, can induce significant alterations in iron death-related genes such as PPARG, SCD, ADIPOQ, SAT1, EGR1, and HMOX1 in cerebral cortex nerve cells. These changes lead to iron ion accumulation, lipid peroxidation, and marked expression of iron death-related proteins. The application of the iron death inhibitor Ferrostatin-1 (Fer-1) effectively modulates the expression of these genes, reduces lipid peroxidation, and improves the expression of iron death-related proteins. Severe hypothermia disrupts the metabolism of cerebral cortex nerve cells, causing significant alterations in ferroptosis-related genes. These genetic changes promote ferroptosis through multiple pathways.
Sujet(s)
Cortex cérébral , Ferroptose , Hypothermie , Neurones , Ferroptose/génétique , Animaux , Hypothermie/métabolisme , Cortex cérébral/métabolisme , Cortex cérébral/anatomopathologie , Neurones/métabolisme , Fer/métabolisme , Peroxydation lipidique , Mâle , Rats , Phénylènediamines/pharmacologie , CyclohexylaminesRÉSUMÉ
Atherosclerosis is a leading cause of cardiovascular diseases (CVDs), often resulting in major adverse cardiovascular events (MACEs), such as myocardial infarction and stroke due to the rupture or erosion of vulnerable plaques. Ferroptosis, an iron-dependent form of cell death, has been implicated in the development of atherosclerosis. Despite its involvement in CVDs, the specific role of ferroptosis in atherosclerotic plaque stability remains unclear. In this study, we confirmed the presence of ferroptosis in unstable atherosclerotic plaques and demonstrated that the ferroptosis inhibitor ferrostatin-1 (Fer-1) stabilizes atherosclerotic plaques in apolipoprotein E knockout (Apoe-/-) mice. Using bioinformatic analysis combining RNA sequencing (RNA-seq) with single-cell RNA sequencing (scRNA-seq), we identified Yes-associated protein 1 (YAP1) as a potential key regulator of ferroptosis in vascular smooth muscle cells (VSMCs) of unstable plaques. In vitro, we found that YAP1 protects against oxidized low-density lipoprotein (oxLDL)-induced ferroptosis in VSMCs. Mechanistically, YAP1 exerts its anti-ferroptosis effects by regulating the expression of glutaminase 1 (GLS1) to promote the synthesis of glutamate (Glu) and glutathione (GSH). These findings establish a novel mechanism where the inhibition of ferroptosis promotes the stabilization of atherosclerotic plaques through the YAP1/GLS1 axis, attenuating VSMC ferroptosis. Thus, targeting the YAP1/GLS1 axis to suppress VSMC ferroptosis may represent a novel strategy for preventing and treating unstable atherosclerotic plaques.
Sujet(s)
Ferroptose , Muscles lisses vasculaires , Plaque d'athérosclérose , Protéines de signalisation YAP , Animaux , Muscles lisses vasculaires/métabolisme , Muscles lisses vasculaires/anatomopathologie , Souris , Plaque d'athérosclérose/métabolisme , Plaque d'athérosclérose/anatomopathologie , Protéines de signalisation YAP/métabolisme , Myocytes du muscle lisse/métabolisme , Myocytes du muscle lisse/anatomopathologie , Humains , Mâle , Souris de lignée C57BL , Athérosclérose/métabolisme , Athérosclérose/anatomopathologie , Athérosclérose/génétique , Souris knockout , Protéines adaptatrices de la transduction du signal/métabolisme , Protéines adaptatrices de la transduction du signal/génétique , Phénylènediamines/pharmacologie , Cyclohexylamines/pharmacologie , Apolipoprotéines E/métabolisme , Apolipoprotéines E/génétiqueRÉSUMÉ
Background: Myocardial infarction (MI) is characterized by irreversible cardiomyocyte death resulting from an inadequate supply of oxygenated blood to the myocardium. Recent studies have indicated that ferroptosis, a form of regulated cell death, exacerbates myocardial injury during MI. Concurrently, the upregulation of CD47 on the surface of damaged myocardium following MI impairs the clearance of dead cells by macrophages, thereby hindering efferocytosis. In this context, simultaneously inhibiting ferroptosis and enhancing efferocytosis may represent a promising strategy to mitigate myocardial damage post-MI. Methods: In this study, we engineered platelet membrane-coated hollow mesoporous silicon nanoparticles (HMSN) to serve as a drug delivery system, encapsulating ferroptosis inhibitor, Ferrostatin-1, along with an anti-CD47 antibody. We aimed to assess the potential of these nanoparticles (designated as Fer-aCD47@PHMSN) to specifically target the site of MI and evaluate their efficacy in reducing cardiomyocyte death and inflammation. Results: The platelet membrane coating on the nanoparticles significantly enhanced their ability to successfully target the site of myocardial infarction (MI). Our findings demonstrate that treatment with Fer-aCD47@PHMSN resulted in a 38.5% reduction in cardiomyocyte ferroptosis under hypoxia, indicated by decreased lipid peroxidation and increased in vitro. Additionally, Fer-aCD47@PHMSN improved cardiomyocyte efferocytosis by approximately 15% in vitro. In MI mice treated with Fer-aCD47@PHMSN, we observed a substantial reduction in cardiomyocyte death (nearly 30%), decreased inflammation, and significant improvement in cardiac function. Conclusion: Our results demonstrated that the cooperation between the two agents induced anti-ferroptosis effects and enhanced dead cardiomyocyte clearance by macrophage as well as anti-inflammation effects. Thus, our nanoparticle Fer-aCD47@PHMSN provides a new therapeutic strategy for targeted therapy of MI.
Sujet(s)
Antigènes CD47 , Ferroptose , Infarctus du myocarde , Myocytes cardiaques , Nanoparticules , Infarctus du myocarde/traitement médicamenteux , Infarctus du myocarde/métabolisme , Ferroptose/effets des médicaments et des substances chimiques , Animaux , Myocytes cardiaques/effets des médicaments et des substances chimiques , Myocytes cardiaques/métabolisme , Nanoparticules/composition chimique , Souris , Antigènes CD47/métabolisme , Phagocytose/effets des médicaments et des substances chimiques , Cyclohexylamines/pharmacologie , Cyclohexylamines/composition chimique , Mâle , Phénylènediamines/pharmacologie , Phénylènediamines/composition chimique , Macrophages/effets des médicaments et des substances chimiques , Plaquettes/effets des médicaments et des substances chimiques , Souris de lignée C57BL , Matériaux biomimétiques/composition chimique , Matériaux biomimétiques/pharmacologie , Vecteurs de médicaments/composition chimique , Humains ,RÉSUMÉ
In recent years, great progress has been made on the study of nanozymes with enzyme-like properties. Here, bimetallic Fe and Ni nanoclusters were anchored on the nanosheets of nitrogen-rich layered graphitic carbon nitride by one-step pyrolysis at high temperature (Fe/Ni-CN). The loading content of Fe and Ni on Fe/Ni-CN is as high as 8.0%, and Fe/Ni-CN has a high specific surface area of 121.86 m2 g-1. The Fe/Ni-CN can effectively oxidize 3,3',5,5'-tetramethylbenzidine (TMB) in the presence of H2O2, and exhibits efficient peroxidase-like activity, leading to a 17.2-fold increase compared to pure graphitic carbon nitride (CN). Similar to the natural horseradish peroxidase (HRP), the Fe/Ni-CN nanozyme follows catalytic kinetics. The Michaelis-Menten constant (Km) value of the Fe/Ni-CN nanozyme for TMB is about 8.3-fold lower than that for HRP, which means that the Fe/Ni-CN nanozyme has better affinity for TMB. In addition, the catalytic mechanism was investigated by combination of free radical quenching experiments and density-functional theory (DFT) calculations. The results show that the high peroxidase-like activity is due to the easy adsorption of H2O2 after bimetal loading, which is conducive to the production of hydroxyl radicals. Based on the extraordinary peroxidase-like activity, the colorimetric detection of p-phenylenediamine (PPD) was constructed with a wide linear range of 0.2-30 µM and a low detection limit of 0.02 µM. The sensor system has been successfully applied to the detection of residual PPD in real dyed hair samples. The results show that the colorimetric method is sensitive, highly selective and accurate. This study provides a new idea for the efficient enhancement of nanozyme activity and effective detection of PPD by a bimetallic synergistic strategy.
Sujet(s)
Colorimétrie , Graphite , Fer , Nickel , Composés de l'azote , Phénylènediamines , Graphite/composition chimique , Phénylènediamines/composition chimique , Colorimétrie/méthodes , Composés de l'azote/composition chimique , Nickel/composition chimique , Fer/composition chimique , Peroxyde d'hydrogène/analyse , Peroxyde d'hydrogène/composition chimique , Nitriles/composition chimique , Limite de détection , Catalyse , Benzidines/composition chimiqueRÉSUMÉ
Redox nanozymes have exhibited various applications in recognizing environmental pollutants but not aromatic amines (a type of typical pollutant). Herein, with Cu2+ as a node and tryptophan (Trp) as a linker, Cu-Trp as a specific ascorbic acid oxidase mimic was synthesized, which could catalyze ascorbic acid (AA) oxidation to dehydroascorbic acid (DHAA). Alternatively, with other natural amino acids as linkers to synthesize Cu-based nanozymes, such catalytic performances are also observed. The as-produced DHAA could react with o-phenylenediamine (OPD) and its derivatives (2,3-naphthalene diamine (NDA), 4-nitro-o-phenylenediamine (4-NO2-OPD), 4-fluoro-o-phenylenediamine (4-F-OPD), 4-chloro-o-phenylenediamine(4-Cl-OPD), and 4-bromo-o-phenylenediamine(4-Br-OPD)) to form a Schiff base and emit fluorescence. Based on the results, with Cu-Trp + AA and Cu-Arg (with arginine (Arg) as a linker) + AA as two sensing channels and extracted red, green, and blue (RGB) values from emitted fluorescence as read-out signals, a visual sensor array was constructed to efficiently distinguish OPD, NDA, 4-NO2-OPD, 4-F-OPD, 4-Cl-OPD, and 4-Br-OPD as low as 10 µM. Such detecting performance was further confirmed through discriminating binary, ternary, quinary, and senary mixtures with various concentration ratios, recognizing 18 unknown samples, and even quantitatively analyzing single aromatic amine. Finally, the discriminating ability was further validated in environmental waters, providing an efficient assay for large-scale scanning levels of multiple aromatic amines.
Sujet(s)
Amines , Ascorbate oxidase , Bases de Schiff , Bases de Schiff/composition chimique , Amines/composition chimique , Amines/analyse , Ascorbate oxidase/composition chimique , Ascorbate oxidase/métabolisme , Cuivre/composition chimique , Cuivre/analyse , Acide ascorbique/composition chimique , Acide ascorbique/analyse , Phénylènediamines/composition chimique , OxydoréductionRÉSUMÉ
Crizotinib carries an FDA hepatotoxicity warning, yet analysis of the FAERS database suggests that the severity of its hepatotoxicity risks, including progression to hepatitis and liver failure, might be underreported. However, the underlying mechanism remains poorly understood, and effective intervention strategies are lacking. Here, mRNA-sequencing analysis, along with KEGG and GO analyses, revealed that DEGs linked to Crizotinib-induced hepatotoxicity predominantly associate with the ferroptosis pathway which was identified as the principal mechanism behind Crizotinib-induced hepatocyte death. Furthermore, we found that ferroptosis inhibitors, namely Ferrostatin-1 and Deferoxamine mesylate, significantly reduced Crizotinib-induced hepatotoxicity and ferroptosis in both in vivo and in vitro settings. We have also discovered that overexpression of AAV8-mediated Nrf2 could mitigate Crizotinib-induced hepatotoxicity and ferroptosis in vivo by restoring the imbalance in glutathione metabolism, iron homeostasis, and lipid peroxidation. Additionally, both Stat1 deficiency and the Stat1 inhibitor NSC118218 were found to reduce Crizotinib-induced ferroptosis. Mechanistically, Crizotinib induces the phosphorylation of Stat1 at Ser727 but not Tyr701, promoting the transcriptional inhibition of Nrf2 expression after its entry into the nucleus to promote ferroptosis. Meanwhile, we found that MgIG and GA protected against hepatotoxicity to counteract ferroptosis without affecting or compromising the anti-cancer activity of Crizotinib, with a mechanism potentially related to the Stat1/Nrf2 pathway. Overall, our findings identify that the phosphorylation activation of Stat1 Ser727, rather than Tyr701, promotes ferroptosis through transcriptional inhibition of Nrf2, and highlight MgIG and GA as potential therapeutic approaches to enhance the safety of Crizotinib-based cancer therapy.
Sujet(s)
Lésions hépatiques dues aux substances , Crizotinib , Ferroptose , Facteur-2 apparenté à NF-E2 , Facteur de transcription STAT-1 , Ferroptose/effets des médicaments et des substances chimiques , Facteur-2 apparenté à NF-E2/métabolisme , Humains , Animaux , Crizotinib/pharmacologie , Crizotinib/effets indésirables , Lésions hépatiques dues aux substances/métabolisme , Lésions hépatiques dues aux substances/anatomopathologie , Lésions hépatiques dues aux substances/génétique , Facteur de transcription STAT-1/métabolisme , Facteur de transcription STAT-1/génétique , Souris , Transduction du signal/effets des médicaments et des substances chimiques , Mâle , Phénylènediamines/pharmacologie , Souris de lignée C57BL , Hépatocytes/métabolisme , Hépatocytes/effets des médicaments et des substances chimiques , Phosphorylation/effets des médicaments et des substances chimiquesRÉSUMÉ
Molecularly imprinted polymers (MIP) have been widely owing to their specificity, however, their singular structure imposes limitations on their performance. Current enhancement methods, such as doping with inorganic nanomaterials or introducing various functional monomers, are limited and single, indicating that MIP performances require further advancement. In this work, a dual-modification approach that integrates both conductive inorganic nanomaterials and diverse bifunctional monomers was proposed to develop a multifunctional MIP-based electrochemical (MMIP-EC) sensor for diuron (DU) detection. The MMIP was synthesized through a one-step electrochemical copolymerization of silver nanowires (AgNWs), o-phenylenediamine (O-PD), and 3,4-ethylenedioxythiophene (EDOT). DU molecules could conduct fluent electron transfer within the MMIP layer through the interaction between anchored AgNWs and bifunctional monomers, and the abundant recognition sites and complementary cavity shapes ensured that the imprinted cavities exhibit high specificity. The current intensity amplified by the two modification strategies of MMIP (3.7 times) was significantly higher than the sum of their individual values (3.2 times), exerting a synergistic effect. Furthermore, the adsorption performance of the MMIP was characterized by examining the kinetics and isotherms of the adsorption process. Under optimal conditions, the MMIP-EC sensor exhibits a wide linear range (0.2 ng/mL to 10 µg/mL) for DU detection, with a low detection limit of 89 pg/mL and excellent selectivity (an imprinted factor of 10.4). In summary, the present study affords innovative perspectives for the fabrication of MIP-EC sensor with superior analytical performance.
Sujet(s)
Techniques de biocapteur , Diuron , Techniques électrochimiques , Limite de détection , Polymères à empreintes moléculaires , Nanofils , Argent , Nanofils/composition chimique , Techniques de biocapteur/méthodes , Argent/composition chimique , Techniques électrochimiques/méthodes , Polymères à empreintes moléculaires/composition chimique , Diuron/analyse , Diuron/isolement et purification , Empreinte moléculaire/méthodes , Polymères/composition chimique , Phénylènediamines/composition chimique , Herbicides/analyse , Herbicides/composition chimiqueRÉSUMÉ
INTRODUCTION: Paraphenylenediamine is the main component in many commercial hair dyes, and can produce severe local and systemic toxicity reactions after acute ingestion or dermal absorption. The aim of this study was to assess the factors contributing to morbidity and mortality in cases of acute paraphenylenediamine poisoning, with a focus on evaluating the resultant hepatic and cardiac toxicity. METHODS: This observational study was conducted on patients with acute paraphenylenediamine poisoning presenting to Sohag University Hospitals, and included a retrospective part from February 2021 to January 2022 and a prospective part from February 2022 to July 2022. Clinical data were extracted and receiver operating characteristic curves created to identify prognostic markers. RESULTS: Among 50 eligible patients 39 (78 percent) recovered, and 11 (22 percent) died or had permanent complications. Angioedema and anuria were the most frequent features in complicated cases. By receiver operating characteristic analysis, either an increase in aspartate aminotransferase activity greater than 644 IU/L or alanine aminotransferase activity greater than 798 IU/L, a time delay to presentation of greater than 4.5 hours, and a pH of less than 7.32 were associated with a significant increase in morbidity and mortality. While cardiac enzyme activities, and concentrations of blood urea nitrogen and creatinine increased in most cases, they were not associated with mortality. DISCUSSION: Management of patients with paraphenylenediamine poisoning is mainly supportive, as there is no specific antidote. Respiratory failure and kidney failure are the most life threatening complications. Hepatoxicity and cardiotoxicity also occur. The ability to predict the events can help guide patient disposition and care. CONCLUSION: Elevated liver enzyme activities, increased time delay to admission, decreased pH, and the presence of angioedema and anuria can be used as predictors of morbidity and mortality in patients with acute paraphenylenediamine poisoning.
Sujet(s)
Teintures capillaires , Phénylènediamines , Humains , Phénylènediamines/intoxication , Mâle , Femelle , Adulte , Adulte d'âge moyen , Études rétrospectives , Teintures capillaires/intoxication , Teintures capillaires/toxicité , Études prospectives , Lésions hépatiques dues aux substances/étiologie , Jeune adulte , Sujet âgé , Cardiotoxicité/étiologie , AdolescentRÉSUMÉ
Liver injury caused by acetaminophen (APAP) overdose is the leading cause of acute liver failure in western countries. The mode of APAP-induced cell death has been controversially discussed with ferroptosis emerging as a more recent hypothesis. Ferroptosis is characterized by ferrous iron-catalyzed lipid peroxidation (LPO) causing cell death, which can be prevented by the lipophilic antioxidants ferrostatin-1 and UAMC-3203. To assess the efficacy of these ferroptosis inhibitors, we used two murine models of APAP hepatotoxicity, APAP overdose alone or in combination with FeSO4 in fasted male C57BL/6J mice. APAP triggered severe liver injury in the absence of LPO measured as hepatic malondialdehyde (MDA) levels. In contrast, ferrous iron co-treatment aggravated APAP-induced liver injury and caused extensive LPO. Standard doses of ferrostatin-1 did not affect MDA levels or the injury in both models. In contrast, UAMC-3203 partially protected in both models and reduced LPO in the presence of ferrous iron. However, UAMC-3203 attenuated the translocation of phospho-JNK through downregulation of the mitochondrial anchor protein Sab resulting in reduced mitochondrial dysfunction and liver injury. Thus, APAP toxicity does not involve ferroptosis under normal conditions. The lack of effects of ferroptosis inhibitors in the pathophysiology indicates that ferroptosis signaling pathways are not relevant therapeutic targets.
Sujet(s)
Acétaminophène , Lésions hépatiques dues aux substances , Modèles animaux de maladie humaine , Ferroptose , Souris de lignée C57BL , Animaux , Acétaminophène/effets indésirables , Acétaminophène/toxicité , Ferroptose/effets des médicaments et des substances chimiques , Mâle , Lésions hépatiques dues aux substances/métabolisme , Lésions hépatiques dues aux substances/anatomopathologie , Lésions hépatiques dues aux substances/traitement médicamenteux , Souris , Cyclohexylamines/pharmacologie , Peroxydation lipidique/effets des médicaments et des substances chimiques , Phénylènediamines/pharmacologieRÉSUMÉ
The widespread occurrence and accumulation of N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its quinone metabolite, 6PPD quinone (6PPD-Q), have been globally recognized as a critical environmental issue. However, knowledge on the adverse effects of 6PPD and 6PPD-Q on freshwater invertebrates is limited. This study investigated the effects of 6PPD and its oxidative byproduct, 6PPD-Q, on the growth and reproduction of Daphnia pulex. Through 21-day exposure experiments, we measured the uptake of 0.1, 1, and 10 µg/L 6PPD and 6PPD-Q by D. pulex and assessed the effects on growth and fecundity of D. pulex. While 6PPD and 6PPD-Q did not affect the mortality rate of D. pulex, 6PPD-Q exposure inhibited the growth of D. pulex, indicating potential ecological risks. In particular, the reproductive capacity of D. pulex remained unaffected across the tested concentrations of 6PPD and 6PPD-Q, suggesting specific toxicological pathways that warrant further investigation. This study underscored the importance of evaluating the sublethal effects of emerging contaminants such as 6PPD and 6PPD-Q on aquatic invertebrates, and highlighted the need for comprehensive risk assessments to better understand their environmental impacts.
Sujet(s)
Daphnia , Reproduction , Polluants chimiques de l'eau , Animaux , Polluants chimiques de l'eau/toxicité , Reproduction/effets des médicaments et des substances chimiques , Daphnia/effets des médicaments et des substances chimiques , Daphnia/physiologie , Phénylènediamines/toxicité , Quinones/métabolisme , Quinones/toxicité , Eau douce , Cladocera/effets des médicaments et des substances chimiques , Cladocera/physiologieRÉSUMÉ
Objective: The aim of this study was to explore the role and mechanism of ferroptosis in SiO 2-induced cardiac injury using a mouse model. Methods: Male C57BL/6 mice were intratracheally instilled with SiO 2 to create a silicosis model. Ferrostatin-1 (Fer-1) and deferoxamine (DFO) were used to suppress ferroptosis. Serum biomarkers, oxidative stress markers, histopathology, iron content, and the expression of ferroptosis-related proteins were assessed. Results: SiO 2 altered serum cardiac injury biomarkers, oxidative stress, iron accumulation, and ferroptosis markers in myocardial tissue. Fer-1 and DFO reduced lipid peroxidation and iron overload, and alleviated SiO 2-induced mitochondrial damage and myocardial injury. SiO 2 inhibited Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes, while Fer-1 more potently reactivated Nrf2 compared to DFO. Conclusion: Iron overload-induced ferroptosis contributes to SiO 2-induced cardiac injury. Targeting ferroptosis by reducing iron accumulation or inhibiting lipid peroxidation protects against SiO 2 cardiotoxicity, potentially via modulation of the Nrf2 pathway.
Sujet(s)
Modèles animaux de maladie humaine , Ferroptose , Surcharge en fer , Souris de lignée C57BL , Myocytes cardiaques , Silice , Silicose , Animaux , Ferroptose/effets des médicaments et des substances chimiques , Mâle , Souris , Surcharge en fer/métabolisme , Silice/toxicité , Silicose/métabolisme , Silicose/traitement médicamenteux , Silicose/anatomopathologie , Myocytes cardiaques/effets des médicaments et des substances chimiques , Myocytes cardiaques/métabolisme , Déferoxamine/pharmacologie , Phénylènediamines/pharmacologie , Facteur-2 apparenté à NF-E2/métabolisme , Facteur-2 apparenté à NF-E2/génétique , Stress oxydatif/effets des médicaments et des substances chimiques , Fer/métabolisme , Cyclohexylamines/pharmacologieRÉSUMÉ
KCNQ4 is a voltage-gated K+ channel was reported to distribute over the basolateral surface of type 1 vestibular hair cell and/or inner surface of calyx and heminode of the vestibular nerve connected to the type 1 vestibular hair cells of the inner ear. However, the precise localization of KCNQ4 is still controversial and little is known about the vestibular phenotypes caused by KCNQ4 dysfunction or the specific role of KCNQ4 in the vestibular organs. To investigate the role of KCNQ4 in the vestibular organ, 6-g hypergravity stimulation for 24 h, which represents excessive mechanical stimulation of the sensory epithelium, was applied to p.W277S Kcnq4 transgenic mice. KCNQ4 was detected on the inner surface of calyx of the vestibular afferent in transmission electron microscope images with immunogold labelling. Vestibular function decrease was more severe in the Kcnq4p.W277S/p.W277S mice than in the Kcnq4+/+ and Kcnq4+/p.W277S mice after the stimulation. The vestibular function loss was resulted from the loss of type 1 vestibular hair cells, which was possibly caused by increased depolarization duration. Retigabine, a KCNQ activator, prevented hypergravity-induced vestibular dysfunction and hair cell loss. Patients with KCNQ4 mutations also showed abnormal clinical vestibular function tests. These findings suggest that KCNQ4 plays an essential role in calyx and afferent of type 1 vestibular hair cell preserving vestibular function against excessive mechanical stimulation.
Sujet(s)
Cellules ciliées vestibulaires , Canaux potassiques KNCQ , Souris transgéniques , Animaux , Canaux potassiques KNCQ/métabolisme , Canaux potassiques KNCQ/génétique , Cellules ciliées vestibulaires/métabolisme , Cellules ciliées vestibulaires/anatomopathologie , Souris , Phénylènediamines/pharmacologie , Carbamates/pharmacologie , Labyrinthe vestibulaire/métabolisme , Labyrinthe vestibulaire/anatomopathologie , Labyrinthe vestibulaire/physiopathologieRÉSUMÉ
The residues of organophosphorus pesticides (OPs) are increasing environmental pollution and public health concerns. Thus, the development of simple, convenient and sensitive method for detection of OPs is crucial. Herein, a multifunctional Fe-based MOF with fluorescence, catalytic and adsorption, is synthesized by a simple one-pot hydrothermal method. The ratiometric fluorescence sensor for detection of OPs is constructed by using only one multifunctional sensing material. The NH2-MIL-101(Fe) is able catalyze the o-phenylenediamine (OPD) into 2,3-diaminophenazine (DAP) in the presence of H2O2. The generated DAP can significantly quench the intrinsic fluorescence of NH2-MIL-101(Fe) by the fluorescence resonance energy transfer (FRET) and internal filtration effect (IFE), while producing a new measurable fluorescence. Without immobilization or molecular imprinting, pyrophosphate ion (PPi) can inhibit the peroxidase-like activity of the NH2-MIL-101(Fe) by chelating with Fe3+/Fe2+ redox couple. Moreover, PPi can also be hydrolyzed by alkaline phosphatase (ALP), the presence of OPs inhibits the activity of ALP, resulting in the increase of extra PPi preservation and signal changes of ratiometric fluorescence, the interactions of ALP with different OPs are explored by molecular docking, the OPs (e.g., glyphosate) interact with crucial amino acid residues (Asp, Ser, Ala, Lys and Arg) are indicated. The proposed sensor exhibits excellent detection performance for OPs with the detection limit of 18.7 nM, which provides a promising strategy for detection of OPs.
Sujet(s)
Fer , Réseaux organométalliques , Composés organiques du phosphore , Pesticides , Phénylènediamines , Réseaux organométalliques/composition chimique , Pesticides/analyse , Pesticides/composition chimique , Composés organiques du phosphore/analyse , Composés organiques du phosphore/composition chimique , Fer/composition chimique , Phénylènediamines/composition chimique , Colorants fluorescents/composition chimique , Peroxyde d'hydrogène/composition chimique , Diphosphates/composition chimique , Diphosphates/analyse , Phosphatase alcaline/composition chimique , Phosphatase alcaline/métabolisme , Simulation de docking moléculaire , Limite de détection , Phénazines/composition chimique , Transfert d'énergie par résonance de fluorescence/méthodes , Spectrométrie de fluorescence/méthodes , FluorescenceRÉSUMÉ
Inhaling polyhexamethylene guanidine (PHMG) aerosol, a broad-spectrum disinfectant, can lead to severe pulmonary fibrosis. Ferroptosis, a form of programmed cell death triggered by iron-dependent lipid peroxidation, is believed to play a role in the chemical-induced pulmonary injury. This study aimed to investigate the mechanism of ferroptosis in the progression of PHMG-induced pulmonary fibrosis. C57BL/6â¯J mice and the alveolar type II cell line MLE-12 were used to evaluate the toxicity of PHMG in vivo and in vitro, respectively. The findings indicated that iron deposition was observed in PHMG induced pulmonary fibrosis mouse model and ferroptosis related genes have changed after 8 weeks PHMG exposure. Additionally, there were disturbances in the antioxidant system and mitochondrial damage in MLE-12 cells following a 12-hour treatment with PHMG. Furthermore, the study observed an increase in lipid peroxidation and a decrease in GPX4 activity in MLE-12 cells after exposure to PHMG. Moreover, pretreatment with the ferroptosis inhibitors Ferrostatin-1 (Fer-1) and Liproxstatin-1 (Lip-1) not only restored the antioxidant system and GPX4 activity but also mitigated lipid peroxidation. Current data exhibit the role of ferroptosis pathway in PHMG-induced pulmonary fibrosis and provide a potential target for future treatment.
Sujet(s)
Ferroptose , Guanidines , Peroxydation lipidique , Souris de lignée C57BL , Phospholipid hydroperoxide glutathione peroxidase , Fibrose pulmonaire , Animaux , Ferroptose/effets des médicaments et des substances chimiques , Fibrose pulmonaire/induit chimiquement , Fibrose pulmonaire/anatomopathologie , Souris , Peroxydation lipidique/effets des médicaments et des substances chimiques , Lignée cellulaire , Guanidines/toxicité , Guanidines/pharmacologie , Mâle , Pneumocytes/effets des médicaments et des substances chimiques , Pneumocytes/anatomopathologie , Cyclohexylamines/pharmacologie , Phénylènediamines , Quinoxalines , SpiranesRÉSUMÉ
N,N'-Substituted p-phenylenediamine quinones (PPD-Qs) are the emerging toxicant, which transform from the rubber tire antioxidant N,N'-substituted p-phenylenediamines (PPDs). Because of their potential toxic and widespread occurrence in the environment, PPD-Qs have received great attention. However, efficiently extracting PPD-Qs from complex samples is still a challenge. Herein, a cysteine functional covalent organic framework (Cys-COF) designed according to the "donor-acceptor" sites of hydrogen bonding of PPD-Qs was synthesized via click reaction and then used as solid-phase extraction (SPE) adsorbent. Cys-COF can form the seven-member ring adsorption structure with PPD-Qs via hydrogen bonding. The adsorption mechanism was tentatively revealed by density functional theory (DFT). After optimizing the Cys-COF-SPE parameters, PPD-Qs were efficiently extracted from water, soil, sediment, and fish, followed by detection using ultra-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The Cys-COF-SPE-UHPLC-MS/MS method exhibited ideal linearity (R2 ≥ 0.9932), high relative recoveries (80.4-111 %), and low limits of detection (0.0001-0.0013 ng mL-1). In addition, the bioconcentration kinetics in goldfish provides a feasible platform to investigate the toxicity and accumulated ability of PPD-Qs.
Sujet(s)
Chimie click , Cystéine , Phénylènediamines , Quinones , Extraction en phase solide , Spectrométrie de masse en tandem , Phénylènediamines/composition chimique , Cystéine/composition chimique , Extraction en phase solide/méthodes , Spectrométrie de masse en tandem/méthodes , Quinones/composition chimique , Quinones/isolement et purification , Chimie click/méthodes , Chromatographie en phase liquide à haute performance/méthodes , Animaux , Limite de détection , Adsorption , Réseaux organométalliques/composition chimique , PoissonsRÉSUMÉ
Hyperexcitability of neuronal networks is central to the pathogenesis of Alzheimer's disease (AD). Pharmacological activation of Kv7 channels is an effective way to reduce neuronal firing. Our results showed that that pharmacologically activating the Kv7 channel with Retigabine (RTG) can alleviate cognitive impairment in mice without affecting spontaneous activity. RTG could also ameliorate damage to the Nissl bodies in cortex and hippocampal CA and DG regions in 9-month-old APP/PS1 mice. Additionally, RTG could reduce the Aß plaque number in the hippocampus and cortex of both 6-month-old and 9-month-old mice. By recordings of electroencephalogram, we showed that a decrease in the number of abnormal discharges in the brains of the AD model mice when the Kv7 channel was opened. Moreover, Western blot analysis revealed a reduction in the expression of the p-Tau protein in both the hippocampus and cortex upon Kv7 channel opening. These findings suggest that Kv7 channel opener RTG may ameliorate cognitive impairment in AD, most likely by reducing brain excitability.
Sujet(s)
Maladie d'Alzheimer , Précurseur de la protéine bêta-amyloïde , Carbamates , Dysfonctionnement cognitif , Modèles animaux de maladie humaine , Hippocampe , Souris transgéniques , Phénylènediamines , Animaux , Phénylènediamines/pharmacologie , Carbamates/pharmacologie , Maladie d'Alzheimer/traitement médicamenteux , Maladie d'Alzheimer/métabolisme , Maladie d'Alzheimer/anatomopathologie , Souris , Précurseur de la protéine bêta-amyloïde/génétique , Précurseur de la protéine bêta-amyloïde/métabolisme , Hippocampe/effets des médicaments et des substances chimiques , Hippocampe/métabolisme , Dysfonctionnement cognitif/traitement médicamenteux , Dysfonctionnement cognitif/métabolisme , Préséniline-1/génétique , Mâle , Plaque amyloïde/traitement médicamenteux , Plaque amyloïde/anatomopathologie , Plaque amyloïde/métabolisme , Cortex cérébral/effets des médicaments et des substances chimiques , Cortex cérébral/métabolisme , Cortex cérébral/anatomopathologie , Protéines tau/métabolisme , Comportement animal/effets des médicaments et des substances chimiques , Souris de lignée C57BLRÉSUMÉ
Organic Raman probes, including polymers and small molecules, have attracted great attention in biomedical imaging owing to their excellent biocompatibility. However, the development of organic Raman probes is usually hindered by a mismatch between their absorption spectra and wavelength-fixed excitation, which makes it difficult to achieve resonance excitation necessary to obtain strong Raman signals. Herein, we introduce a covalent organic framework (COF) into the fine absorption spectrum regulation of organic Raman probes, resulting in their significant Raman signal enhancement. In representative examples, a polymer poly(diketopyrrolopyrrole-p-phenylenediamine) (DPP-PD) and a small molecule azobenzene are transformed into the corresponding COF-structured Raman probes. Their absorption peaks show an accurate match of less than 5 nm with the NIR excitation. As such, the COF-structured Raman probes acquire highly sensitive bioimaging capabilities compared to their precursors with negligible signals. By further mechanism studies, we discover that the crystallinity and size of COFs directly affect the π-conjugation degree of Raman probes, thus changing their bandgaps and absorption spectra. Our study offers a universal and flexible method for improving the signal performance of organic Raman probes without changing their structural units, making it more convenient to obtain the highly sensitive organic Raman probes for in vivo bioimaging.