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1.
Int J Mol Sci ; 25(11)2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38891838

RESUMO

Nanoparticles (NPs) are becoming increasingly important novel materials for many purposes, including basic research, medicine, agriculture, and engineering. Increasing human and environmental exposure to these promising compounds requires assessment of their potential health risks. While the general direct cytotoxicity of NPs is often routinely measured, more indirect possible long-term effects, such as reproductive or developmental neurotoxicity (DNT), have been studied only occasionally and, if so, mostly on non-human animal models, such as zebrafish embryos. In this present study, we employed a well-characterized human neuronal precursor cell line to test the concentration-dependent DNT of green-manufactured copper sulfide (CuS) nanoparticles on crucial early events in human brain development. CuS NPs turned out to be generally cytotoxic in the low ppm range. Using an established prediction model, we found a clear DNT potential of CuS NPs on neuronal precursor cell migration and neurite outgrowth, with IC50 values 10 times and 5 times, respectively, lower for the specific DNT endpoint than for general cytotoxicity. We conclude that, in addition to the opportunities of NPs, their risks to human health should be carefully considered.


Assuntos
Cobre , Nanopartículas Metálicas , Neurônios , Humanos , Cobre/toxicidade , Nanopartículas Metálicas/toxicidade , Nanopartículas Metálicas/química , Neurônios/efeitos dos fármacos , Sulfetos/toxicidade , Sulfetos/química , Movimento Celular/efeitos dos fármacos , Linhagem Celular , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Nanopartículas/toxicidade , Nanopartículas/química , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Sobrevivência Celular/efeitos dos fármacos
2.
Crit Rev Toxicol ; 54(5): 330-343, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38832580

RESUMO

Despite the growing epidemiological evidence of an association between toxin exposure and developmental neurotoxicity (DNT), systematic testing of DNT is not mandatory in international regulations for admission of pharmaceuticals or industrial chemicals. However, to date around 200 compounds, ranging from pesticides, pharmaceuticals and industrial chemicals, have been tested for DNT in the current OECD test guidelines (TG-443 or TG-426). There are calls for the development of new approach methodologies (NAMs) for DNT, which has resulted in a DNT testing battery using in vitro human cell-based assays. These assays provide a means to elucidate the molecular mechanisms of toxicity in humans which is lacking in animal-based toxicity tests. However, cell-based assays do not represent all steps of the complex process leading to DNT. Validated models with a multi-organ network of pathways that interact at the molecular, cellular and tissue level at very specific timepoints in a life cycle are currently missing. Consequently, whole model organisms are being developed to screen for, and causally link, new molecular targets of DNT compounds and how they affect whole brain development and neurobehavioral endpoints. Given the practical and ethical restraints associated with vertebrate testing, lower animal models that qualify as 3 R (reduce, refine and replace) models, including the nematode (Caenorhabditis elegans) and the zebrafish (Danio rerio) will prove particularly valuable for unravelling toxicity pathways leading to DNT. Although not as complex as the human brain, these 3 R-models develop a complete functioning brain with numerous neurodevelopmental processes overlapping with human brain development. Importantly, the main signalling pathways relating to (neuro)development, metabolism and growth are highly conserved in these models. We propose the use of whole model organisms specifically zebrafish and C. elegans for DNT relevant endpoints.


Assuntos
Caenorhabditis elegans , Síndromes Neurotóxicas , Testes de Toxicidade , Peixe-Zebra , Animais , Caenorhabditis elegans/efeitos dos fármacos , Modelos Animais , Testes de Toxicidade/métodos
3.
Turk Psikiyatri Derg ; 35(2): 150-155, 2024.
Artigo em Inglês, Turco | MEDLINE | ID: mdl-38842156

RESUMO

Lithium may cause toxicity as it has a narrow therapeutic range. Lithium intoxication may manifest in the form of acute, acute on chronic and chronic intoxication. Neurotoxicity is a common component of chronic lithium intoxication and the symptoms include tremor, ataxia, dysarthria, extrapyramidal symptoms, hyperreflexia, seizures and status epilepticus. Although rare, catatonia could as a manifestation of lithium neurotoxicity. In this report, we present a patient with bipolar disorder presenting with catatonic symptoms secondary to lithium intoxication. We will discuss the risk factors, differential diagnosis and the treatment of catatonic symptoms. Lithium neurotoxicity may present with various clinical symptoms including catatonia, and differential diagnosis should be made well in such cases. If lithium neurotoxicity is suspected, rapid and appropriate intervention is required to prevent permanent neurological damage. Keywords: Lithium, Neurotoxicity, Catatonia.


Assuntos
Transtorno Bipolar , Catatonia , Humanos , Antimaníacos/efeitos adversos , Transtorno Bipolar/tratamento farmacológico , Catatonia/induzido quimicamente , Diagnóstico Diferencial , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/diagnóstico
4.
Environ Pollut ; 355: 124280, 2024 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-38815890

RESUMO

Cr(VI) is a common hazardous heavy metal contaminant that seriously endangers human and aquatic animal health. GPX4 was the key enzyme that reduces heavy metal toxicity through inhibiting ferroptosis pathway. Astaxanthin was GPX4 activator that can weaken biological toxicity induced by Cr(VI) exposure. The present study was conducted to evaluate the major role of GPX4 in astaxanthin protects Cr(VI)-induced oxidative damage, blood-brain barrier injury and neurotoxicity in brain-liver axis through inhibiting ferroptosis pathway. In the current study, astaxanthin intervention can effectively alleviate Cr(VI)-induced oxidative stress, blood-brain barrier damage, and neurotoxicity. GPX4 plays a major role in mediating astaxanthin nutritional intervention to reduce ROS and liver non-heme iron accumulation, which would contribute to the reduction of ferroptosis. Meanwhile, astaxanthin maintains the stability of transport receptors and protein macromolecules such as TMEM163, SLC7A11, SLC3A2, FPN1 and GLUT1 in the brain liver axis, promoting substance exchange and energy supply. Moreover, astaxanthin alleviates Cr(VI)-induced neurotoxicity by promoting tight protein expression and reducing blood-brain barrier permeability.


Assuntos
Barreira Hematoencefálica , Cromo , Poluentes Químicos da Água , Xantofilas , Peixe-Zebra , Xantofilas/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Cromo/toxicidade , Poluentes Químicos da Água/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Síndromes Neurotóxicas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo
5.
Basic Clin Pharmacol Toxicol ; 135(1): 81-97, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38780039

RESUMO

We established experimental models of manganese (Mn) and iron (Fe) exposure in vitro and in vivo, and addressed the effects of manganese and iron combined exposure on the synaptic function of pheochromocytoma derived cell line 12 (PC12) cells and rat cortex, respectively. We investigated the protective effect of sodium para-aminosalicylate (PAS-Na) on manganese and iron combined neurotoxicity, providing a scientific basis for the prevention and treatment of ferromanganese combined neurotoxicity. Western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were performed to detect the expression levels of protein and mRNA related to synaptic damage. Y-maze novelty test and balance beam test were used to evaluate the motor and cognitive function of rats. Haematoxylin and eosin (H&E) and Nissl staining were performed to observe the cortical damage of rats. The results showed that the combined exposure of Mn and Fe in rats led to a synergistic effect, attenuating growth and development, and altering learning and memory as well as motor function. The combination of Mn and Fe also caused damage to the synaptic structure of PC12 cells, which is manifested as swelling of dendrites and axon terminals, and even lead to cell death. PAS-Na displayed some antagonistic effects against the Mn- and Fe-induced synaptic structural damage, growth, learning and memory impairment.


Assuntos
Ácido Aminossalicílico , Manganês , Sinapses , Animais , Ratos , Células PC12 , Sinapses/efeitos dos fármacos , Masculino , Ácido Aminossalicílico/farmacologia , Manganês/toxicidade , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/patologia , Córtex Cerebral/metabolismo , Ratos Sprague-Dawley , Ferro/metabolismo , Fármacos Neuroprotetores/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Modelos Animais de Doenças
6.
Mol Biol Rep ; 51(1): 660, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750264

RESUMO

BACKGROUND: Cadmium (Cd) is a heavy metal with extremely harmful toxic effects on the brain. Quetiapine (QTP) has unique neuroprotective effects with anti-inflammatory and antioxidant actions. However, its neuroprotective effect against Cd-induced neurotoxicity has not been previously studied. METHODS: QTP was administered in 10 and 20 mg/kg doses, while Cd was given in a dose of 6.5 mg/kg. RESULTS: In our study, QTP dose-dependently attenuated neuronal injury by downregulating p-tau and ß-amyloid. QTP potently attenuates histological abrasions induced by Cd. QTP counteracted oxidative injury by decreasing neuronal MDA and increased GSH levels mediated by downregulating Keap1 and upregulating Nrf2 and HO-1. QTP mitigated inflammation by decreasing MPO and NO2 and neuronal cytokines TNF-α and IL-1ß and upregulating IL-10 levels mediated by NF-κB downregulation. Additionally, QTP counteracted Cd-induced pyroptosis by downregulating caspase-1, ASC, and NLRP3 protein levels. CONCLUSION: In conclusion, QTP mitigates neurotoxicity induced by Cd through suppression of inflammation, pyroptosis, and oxidative stress by controlling the NF-κB, Keap1/Nrf2, and pyroptosis signals.


Assuntos
Cádmio , Inflamação , Estresse Oxidativo , Piroptose , Fumarato de Quetiapina , Estresse Oxidativo/efeitos dos fármacos , Piroptose/efeitos dos fármacos , Animais , Cádmio/toxicidade , Fumarato de Quetiapina/farmacologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Antioxidantes/farmacologia , Anti-Inflamatórios/farmacologia , NF-kappa B/metabolismo
7.
Ann Med ; 56(1): 2349796, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38738799

RESUMO

BACKGROUND: Relapse/refractory B-cell acute lymphoblastic leukaemia (r/r B-ALL) represents paediatric cancer with a challenging prognosis. CAR T-cell treatment, considered an advanced treatment, remains controversial due to high relapse rates and adverse events. This study assessed the efficacy and safety of CAR T-cell therapy for r/r B-ALL. METHODS: The literature search was performed on four databases. Efficacy parameters included minimal residual disease negative complete remission (MRD-CR) and relapse rate (RR). Safety parameters constituted cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). RESULTS: Anti-CD22 showed superior efficacy with the highest MRD-CR event rate and lowest RR, compared to anti-CD19. Combining CAR T-cell therapy with haploidentical stem cell transplantation improved RR. Safety-wise, bispecific anti-CD19/22 had the lowest CRS rate, and anti-CD22 showed the fewest ICANS. Analysis of the costimulatory receptors showed that adding CD28ζ to anti-CD19 CAR T-cell demonstrated superior efficacy in reducing relapses with favorable safety profiles. CONCLUSION: Choosing a more efficacious and safer CAR T-cell treatment is crucial for improving overall survival in acute leukaemia. Beyond the promising anti-CD22 CAR T-cell, exploring costimulatory domains and new CD targets could enhance treatment effectiveness for r/r B-ALL.


Assuntos
Antígenos CD19 , Imunoterapia Adotiva , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/imunologia , Antígenos CD19/imunologia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Receptores de Antígenos Quiméricos/imunologia , Criança , Resultado do Tratamento , Neoplasia Residual , Síndrome da Liberação de Citocina/etiologia , Recidiva , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/imunologia
8.
J Neuroimmune Pharmacol ; 19(1): 21, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38771510

RESUMO

The neurotoxicity of Semen Strychni has been reported recently in several clinical cases. Therefore, this study was conducted to investigate the role of HMGB1 in a model of neurotoxicity induced by Semen Strychni and to assess the potential alleviating effects of glycyrrhizic acid (GA), which is associated with the regulation of HMGB1 release. Forty-eight SD rats were intraperitoneally injected with Semen Strychni extract (175 mg/kg), followed by oral administration of GA (50 mg/kg) for four days. After treatment of SS and GA, neuronal degeneration, apoptosis, and necrosis were observed via histopathological examination. Inflammatory cytokines (TNF-α and IL-1ß), neurotransmitter associated enzymes (MAO and AChE), serum HMGB1, nuclear and cytoplasmic HMGB1/ph-HMGB1, and the interaction between PP2A, PKC, and HMGB1 were evaluated. The influence of the MAPK pathway was also examined. As a result, this neurotoxicity was characterized by neuronal degeneration and apoptosis, the induction of pro-inflammatory cytokines, and a reduction in neurotransmitter-metabolizing enzymes. In contrast, GA treatment significantly ameliorated the abovementioned effects and alleviated nerve injury. Furthermore, Semen Strychni promoted HMGB1 phosphorylation and its translocation between the nucleus and cytoplasm, thereby activating the NF-κB and MAPK pathways, initiating various inflammatory responses. Our experiments demonstrated that GA could partially reverse these effects. In summary, GA acid alleviated Semen Strychni-induced neurotoxicity, possibly by inhibiting HMGB1 phosphorylation and preventing its release from the cell.


Assuntos
Ácido Glicirrízico , Proteína HMGB1 , Ratos Sprague-Dawley , Animais , Ácido Glicirrízico/farmacologia , Ácido Glicirrízico/uso terapêutico , Proteína HMGB1/metabolismo , Proteína HMGB1/antagonistas & inibidores , Ratos , Masculino , Fosforilação/efeitos dos fármacos , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo
9.
Sci Total Environ ; 935: 173457, 2024 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-38782285

RESUMO

Microplastics and chlorine-containing triclosan (TCS) are widespread in aquatic environments and may pose health risks to organisms. However, studies on the combined toxicity of aged microplastics and TCS are limited. To investigate the toxic effects and potential mechanisms associated with co-exposure to TCS adsorbed on aged polyethylene microplastics (aPE-MPs) at environmentally relevant concentrations, a 7-day chronic exposure experiment was conducted using Xenopus tropicalis tadpoles. The results showed that the overall particle size of aPE-MPs decreased after 30 days of UV aging, whereas the increase in specific surface area improved the adsorption capacity of aPE-MPs for TCS, resulting in the bioaccumulation of TCS under dual-exposure conditions in the order of aPE-TCS > PE-TCS > TCS. Co-exposure to aPE-MPs and TCS exacerbated oxidative stress and neurotoxicity to a greater extent than a single exposure. Significant upregulation of pro-symptomatic factors (IL-ß and IL-6) and antioxidant enzyme activities (SOD and CAT) indicated that the aPE-TCS combination caused more severe oxidative stress and inflammation. Molecular docking revealed the molecular mechanism of the direct interaction between TCS and SOD, CAT, and AChE proteins, which explains why aPE-MPs promote the bioaccumulation of TCS, causing increased toxicity upon combined exposure. These results emphasize the need to be aware of the combined toxicity caused by the increased ability of aged microplastics to carry contaminants.


Assuntos
Larva , Microplásticos , Estresse Oxidativo , Triclosan , Poluentes Químicos da Água , Xenopus , Animais , Microplásticos/toxicidade , Poluentes Químicos da Água/toxicidade , Triclosan/toxicidade , Larva/efeitos dos fármacos , Bioacumulação , Síndromes Neurotóxicas
10.
Front Immunol ; 15: 1380451, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38765003

RESUMO

Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse overall survival (OS) and progression-free survival (PFS) after chimeric antigen receptor T-cell (CAR-T cell) therapy. Many options are being investigated for prophylaxis and management. Accumulating evidence supports the use of intrathecal (IT) chemotherapy for the management of high-grade ICANS. Here, we describe a case of a patient with stage IV Primary mediastinal B-cell lymphoma (PMBCL) successfully treated with IT methotrexate, cytarabine, and dexamethasone as first-line therapy for CD19 CAR-T cell-associated grade IV ICANS. The stable and rapid resolution of ICANS to grade 0 allowed us to discontinue systemic corticosteroid use, avoiding CAR-T cells ablation and ensuring preservation of CAR-T cell function. The described patient achieved a complete radiologic and clinical response to CD19 CAR-T cell therapy and remains disease-free after 9 months. This case demonstrates a promising example of how IT chemotherapy could be used as first-line treatment for the management of high-grade ICANS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina , Dexametasona , Injeções Espinhais , Metotrexato , Humanos , Dexametasona/administração & dosagem , Dexametasona/uso terapêutico , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Citarabina/administração & dosagem , Citarabina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Masculino , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/diagnóstico , Pessoa de Meia-Idade , Resultado do Tratamento , Imunoterapia Adotiva/efeitos adversos , Linfoma de Células B/tratamento farmacológico , Feminino
11.
Ecotoxicol Environ Saf ; 278: 116404, 2024 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-38705038

RESUMO

Manganese (Mn) is an essential trace element for maintaining bodily functions. Excessive exposure to Mn can pose serious health risks to humans and animals, particularly to the nervous system. While Mn has been implicated as a neurotoxin, the exact mechanism of its toxicity remains unclear. Ferroptosis is a form of programmed cell death that results from iron-dependent lipid peroxidation. It plays a role in various physiological and pathological cellular processes and may be closely related to Mn-induced neurotoxicity. However, the mechanism of ferroptosis in Mn-induced neurotoxicity has not been thoroughly investigated. Therefore, this study aims to investigate the role and mechanism of ferroptosis in Mn-induced neurotoxicity. Using bioinformatics, we identified significant changes in genes associated with ferroptosis in Mn-exposed animal and cellular models. We then evaluated the role of ferroptosis in Mn-induced neurotoxicity at both the animal and cellular levels. Our findings suggest that Mn exposure causes weight loss and nervous system damage in mice. In vitro and in vivo experiments have shown that exposure to Mn increases malondialdehyde, reactive oxygen species, and ferrous iron, while decreasing glutathione and adenosine triphosphate. These findings suggest that Mn exposure leads to a significant increase in lipid peroxidation and disrupts iron metabolism, resulting in oxidative stress injury and ferroptosis. Furthermore, we assessed the expression levels of proteins and mRNAs related to ferroptosis, confirming its significant involvement in Mn-induced neurotoxicity.


Assuntos
Ferroptose , Sobrecarga de Ferro , Peroxidação de Lipídeos , Manganês , Oxirredução , Ferroptose/efeitos dos fármacos , Animais , Manganês/toxicidade , Camundongos , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Síndromes Neurotóxicas/patologia , Masculino , Ferro/toxicidade , Ferro/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Humanos
12.
Behav Brain Res ; 468: 115040, 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38723675

RESUMO

Neurotoxins have been extensively investigated, particularly in the field of neuroscience. They induce toxic damage, oxidative stress, and inflammation on neurons, triggering neuronal dysfunction and neurodegenerative diseases. Here we demonstrate the neuroprotective effect of a silicon (Si)-based hydrogen-producing agent (Si-based agent) in a juvenile neurotoxic mouse model induced by 6-hydroxydopamine (6-OHDA). The Si-based agent produces hydrogen in bowels and functions as an antioxidant and anti-inflammatory agent. However, the effects of the Si-based agent on neural degeneration in areas other than the lesion and behavioral alterations caused by it are largely unknown. Moreover, the neuroprotective effects of Si-based agent in the context of lactation and use during infancy have not been explored in prior studies. In this study, we show the neuroprotective effect of the Si-based agent on 6-OHDA during lactation period and infancy using the mouse model. The Si-based agent safeguards against the degradation and neuronal cell death of dopaminergic neurons and loss of dopaminergic fibers in the striatum (STR) and ventral tegmental area (VTA) caused by 6-OHDA. Furthermore, the Si-based agent exhibits a neuroprotective effect on the length of axon initial segment (AIS) in the layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC). As a result, the Si-based agent mitigates hyperactive behavior in a juvenile neurotoxic mouse model induced by 6-OHDA. These results suggest that the Si-based agent serves as an effective neuroprotectant and antioxidant against neurotoxic effects in the brain, offering the possibility of the Si-based agent as a neuroprotectant for nervous system diseases.


Assuntos
Modelos Animais de Doenças , Neurônios Dopaminérgicos , Hidrogênio , Fármacos Neuroprotetores , Oxidopamina , Silício , Animais , Fármacos Neuroprotetores/farmacologia , Oxidopamina/farmacologia , Camundongos , Silício/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Hidrogênio/farmacologia , Hidrogênio/administração & dosagem , Masculino , Síndromes Neurotóxicas/tratamento farmacológico , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Camundongos Endogâmicos C57BL
13.
Int Immunopharmacol ; 135: 112308, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38788447

RESUMO

Although colistin has a crucial antibacterial activity in treating multidrug-resistant gram-negative bacteria strains; it exhibited renal and neuronal toxicities rendering its use a challenge. Previous studies investigated the incretin hormones either glucose-dependent insulinotropic polypeptide (GIP) or glucagonlike peptide-1 (GLP-1) for their neuroprotective and nephroprotective effectiveness. The present study focused on investigating Tirzepatide (Tirze), a dual GLP-1/GIP agonist, as an adjuvant therapy in the colistin treatment protocol for attenuating its renal and neuronal complications. Rats were divided into; The normal control group, the colistin-treated group received colistin (300,000 IU/kg/day for 7 days; i.p.). The Tirze-treated group received Tirze (1.35 mg/kg on the 1,4,7thdays; s.c.) and daily colistin. Tirze effectively enhanced histopathological alterations, renal function parameters, and locomotor activity in rats. Tirze mechanistically acted via modulating various signaling axes evolved under the insult of phosphatidylinositol 3-kinases (PI3K)/phosphorylated protein kinase-B (p-Akt)/ glycogen synthase kinase (GSK)3-ß hub causing mitigation of nuclear factor (NF)-κB (NF-κB) / tumor necrosis factor-α (TNF-α), increment of nuclear factor erythroid 2-related factor 2 (Nrf2)/ glutathione (GSH), downregulation of ER stress-related biomarkers (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)), antiapoptotic effects coupling with reduction of glial fibrillary acidic protein (GFAP) immunoreactivity and enhancement of phosphorylated c-AMP response element-binding (p-CREB) / brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) neuroprotective pathway. Briefly, Tirze exerts a promising role as adjuvant therapy in the colistin treatment protocol for protection against colistin's nephro- and neurotoxicity according to its anti-inflammatory, antioxidant, and antiapoptotic impacts besides its ability to suppress ER stress-related biomarkers.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Colistina , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico , Estresse do Retículo Endoplasmático , Glicogênio Sintase Quinase 3 beta , Rim , Estresse Oxidativo , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Animais , Estresse Oxidativo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Transdução de Sinais/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Rim/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Receptor trkB/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Ratos Wistar , Antibacterianos/uso terapêutico , Antibacterianos/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/prevenção & controle , Nefropatias/metabolismo
14.
Ecotoxicol Environ Saf ; 279: 116497, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38805827

RESUMO

Methamphetamine (METH) is a highly abused substance on a global scale and has the capacity to elicit toxicity within the central nervous system. The neurotoxicity induced by METH encompasses neuronal degeneration and cellular demise within the substantia nigra-striatum and hippocampus. Caffeic acid phenethyl ester (CAPE), a constituent of propolis, is a diminutive compound that demonstrates antioxidative and anti-inflammatory characteristics. Numerous investigations have demonstrated the safeguarding effects of CAPE in various neurodegenerative ailments. Our hypothesis posits that CAPE may exert a neuroprotective influence on METH-induced neurotoxicity via specific mechanisms. In order to validate the hypothesis, a series of experimental techniques including behavioral tests, immunofluorescence labeling, RNA sequencing, and western blotting were employed to investigate the neurotoxic effects of METH and the potential protective effects of CAPE. The results of our study demonstrate that CAPE effectively ameliorates cognitive memory deficits and anxiety symptoms induced by METH in mice. Furthermore, CAPE has been observed to attenuate the upregulation of neurotoxicity-associated proteins that are induced by METH exposure and also reduced the loss of hippocampal neurons in mice. Moreover, transcriptomics analysis was conducted to determine alterations in gene expression within the hippocampus of mice. Subsequently, bioinformatics analysis was employed to investigate the divergent outcomes and identify potential key genes. Interferon-stimulated gene 15 (ISG15) was successfully identified and confirmed through RT-qPCR, western blotting, and immunofluorescence techniques. Our research findings unequivocally demonstrated the neuroprotective effect of CAPE against METH-induced neurotoxicity, with ISG15 may have an important role in the underlying protective mechanism. These results offer novel perspectives on the treatment of METH-induced neurotoxicity.


Assuntos
Ácidos Cafeicos , Metanfetamina , Fármacos Neuroprotetores , Síndromes Neurotóxicas , Álcool Feniletílico , Animais , Ácidos Cafeicos/farmacologia , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Metanfetamina/toxicidade , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Camundongos , Masculino , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos
15.
Chemosphere ; 359: 142246, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38710414

RESUMO

The knowledge and assessment of mixtures of chemical pollutants in the aquatic environment is a complex issue that is often challenging to address. In this review, we focused on the use of zebrafish (Danio rerio), a vertebrate widely used in biomedical research, as a model for detecting the effects of chemical mixtures with a focus on behaviour. Our aim was to summarize the current status of the ecotoxicological research in this sector. Specifically, we limited our research to the period between January 2012 and September 2023, including only those works aimed at detecting neurotoxicity through behavioural endpoints, utilizing zebrafish at one or more developmental stages, from egg to adult. Additionally, we gathered the findings for every group of chemicals involved and summarised data from all the works we included. At the end of the screening process 101 papers were considered eligible for inclusion. Results show a growing interest in zebrafish at all life stages for this kind of research in the last decade. Also, a wide variety of different assays, involving different senses, was used in the works we surveyed, with exposures ranging from acute to chronic. In conclusion, the results of this study show the versatility of zebrafish as a model for the detection of mixture toxicity although, for what concerns behavioural analysis, the lack of standardisation of methods and endpoints might still be limiting.


Assuntos
Comportamento Animal , Síndromes Neurotóxicas , Poluentes Químicos da Água , Peixe-Zebra , Animais , Poluentes Químicos da Água/toxicidade , Comportamento Animal/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Testes de Toxicidade/métodos , Ecotoxicologia/métodos
16.
Biomed Pharmacother ; 175: 116698, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38713946

RESUMO

Neurotoxicity can cause a range of symptoms and disorders in humans, including neurodegenerative diseases, neurodevelopmental disorders, nerve conduction abnormalities, neuroinflammation, autoimmune disorders, and cognitive deficits. The cyclic guanosine-adenosine synthase (cGAS)-stimulator of interferon genes (STING) pathway and NF-κB pathway are two important signaling pathways involved in the innate immune response. The cGAS-STING pathway is activated by the recognition of intracellular DNA, which triggers the production of type I interferons and pro-inflammatory cytokines, such as tumor necrosis factor, IL-1ß, and IL-6. These cytokines play a role in oxidative stress and mitochondrial dysfunction in neurons. The NF-κB pathway is activated by various stimuli, such as bacterial lipopolysaccharide, viral particle components, and neurotoxins. NF-κB activation may lead to the production of pro-inflammatory cytokines, which promote neuroinflammation and cause neuronal damage. A potential interaction exists between the cGAS-STING and NF-κB pathways, and NF-κB activation blocks STING degradation by inhibiting microtubule-mediated STING transport. This review examines the progress of research on the roles of these pathways in neurotoxicity and their interrelationships. Understanding the mechanisms of these pathways will provide valuable therapeutic insights for preventing and controlling neurotoxicity.


Assuntos
Proteínas de Membrana , NF-kappa B , Nucleotidiltransferases , Transdução de Sinais , Humanos , NF-kappa B/metabolismo , Nucleotidiltransferases/metabolismo , Proteínas de Membrana/metabolismo , Animais , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/etiologia
17.
Folia Neuropathol ; 62(1): 1-12, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38741432

RESUMO

Polychlorinated biphenyls (PCBs) and brominated flame retardants (BFRs) are dominant environmental and food contaminants. Tetrabromobisphenol A (TBBPA) is the most widely used BFR in the world to improve the fire safety of laminates in electrical and electronic equipment. Aroclor 1254, one of the PCBs, is widely distributed in the environment due to its extensive use in industrial applications around the world. Both groups of substances are potent toxicants. There is also increasing evidence that they have neurotoxic effects. In this study we tested the pro-inflammatory effects of Aroclor 1254 and TBBPA based on markers of microglial reactivity and levels of pro-inflammatory factors in the brain of immature rats. Aroclor 1254 or TBBPA were administered to the rats by oral gavage for two weeks at a dose of 10 mg/kg b.w. Both light and electron microscopy studies revealed features indicative of microglia activation in brains of exposed rats. Morphological changes were associated with overexpression of pro-inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Analysis of cytokine/chemokine array revealed significant secretion of inflammatory mediators following exposure to both TBBPA and Aroclor 1254, which was stronger in the cerebellum than in the forebrain of exposed immature rats. The results indicate a pro-inflammatory profile of microglia activation as one of the neurotoxic mechanisms of both examined toxicants.


Assuntos
Microglia , Síndromes Neurotóxicas , Bifenil Polibromatos , Animais , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Bifenil Polibromatos/toxicidade , Ratos , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/etiologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Masculino , Retardadores de Chama/toxicidade , Ratos Wistar
18.
J Sep Sci ; 47(11): e2400164, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38819794

RESUMO

Oxaliplatin (L-OHP), a third-generation platinum-based anti-tumor drug, finds widespread application in the first-line treatment of metastatic colorectal cancer. Despite its efficacy, the drug's usage is curtailed by a litany of side effects, with L-OHP-induced peripheral neuropathy (OIPN) being the most debilitating. This condition can be classified into varying degrees of severity. Employing serum metabolomics, a high-sensitivity, high-throughput technique, holds promise as a method to identify biomarkers for clinical assessment and monitoring of OIPN patients across different severity levels. In our study, we analyzed serum metabolites in patients with different OIPN levels using ultra-performance liquid chromatography-high resolution mass spectrometry. By employing statistical analyses and pathway enrichment studies, we aimed to identify potential biomarkers and metabolic pathways. Our findings characterized the serum metabolic profiles of patients with varying OIPN levels. Notably, pathway analysis revealed a significant correlation with lipid metabolism, amino acid metabolism, and energy metabolism. Multivariate statistical analysis and receiver operator characteristic curve evaluation pointed to anhalamine and glycochenodeoxycholic acid as potential biomarkers for OIPN C and A, which suggest that serum metabolomics may serve as a potent tool for exploring the metabolic status of patients suffering from diverse diseases and for discovering novel biomarkers.


Assuntos
Metabolômica , Oxaliplatina , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Antineoplásicos/sangue , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/metabolismo , Cromatografia Líquida de Alta Pressão , Idoso , Biomarcadores/sangue , Síndromes Neurotóxicas/sangue , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/diagnóstico
19.
Exp Neurol ; 377: 114804, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38704083

RESUMO

BACKGROUND: Sevoflurane (SEV) has been found to induce neurotoxicity and cognitive impairment, leading to the development of degenerative diseases. Protein kinase C delta (PRKCD) is upregulated in the hippocampus of SEV-treated mice and may be related to SEV-related neurotoxicity. However, the underlying molecular mechanisms by which SEV mediates neurotoxicity via PRKCD remain unclear. METHODS: Normal mice and PRKCD knockout (KO) mice were exposed to SEV. Hippocampal neurons were isolated from mice hippocampal tissues. H&E staining was used for pathological morphology of hippocampal tissues, and NISSL staining was used to analyze the number of hippocampal neurons. The mRNA and protein levels were determined using quantitative real-time PCR, western blot, immunofluorescence staining and immunohistochemical staining. The mitochondrial microstructure was observed by transmission electron microscopy. Cell viability was detected by cell counting kit 8 assay, and ferroptosis was assessed by detecting related marker levels. The cognitive ability of mice was assessed by morris water maze test. And the protein levels of PRKCD, ferroptosis-related markers and Hippo pathway-related markers were examined by western bolt. RESULTS: SEV increased PRKCD expression and ferroptosis in hippocampal tissues of mice. Also, SEV promoted mouse hippocampal neuron injury by inducing ferroptosis via upregulating PRKCD expression. Knockout of PRKCD alleviated SEV-induced neurotoxicity and cognitive impairment in mice, and relieved SEV-induced ferroptosis in hippocampal neurons. PRKCD could inhibit the activity of Hippo pathway, and its knockdown also overturned SEV-mediated ferroptosis by activating Hippo pathway. CONCLUSION: SEV could induce neurotoxicity and cognitive impairment by promoting ferroptosis via inactivating Hippo pathway through increasing PRKCD expression.


Assuntos
Disfunção Cognitiva , Ferroptose , Via de Sinalização Hippo , Hipocampo , Camundongos Knockout , Proteína Quinase C-delta , Proteínas Serina-Treonina Quinases , Sevoflurano , Transdução de Sinais , Regulação para Cima , Animais , Sevoflurano/toxicidade , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/genética , Camundongos , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Regulação para Cima/efeitos dos fármacos , Proteína Quinase C-delta/metabolismo , Proteína Quinase C-delta/genética , Ferroptose/efeitos dos fármacos , Ferroptose/fisiologia , Camundongos Endogâmicos C57BL , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Anestésicos Inalatórios/toxicidade , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/metabolismo
20.
J Hazard Mater ; 473: 134607, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38761765

RESUMO

Paraquat (PQ) exposure is strongly associated with neurotoxicity. However, research on the neurotoxicity mechanisms of PQ varies in terms of endpoints of toxic assessment, resulting in a great challenge to understand the early neurotoxic effects of PQ. In this study, we developed an adverse outcome pathway (AOP) to investigate PQ-induced neuro-immunotoxicity from an immunological perspective, combining of traditional toxicology methods and computer simulations. In vivo, PQ can microstructurally lead to an early synaptic loss in the brain mice, which is a large degree regarded as a main reason for cognitive impairment to mice behavior. Both in vitro and in vivo demonstrated synapse loss is caused by excessive activation of the complement C1q/C3-CD11b pathway, which mediates microglial phagocytosis dysfunction. Additionally, the interaction between PQ and C1q was validated by molecular simulation docking. Our findings extend the AOP framework related to PQ neurotoxicity from a neuro-immunotoxic perspective, highlighting C1q activation as the initiating event for PQ-induced neuro-immunotoxicity. In addition, downstream complement cascades induce abnormal microglial phagocytosis, resulting in reduced synaptic density and subsequent non-motor dysfunction. These findings deepen our understanding of neurotoxicity and provide a theoretical basis for ecological risk assessment of PQ.


Assuntos
Complemento C1q , Simulação por Computador , Microglia , Paraquat , Fagocitose , Paraquat/toxicidade , Animais , Complemento C1q/imunologia , Complemento C1q/metabolismo , Fagocitose/efeitos dos fármacos , Microglia/efeitos dos fármacos , Rotas de Resultados Adversos , Masculino , Síndromes Neurotóxicas/imunologia , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/etiologia , Camundongos , Encéfalo/efeitos dos fármacos , Herbicidas/toxicidade , Antígeno CD11b/metabolismo , Complemento C3/metabolismo , Simulação de Acoplamento Molecular , Sinapses/efeitos dos fármacos , Camundongos Endogâmicos C57BL
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