RESUMEN
The recent acceleration of industrialization and urbanization has brought significant attention to N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine quinone (6-PPDQ), an emerging environmental pollutant from tire wear, due to its long-term effects on the environment and organisms. Recent studies suggest that 6-PPDQ can disrupt neurotransmitter synthesis and release, impact receptor function, and alter signaling pathways, potentially causing oxidative stress, inflammation, and apoptosis. This review investigates the potential neurotoxic effects of prolonged 6-PPDQ exposure, the mechanisms underlying its cytotoxicity, and the associated health risks. We emphasize the need for future research, including precise exposure assessments, identification of individual differences, and development of risk assessments and intervention strategies. This article provides a comprehensive overview of 6-PPDQ's behavior, impact, and neurotoxicity in the environment, highlighting key areas and challenges for future research.
Asunto(s)
Contaminantes Ambientales , Síndromes de Neurotoxicidad , Humanos , Contaminantes Ambientales/toxicidad , Síndromes de Neurotoxicidad/etiología , Animales , Estrés Oxidativo/efectos de los fármacos , Fenilendiaminas/toxicidad , Medición de Riesgo , Exposición a Riesgos Ambientales/efectos adversos , Apoptosis/efectos de los fármacosRESUMEN
Hyperglycemia aggravates cerebral ischemia/reperfusion (I/R) injury via vascular injury. There is still a lack of effective pharmaceutical preparations for cerebral I/R injury under hyperglycemia. This study aimed to investigate the effects of oxymatrine (OMT) on hyperglycemia-exacerbated cerebral I/R injury in vitro and in vivo. The middle cerebral artery occlusion (MCAO) and reperfusion was established in the rats under hyperglycemia. Meanwhile, oxygen-glucose deprivation and reoxygenation (OGD/R) with high glucose was used as an in vitro model of hyperglycemic cerebral I/R injury. The results showed that the neurological deficit score, mortality, infarct volume and penumbra apoptosis in hyperglycemia group were significantly higher than those in normal glucose group. OMT pre-treated obviously reduced the degree of neurological deficit, mortality, infarct volume, improve cerebral blood flow after I/R in rats with hyperglycemia, and increase the survival rate of human brain microvascular endothelial cells (HBMECs) in high glucose and OGD/R group. OMT significantly improved the ultrastructure changes of endothelial cells, and maintain the migration and angiogenesis potency of HBMECs in high glucose and OGD/R group. OMT obviously alleviated the down-regulating CD31 and CD105 expression in cerebral microvessels caused by hyperglycemia. It is concluded that OMT treatment might alleviate cerebral I/R injury under hyperglycemia via protecting microvessels.
Asunto(s)
Alcaloides , Isquemia Encefálica , Quinolizinas , Daño por Reperfusión , Alcaloides/uso terapéutico , Animales , Apoptosis , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Células Endoteliales/metabolismo , Humanos , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/metabolismo , Microvasos/metabolismo , Quinolizinas/uso terapéutico , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismoRESUMEN
Mitochondrial uncoupling protein 2 (UCP2) deficiency exacerbates brain damage following cerebral ischemia/reperfusion (I/R). The Nod-like receptor protein-3 (NLRP3) inflammasome also plays a vital role in cerebral I/R damage. However, the effect of UCP2 on NLRP3 inflammasome-mediated hyperglycemia and I/R damage is not clear. In the present study, UCP2-knockout (UCP2-/-) and wild-type (WT) mice were used to establish a model of middle cerebral artery occlusion (MCAO) and reperfusion under normo- and hyperglycemic conditions. HT22 cells were established as a model of oxygen-glucose deprivation and reoxygenation (OGD/R) with high glucose to mimic hyperglycemia and I/R in vitro. HT22 cells were treated with/without different concentrations of the UCP2-specific inhibitor genipin for different periods of time. The results showed that UCP2 deficiency significantly increased histopathological changes and apoptosis after cerebral I/R damage in hyperglycemic mice. Moreover, UCP2 deficiency enhanced NLRP3 inflammasome activation in neurons when cerebral I/R damage was exacerbated by hyperglycemia. Furthermore, UCP2 deficiency enhanced NLRP3 inflammasome activation and reactive oxygen species (ROS) production in HT22 cells under OGD/R and high-glucose conditions. UCP2 deficiency aggravated hyperglycemia-induced exacerbation of cerebral I/R damage. UCP2 deficiency also enhanced NLRP3 inflammasome activation and ROS production in neurons in vitro and in vivo. These findings suggest that UCP2 deficiency enhances NLRP3 inflammasome activation following hyperglycemia-induced exacerbation of cerebral I/R damage in vitro and in vivo. UCP2 may be a potential therapeutic target for hyperglycemia-induced exacerbation of cerebral I/R damage.
Asunto(s)
Hiperglucemia/metabolismo , Infarto de la Arteria Cerebral Media/metabolismo , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Daño por Reperfusión/metabolismo , Proteína Desacopladora 2/deficiencia , Animales , Apoptosis/fisiología , Encéfalo/patología , Línea Celular , Femenino , Glucosa/deficiencia , Glucosa/farmacología , Hiperglucemia/patología , Hipoxia/fisiopatología , Infarto de la Arteria Cerebral Media/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Daño por Reperfusión/patologíaRESUMEN
Stroke is a severe neurological disease that is associated with high rates of morbidity and mortality, and the underlying pathological processes are complex. Ferroptosis fulfills a significant role in the progression and treatment of stroke. It is well established that ferroptosis is a type of programmed cell death that is distinct from other forms or types of cell death. The process of ferroptosis involves multiple signaling pathways and regulatory mechanisms that interact with mechanisms inherent to stroke development. Inducers and inhibitors of ferroptosis have been shown to exert a role in the onset of this cell death process. Furthermore, it has been shown that interfering with ferroptosis affects the occurrence of stroke, indicating that targeting ferroptosis may offer a promising therapeutic approach for treating patients of stroke. Hence, the present review aimed to summarize the latest progress that has been made in terms of using therapeutic interventions for ferroptosis as treatment targets in cases of stroke. It provides an overview of the relevant pathways and molecular mechanisms that have been investigated in recent years, highlighting the roles of inducers and inhibitors of ferroptosis in stroke. Additionally, the intervention potential of various types of Traditional Chinese Medicine is also summarized. In conclusion, the present review provides a comprehensive overview of the potential therapeutic targets afforded by ferroptosisassociated pathways in stroke, offering new insights into how ferroptosis may be exploited in the treatment of stroke.
Asunto(s)
Ferroptosis , Transducción de Señal , Accidente Cerebrovascular , Ferroptosis/efectos de los fármacos , Humanos , Accidente Cerebrovascular/metabolismo , Accidente Cerebrovascular/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Animales , Terapia Molecular Dirigida , Medicina Tradicional China/métodosRESUMEN
O6-methylguanine methyltransferase (MGMT) is responsible for dealkylation of naturally occurring O6-methylguanines, and it is closely related with DNA replication, transcription, and cancers. Herein, we develop a chemiluminescent biosensor based on enzymatic extension and click chemistry for sensitive measurement of MGMT activity. When MGMT is present, the MGMT-catalyzed demethylation reaction initiates the cleavage of biotinylated dumbbell probes by PvuII restrictive enzyme, releasing two DNA fragments with 3'-OH end. The resultant DNA fragments can trigger terminal transferase (TdT)- and click chemistry-assisted isothermal amplification to obtain abundant G-rich sequences. The G-rich sequences can be captured by magnetic beads to produce a high chemiluminescence signal. This biosensor can greatly amplify the chemiluminescence signal, facilitating label-free and template-free measurement of MGMT. Especially, the introduction of dumbbell probe and PvuII enzyme can efficiently eliminate the false positive and improve the assay specificity. This biosensor possesses high sensitivity with a detection limit of 1.4 × 10-9 ng/µL, and it may accurately quantify the intracellular MGMT. Importantly, this biosensor can be used to screen the MGMT inhibitors and distinguish the MGMT level in breast tumor tissues and normal tissues, with great potential in drug discovery and cancer diagnosis.
RESUMEN
Ischemic stroke poses a major threat to human health. Therefore, the molecular mechanisms of cerebral ischemia/reperfusion injury (CIRI) need to be further clarified, and the associated treatment approaches require exploration. The NODlike receptor thermal protein domain associated protein 3 (NLRP3) inflammasome serves an important role in causing CIRI, and its activation exacerbates the underlying injury. Activation of the NLRP3 inflammasome triggers the maturation and production of the inflammatory molecules IL1ß and IL18, as well as gasderminDmediated pyroptosis and CIRI damage. Thus, the NLRP3 inflammasome may be a viable target for the treatment of CIRI. In the present review, the mechanisms of the NLRP3 inflammasome in the intense inflammatory response and pyroptosis induced by CIRI are discussed, and the therapeutic strategies that target the NLRP3mediated inflammatory response and pyroptosis in CIRI are summarized. At present, certain drugs have already been studied, highlighting future therapeutic perspectives.
Asunto(s)
Isquemia Encefálica , Daño por Reperfusión , Humanos , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Inflamasomas/metabolismo , Piroptosis , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismoRESUMEN
Stroke poses a significant risk of mortality, particularly among the elderly population. The pathophysiological process of ischemic stroke is complex, and it is crucial to elucidate its molecular mechanisms and explore potential protective drugs. Ferroptosis, a newly recognized form of programmed cell death distinct from necrosis, apoptosis, and autophagy, is closely associated with the pathophysiology of ischemic stroke. N6022, a selective inhibitor of S-nitrosoglutathione reductase (GSNOR), is a "first-in-class" drug for asthma with potential therapeutic applications. However, it remains unclear whether N6022 exerts protective effects in ischemic stroke, and the precise mechanisms of its action are unknown. This study aimed to investigate whether N6022 mitigates cerebral ischemia/reperfusion (I/R) injury by reducing ferroptosis and to elucidate the underlying mechanisms. Accordingly, we established an oxygen-glucose deprivation/reperfusion (OGD/R) cell model and a middle cerebral artery occlusion/reperfusion (MCAO/R) mouse model to mimic cerebral I/R injury. Our data, both in vitro and in vivo, demonstrated that N6022 effectively protected against I/R-induced brain damage and neurological deficits in mice, as well as OGD/R-induced BV2 cell damage. Mechanistically, N6022 promoted Nrf2 nuclear translocation, enhancing intracellular antioxidant capacity of SLC7A11-GPX4 system. Furthermore, N6022 interfered with the interaction of GSNOR with GSTP1, thereby boosting the antioxidant capacity of GSTP1 and attenuating ferroptosis. These findings provide novel insights, showing that N6022 attenuates microglial ferroptosis induced by cerebral I/R injury through the promotion of Nrf2 nuclear translocation and inhibition of the GSNOR/GSTP1 axis.
Asunto(s)
Benzamidas , Ferroptosis , Microglía , Factor 2 Relacionado con NF-E2 , Pirroles , Daño por Reperfusión , Animales , Ferroptosis/efectos de los fármacos , Factor 2 Relacionado con NF-E2/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Ratones , Microglía/efectos de los fármacos , Microglía/metabolismo , Microglía/patología , Masculino , Ratones Endogámicos C57BL , Transducción de Señal/efectos de los fármacos , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/metabolismo , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Fármacos Neuroprotectores/farmacología , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Núcleo Celular/metabolismo , Núcleo Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Línea Celular , Transporte Activo de Núcleo Celular/efectos de los fármacosRESUMEN
Purpose: Ischemic stroke is a refractory disease wherein the reperfusion injury caused by sudden restoration of blood supply is the main cause of increased mortality and disability. However, current therapeutic strategies for the inflammatory response induced by cerebral ischemia-reperfusion (I/R) injury are unsatisfactory. This study aimed to develop a functional nanoparticle (MM/ANPs) comprising apelin-13 (APNs) encapsulated in macrophage membranes (MM) modified with distearoyl phosphatidylethanolamine-polyethylene glycol-RVG29 (DSPE-PEG-RVG29) to achieve targeted therapy against ischemic stroke. Methods: MM were extracted from RAW264.7. PLGA was dissolved in dichloromethane, while Apelin-13 was dissolved in water, and CY5.5 was dissolved in dichloromethane. The precipitate was washed twice with ultrapure water and then resuspended in 10 mL to obtain an aqueous solution of PLGA nanoparticles. Subsequently, the cell membrane was evenly dispersed homogeneously and mixed with PLGA-COOH at a mass ratio of 1:1 for the hybrid ultrasound. DSPE-PEG-RVG29 was added and incubated for 1 h to obtain MM/ANPs. Results: In this study, we developed a functional nanoparticle delivery system (MM/ANPs) that utilizes macrophage membranes coated with DSPE-PEG-RVG29 peptide to efficiently deliver Apelin-13 to inflammatory areas using ischemic stroke therapy. MM/ANPs effectively cross the blood-brain barrier and selectively accumulate in ischemic and inflamed areas. In a mouse I/R injury model, these nanoparticles significantly improved neurological scores and reduced infarct volume. Apelin-13 is gradually released from the MM/ANPs, inhibiting NLRP3 inflammasome assembly by enhancing sirtuin 3 (SIRT3) activity, which suppresses the inflammatory response and pyroptosis. The positive regulation of SIRT3 further inhibits the NLRP3-mediated inflammation, showing the clinical potential of these nanoparticles for ischemic stroke treatment. The biocompatibility and safety of MM/ANPs were confirmed through in vitro cytotoxicity tests, blood-brain barrier permeability tests, biosafety evaluations, and blood compatibility studies. Conclusion: MM/ANPs offer a highly promising approach to achieve ischemic stroke-targeted therapy inhibiting NLRP3 inflammasome-mediated pyroptosis.
Asunto(s)
Inflamasomas , Accidente Cerebrovascular Isquémico , Macrófagos , Proteína con Dominio Pirina 3 de la Familia NLR , Nanopartículas , Piroptosis , Animales , Ratones , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Células RAW 264.7 , Piroptosis/efectos de los fármacos , Nanopartículas/química , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de los fármacos , Masculino , Péptidos y Proteínas de Señalización Intercelular/farmacología , Péptidos y Proteínas de Señalización Intercelular/química , Polietilenglicoles/química , Ratones Endogámicos C57BL , Daño por Reperfusión/tratamiento farmacológico , Fosfatidiletanolaminas/química , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismoRESUMEN
BACKGROUND: Hyperglycemia exacerbates brain damage in cerebral ischemia/reperfusion injury. Previous study found that Lycium barbarum polysaccharides (LBP) has a neuroprotective effect on hyperglycemia-aggravated ischemic brain injury, which raising the possibility for treatment of neurodegenerative diseases. However, the underlying mechanism of LBP-induced protection by ameliorating hyperglycemia-aggravated ischemia/reperfusion injury needs to be tested. This study aimed to investigate the effects of LBP on blood-brain barrier (BBB) integrity with a hyperglycemia-aggravated cerebral ischemia/reperfusion injury model. METHODS: Sprague-Dawley male rats were randomly divided into three groups: normoglycemic (NG), hyperglycemic (HG), and LBP-pretreated hyperglycemic (HG + LBP). Animals underwent middle cerebral artery occlusion (MCAO) for 30 min, followed by 1-, 3-, and 7-day of reperfusion. RESULTS: Our results showed that the neurological deficit, infarct volume, cell apoptosis, and IgG leakage in the HG group significantly increased separately, compared with that of the NG group, (p < 0.05). Pre-treatment with LBP reversed these injury indicators (p < 0.05). And much more severe degree of swelling endothelium, swollen astrocyte, and decreased tight junctions in the micro-vessel were detected in the HG group comparing to that of the NG group. In addition, increased degree of basement membrane degradation, dissociation between the astrocyte endfeet and basement membrane, and tight junction's protein degradation was found in the HG group compared with the NG group (p < 0.05). However, when exposure to LBP therapy could reverse the above alterations (p < 0.05). CONCLUSIONS: These results demonstrated that LBP could ameliorate hyperglycemia-exacerbated cerebral ischemia/reperfusion injury via protecting the blood-brain barrier.
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Isquemia Encefálica , Hiperglucemia , Lycium , Daño por Reperfusión , Ratas , Masculino , Animales , Barrera Hematoencefálica/metabolismo , Ratas Sprague-Dawley , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/metabolismo , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/prevención & control , Hiperglucemia/tratamiento farmacológico , PolisacáridosRESUMEN
Coenzyme Q10 (CoQ10) acts by scavenging reactive oxygen species to protect neuronal cells against oxidative stress in neurodegenerative diseases. The present study was designed to examine whether CoQ10 was capable of protecting astrocytes from reactive oxygen species (ROS) mediated damage. For this purpose, ultraviolet B (UVB) irradiation was used as a tool to induce ROS stress to cultured astrocytes. The cells were treated with 10 and 25 µg/ml of CoQ10 for 3 or 24 h prior to the cells being exposed to UVB irradiation and maintained for 24 h post UVB exposure. Cell viability was assessed by MTT conversion assay. Mitochondrial respiration was assessed by respirometer. While superoxide production and mitochondrial membrane potential were measured using fluorescent probes, levels of cytochrome C (cyto-c), cleaved caspase-9, and caspase-8 were detected using Western blotting and/or immunocytochemistry. The results showed that UVB irradiation decreased cell viability and this damaging effect was associated with superoxide accumulation, mitochondrial membrane potential hyperpolarization, mitochondrial respiration suppression, cyto-c release, and the activation of both caspase-9 and -8. Treatment with CoQ10 at two different concentrations started 24 h before UVB exposure significantly increased the cell viability. The protective effect of CoQ10 was associated with reduction in superoxide, normalization of mitochondrial membrane potential, improvement of mitochondrial respiration, inhibition of cyto-c release, suppression of caspase-9. Furthermore, CoQ10 enhanced mitochondrial biogenesis. It is concluded that CoQ10 may protect astrocytes through suppression of oxidative stress, prevention of mitochondrial dysfunction, blockade of mitochondria-mediated cell death pathway, and enhancement of mitochondrial biogenesis.