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1.
Front Immunol ; 15: 1422591, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39253080

RESUMO

Malignant tumors of the hematologic system have a high degree of malignancy and high mortality rates. Chimeric antigen receptor T cell (CAR-T) therapy has become an important option for patients with relapsed/refractory tumors, showing astonishing therapeutic effects and thus, it has brought new hope to the treatment of malignant tumors of the hematologic system. Despite the significant therapeutic effects of CAR-T, its toxic reactions, such as Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), cannot be ignored since they can cause damage to multiple systems, including the cardiovascular system. We summarize biomarkers related to prediction, diagnosis, therapeutic efficacy, and prognosis, further exploring potential monitoring indicators for toxicity prevention. This review aims to summarize the effects of CAR-T therapy on the cardiovascular, hematologic, and nervous systems, as well as potential biomarkers, and to explore potential monitoring indicators for preventing toxicity, thereby providing references for clinical regulation and assessment of therapeutic effects.


Assuntos
Síndrome da Liberação de Citocina , Imunoterapia Adotiva , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Síndrome da Liberação de Citocina/prevenção & controle , Síndrome da Liberação de Citocina/etiologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/prevenção & controle , Biomarcadores , Animais , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Neoplasias/terapia , Neoplasias/imunologia
2.
Support Care Cancer ; 32(10): 677, 2024 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-39304604

RESUMO

PURPOSE: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a prevalent, dose-limiting, tough-to-treat toxicity involving numbness, tingling, and pain in the extremities with enigmatic pathophysiology. This randomized controlled pilot study explored the feasibility and preliminary efficacy of exercise during chemotherapy on CIPN and the role of the interoceptive brain system, which processes bodily sensations. METHODS: Nineteen patients (65 ± 11 years old, 52% women; cancer type: breast, gastrointestinal, multiple myeloma) starting neurotoxic chemotherapy were randomized to 12 weeks of exercise (home-based, individually tailored, moderate intensity, progressive walking, and resistance training) or active control (nutrition education). At pre-, mid-, and post-intervention, we assessed CIPN symptoms (primary clinical outcome: CIPN-20), CIPN signs (tactile sensitivity using monofilaments), and physical function (leg strength). At pre- and post-intervention, we used task-free ("resting") fMRI to assess functional connectivity in the interoceptive brain system, involving the salience and default mode networks. RESULTS: The study was feasible (74-89% complete data across measures) and acceptable (95% retention). We observed moderate/large beneficial effects of exercise on CIPN symptoms (CIPN-20, 0-100 scale: - 7.9 ± 5.7, effect size [ES] = - 0.9 at mid-intervention; - 4.8 ± 7.3, ES = - 0.5 at post-intervention), CIPN signs (ES = - 1.0 and - 0.1), and physical function (ES = 0.4 and 0.3). Patients with worse CIPN after neurotoxic chemotherapy had lower functional connectivity within the default mode network (R2 = 40-60%) and higher functional connectivity within the salience network (R2 = 20-40%). Exercise tended to increase hypoconnectivity and decrease hyperconnectivity seen in CIPN (R2 = 12%). CONCLUSION: Exercise during neurotoxic chemotherapy is feasible and may attenuate CIPN symptoms and signs, perhaps via changes in interoceptive brain circuitry. Future work should test for replication with larger samples. TRIAL REGISTRATION: Registered Jan 2017 on ClinicalTrials.gov as NCT03021174.


Assuntos
Antineoplásicos , Síndromes Neurotóxicas , Doenças do Sistema Nervoso Periférico , Humanos , Feminino , Projetos Piloto , Masculino , Idoso , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Antineoplásicos/efeitos adversos , Síndromes Neurotóxicas/etiologia , Imageamento por Ressonância Magnética/métodos , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Encéfalo/diagnóstico por imagem , Terapia por Exercício/métodos , Interocepção/fisiologia , Exercício Físico/fisiologia , Estudos de Viabilidade
3.
Front Immunol ; 15: 1423263, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39224601

RESUMO

Combination antiretroviral therapy (cART) has dramatically reduced mortality in people with human immunodeficiency virus (HIV), but it does not completely eradicate the virus from the brain. Patients with long-term HIV-1 infection often show neurocognitive impairment, which severely affects the quality of life of those infected. Methamphetamine (METH) users are at a significantly higher risk of contracting HIV-1 through behaviors such as engaging in high-risk sex or sharing needles, which can lead to transmission of the virus. In addition, HIV-1-infected individuals who abuse METH exhibit higher viral loads and more severe cognitive dysfunction, suggesting that METH exacerbates the neurotoxicity associated with HIV-1. Therefore, this review focuses on various mechanisms underlying METH and HIV-1 infection co-induced neurotoxicity and existing interventions targeting the sigma 1 receptor, dopamine transporter protein, and other relevant targets are explored. The findings of this review are envisaged to systematically establish a theoretical framework for METH abuse and HIV-1 infection co-induced neurotoxicity, and to suggest novel clinical treatment targets.


Assuntos
Infecções por HIV , Metanfetamina , Animais , Humanos , Transtornos Relacionados ao Uso de Anfetaminas/complicações , Transtornos Relacionados ao Uso de Anfetaminas/terapia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Infecções por HIV/transmissão , HIV-1/patogenicidade , Metanfetamina/efeitos adversos , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/terapia , Receptor Sigma-1/antagonistas & inibidores
4.
Medicine (Baltimore) ; 103(36): e38659, 2024 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-39252328

RESUMO

RATIONALE: Anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy is a successful treatment for B-cell malignancies associated with cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cardiovascular toxicities have also been reported in this setting. However, there is scarce data regarding development of autonomic disorders after CAR-T cell therapy. PATIENT CONCERNS: We report a case with a patient with non-Hodgkin B-cell lymphoma, refractory to 2 prior lines of immunochemotherapy, treated with CAR-T therapy. DIAGNOSES: Orthostatic hypotension secondary to autonomic dysfunction was diagnosed as manifestation of ICANS. INTERVENTIONS: The patient received metilprednisolone 1000 mg IV daily for 3 days and anakinra 100 mg IV every 6h. OUTCOMES: The vast majority of autonomic symptoms ceased and 4 months after CAR-T therapy, autonomic dysfunction was resolved. LESSONS: New-onset autonomic dysfunction can occur as manifestation of ICANS in patients who experience persistent neurologic and cardiovascular symptoms after resolution of acute neurotoxicity and should be early recognized. Differences in differential diagnosis, mechanisms and treatment approaches are discussed.


Assuntos
Doenças do Sistema Nervoso Autônomo , Humanos , Doenças do Sistema Nervoso Autônomo/etiologia , Doenças do Sistema Nervoso Autônomo/diagnóstico , Imunoterapia Adotiva/efeitos adversos , Masculino , Síndrome da Liberação de Citocina/etiologia , Pessoa de Meia-Idade , Linfoma de Células B/complicações , Linfoma de Células B/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/diagnóstico , Hipotensão Ortostática/etiologia , Hipotensão Ortostática/diagnóstico , Metilprednisolona/uso terapêutico
5.
Sci Rep ; 14(1): 21009, 2024 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-39251717

RESUMO

Hydroxyapatite nanoparticles (HANPs) have extensive applications in biomedicine and tissue engineering. However, little information is known about their toxicity. Here, we aim to investigate the possible neurotoxicity of HANPs and the possible protective role of chitosan nanoparticles (CNPs) and curcumin nanoparticles (CUNPs) against this toxicity. In our study, HANPs significantly reduced the levels of neurotransmitters, including acetylcholine (Ach), dopamine (DA), serotonin (SER), epinephrine (EPI), and norepinephrine (NOR). HANPs significantly suppressed cortical expression of the genes controlling mitochondrial biogenesis such as peroxisome proliferator activator receptor gamma coactivator 1α (PGC-1α) and mitochondrial transcription factor A (mTFA). Our findings revealed significant neuroinflammation associated with elevated apoptosis, lipid peroxidation, oxidative DNA damage and nitric oxide levels with significant decline in the antioxidant enzymes activities and glutathione (GSH) levels in HANPs-exposed rats. Meanwhile, co-supplementation of HANP-rats with CNPs and/or CUNPs significantly showed improvement in levels of neurotransmitters, mitochondrial biogenesis, oxidative stress, DNA damage, and neuroinflammation. The co-supplementation with both CNPs and CUNPs was more effective to ameliorate HANPs-induced neurotoxicity than each one alone. So, CNPs and CUNPs could be promising protective agents for prevention of HANPs-induced neurotoxicity.


Assuntos
Quitosana , Curcumina , Durapatita , Nanopartículas , Estresse Oxidativo , Animais , Curcumina/farmacologia , Quitosana/química , Quitosana/farmacologia , Nanopartículas/química , Ratos , Durapatita/química , Estresse Oxidativo/efeitos dos fármacos , Masculino , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/metabolismo , Fármacos Neuroprotetores/farmacologia , Neurotransmissores/metabolismo , Apoptose/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Dano ao DNA/efeitos dos fármacos
6.
Sci Total Environ ; 952: 175939, 2024 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-39218100

RESUMO

The use of plastic bowls (PB) has garnered increasing scrutiny due to the inevitable generation of microplastics (MPs) throughout their lifecycle. Despite this concern, there exists a limited understanding of the behaviors, toxicological effects, and mechanisms associated with aged PB (A-PB). This research investigated the photoaging properties of A-PB following ultraviolet irradiation and evaluated the neurotoxic impact of exposure to A-PB at environmentally relevant concentrations (0.001-1 mg/L) on Caenorhabditis elegans. Significant alterations in the crystallinity, elemental composition, and functional groups of A-PB were observed compared to virgin PB (V-PB), along with the emergence of environmentally persistent free radicals and reactive oxygen species. Toxicity assessments revealed that exposure to 0.1-1 mg/L A-PB induced greater neurotoxicity on locomotion behaviors compared to V-PB, as evidenced by marked reductions in head thrashes, body bends, wavelength, and mean amplitude. Exposure to A-PB also altered the fluorescence intensities and neurodegeneration percentage of dopaminergic, serotonergic, and GABAergic neurons, suggesting neuronal damage in the nematodes. Correspondingly, decreases in the levels of dopamine, serotonin, and GABA were noted together with significant drops in the expression of neurotransmitter-related genes (e.g., dat-1, tph-1, and unc-47). Correlation analyses established a significant positive relationship between these genes and locomotion behaviors. Further exploration showed the absence of locomotion behaviors in dat-1 (ok157), tph-1 (mg280), and unc-47 (e307) mutants, underscoring the pivotal roles of the dat-1, tph-1, and unc-47 genes in mediating neurotoxicity in C. elegans. This study sheds light on the photoaging characteristics and heightened toxicity of A-PB, elucidating the mechanisms driving A-PB-induced neurotoxicity.


Assuntos
Caenorhabditis elegans , Microplásticos , Animais , Caenorhabditis elegans/efeitos dos fármacos , Caenorhabditis elegans/fisiologia , Microplásticos/toxicidade , Plásticos/toxicidade , Transmissão Sináptica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Síndromes Neurotóxicas
7.
Environ Int ; 191: 108987, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39217723

RESUMO

Triclocarban (TCC) is an antimicrobial ingredient that commonly incorporated in many household and personal care products, raising public concerns about its potential health risks. Previous research has showed that TCC could cross the blood-brain barrier, but to date our understanding of its potential neurotoxicity at human-relevant concentrations remains lacking. In this study, we observed anxiety-like behaviors in mice with continuous percutaneous exposure to TCC. Subsequently, we combined lipidomic, proteomic, and metabolic landscapes to investigate the underlying mechanisms of TCC-related neurotoxicity. The results showed that TCC exposure dysregulated the proteins involved in endocytosis and neurodegenerative disorders in mouse cerebrum. Brain energy homeostasis was also altered, as evidenced by the perturbation of pyruvate metabolism, TCA cycle, and oxidative phosphorylation, which in turn caused mitochondrial dysfunction. Meanwhile, the changing trends of sphingolipid signaling pathway and overproduction of mitochondrial reactive oxygen species (mROS) could enhance the neural apoptosis. The in vitro approach further demonstrated that TCC exposure promoted apoptosis, accompanied by the overproduction of mROS and alteration in the mitochondrial membrane potential in N2A cells. Together, dysregulated endocytosis, mROS-related mitochondrial dysfunction and neural cell apoptosis are considered to be crucial factors for TCC-induced neurotoxicity, which may contribute to the occurrence and development of neurodegenerative disorders. Our findings provide novel perspectives for the mechanisms of TCC-triggered neurotoxicity.


Assuntos
Encéfalo , Carbanilidas , Animais , Camundongos , Carbanilidas/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteômica , Apoptose/efeitos dos fármacos , Síndromes Neurotóxicas/etiologia , Masculino , Multiômica
8.
Cell Biol Toxicol ; 40(1): 63, 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093513

RESUMO

Anesthetic-induced developmental neurotoxicity (AIDN) can arise due to various factors, among which aberrant nerve cell death is a prominent risk factor. Animal studies have reported that repeated or prolonged anesthetic exposure can cause significant neuroapoptosis in the developing brain. Lately, non-apoptotic programmed cell deaths (PCDs), characterized by inflammation and oxidative stress, have gained increasing attention. Substantial evidence suggests that non-apoptotic PCDs are essential for neuronal cell death in AIDN compared to apoptosis. This article examines relevant publications in the PubMed database until April 2024. Only original articles in English that investigated the potential manifestations of non-apoptotic PCD in AIDN were analysed. Specifically, it investigates necroptosis, pyroptosis, ferroptosis, and parthanatos, elucidating the signaling mechanisms associated with each form. Furthermore, this study explores the potential relevance of these non-apoptotic PCDs pathways to the pathological mechanisms underlying AIDN, drawing upon their distinctive characteristics. Despite the considerable challenges involved in translating fundamental scientific knowledge into clinical therapeutic interventions, this comprehensive review offers a theoretical foundation for developing innovative preventive and treatment strategies targeting non-apoptotic PCDs in the context of AIDN.


Assuntos
Anestésicos , Apoptose , Síndromes Neurotóxicas , Humanos , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/etiologia , Animais , Anestésicos/efeitos adversos , Anestésicos/toxicidade , Anestésicos/farmacologia , Apoptose/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neurônios/metabolismo , Piroptose/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Necroptose/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/crescimento & desenvolvimento , Ferroptose/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
9.
Int J Mol Sci ; 25(15)2024 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-39125900

RESUMO

The effects of exposure to environmental pollutants on neurological processes are of increasing concern due to their potential to induce oxidative stress and neurotoxicity. Considering that many industries are currently using different types of plastics as raw materials, packaging, or distribution pipes, microplastics (MPs) have become one of the biggest threats to the environment and human health. These consequences have led to the need to raise the awareness regarding MPs negative neurological effects and implication in neuropsychiatric pathologies, such as schizophrenia. The study aims to use three zebrafish models of schizophrenia obtained by exposure to ketamine (Ket), methionine (Met), and their combination to investigate the effects of MP exposure on various nervous system structures and the possible interactions with oxidative stress. The results showed that MPs can interact with ketamine and methionine, increasing the severity and frequency of optic tectum lesions, while co-exposure (MP+Met+Ket) resulted in attenuated effects. Regarding oxidative status, we found that all exposure formulations led to oxidative stress, changes in antioxidant defense mechanisms, or compensatory responses to oxidative damage. Met exposure induced structural changes such as necrosis and edema, while paradoxically activating periventricular cell proliferation. Taken together, these findings highlight the complex interplay between environmental pollutants and neurotoxicants in modulating neurotoxicity.


Assuntos
Encéfalo , Modelos Animais de Doenças , Microplásticos , Estresse Oxidativo , Esquizofrenia , Peixe-Zebra , Peixe-Zebra/metabolismo , Animais , Estresse Oxidativo/efeitos dos fármacos , Microplásticos/toxicidade , Esquizofrenia/metabolismo , Esquizofrenia/induzido quimicamente , Esquizofrenia/patologia , Esquizofrenia/etiologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Ketamina/efeitos adversos , Ketamina/toxicidade , Metionina/metabolismo , Imuno-Histoquímica
10.
Sci Rep ; 14(1): 19341, 2024 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164364

RESUMO

Peripheral neurotoxicity is a dose-limiting adverse reaction of primary frontline chemotherapeutic agents, including vincristine. Neuropathy can be so disabling that patients drop out of potentially curative therapy, negatively impacting cancer prognosis. The hallmark of vincristine neurotoxicity is axonopathy, yet its underpinning mechanisms remain uncertain. We developed a comprehensive drug discovery platform to identify neuroprotective agents against vincristine-induced neurotoxicity. Among the hits identified, SIN-1-an active metabolite of molsidomine-prevents vincristine-induced axonopathy in both motor and sensory neurons without compromising vincristine anticancer efficacy. Mechanistically, we found that SIN-1's neuroprotective effect is mediated by activating soluble guanylyl cyclase. We modeled vincristine-induced peripheral neurotoxicity in rats to determine molsidomine therapeutic potential in vivo. Vincristine administration induced severe nerve damage and mechanical hypersensitivity that were attenuated by concomitant treatment with molsidomine. This study provides evidence of the neuroprotective properties of molsidomine and warrants further investigations of this drug as a therapy for vincristine-induced peripheral neurotoxicity.


Assuntos
Molsidomina , Fármacos Neuroprotetores , Guanilil Ciclase Solúvel , Vincristina , Vincristina/efeitos adversos , Vincristina/farmacologia , Vincristina/toxicidade , Animais , Fármacos Neuroprotetores/farmacologia , Ratos , Guanilil Ciclase Solúvel/metabolismo , Molsidomina/farmacologia , Molsidomina/análogos & derivados , Humanos , Masculino , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/prevenção & controle , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Ratos Sprague-Dawley , Síndromes Neurotóxicas/tratamento farmacológico , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/etiologia
11.
Sci Rep ; 14(1): 19075, 2024 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-39154055

RESUMO

Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation. A replicable dose-response in viability was demonstrated after 48-h exposure to docetaxel or paclitaxel. Additionally, a replicable dose-dependent reduction in neurite outgrowth was demonstrated, demonstrating the applicability of the model for the examination of additional phenotypes. Overall, we have established an optimized iPSC-dSN model for the study of taxane-induced neurotoxicity.


Assuntos
Sobrevivência Celular , Células-Tronco Pluripotentes Induzidas , Células Receptoras Sensoriais , Taxoides , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Taxoides/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Síndromes Neurotóxicas/etiologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Diferenciação Celular/efeitos dos fármacos , Paclitaxel/farmacologia , Paclitaxel/toxicidade , Linhagem Celular , Células Cultivadas
12.
Toxicology ; 508: 153934, 2024 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-39182714

RESUMO

Neurotoxicity is characterized by the accumulation of harmful chemicals such as heavy metals and drugs in neural tissue, resulting in subsequent neuronal death. Among chemicals platinum-based cancer drugs are frequently used due to their antineoplastic effects, but this drug is also known to cause a wide range of toxicities, such as neurotoxicity. The nuclear-factor-erythroid 2-related factor-2 (NRF2) is crucial in combating oxidative stress and maintaining cellular homeostasis. This study thoroughly explores the protective effects of extracellular vesicles derived from NRF2 gene overexpressed neural progenitor cells (NEVs) on cisplatin-induced neurotoxicity. Therefore, extracellular vesicles derived from neural progenitor cells were isolated and characterized. The Cisplatin neurotoxicity dose was 75 µM in mature, post-mitotic neurons. 1.25 µM of tert-butyl hydroquinone that induces NRF2/ARE pathway was used as the positive control. The effects of extracellular vesicles (EVs) were investigated using functional and molecular assays such as PCR and protein-based assays. Here, we observed that NEVs dose-dependently protected post-mitotic neuron cells in response to cisplatin. The study also examined whether the effect was EV-induced by limiting EV biogenesis. The molecular basis of preventive treatment was established. When pre-administered, 1×108 particles/ml of NEVs maintained antioxidant and detoxifying gene and protein expression levels similar to control cell levels. Furthermore, NEVs reduced both cellular and mitochondrial ROS levels and preserved mitochondrial membrane potential. In addition, Catalase and SOD levels were found higher in NEV-treated cells compared to cisplatin control. The findings in NRF2-based protection of cisplatin-induced neurotoxicity may provide further evidence for the relationship between EVs and inhibition of neuronal stress through the NRF2/ARE pathway, increasing the understanding of neuroprotective responses and the development of gene-engineered EV therapy options for peripheral neuropathy or other neurodegenerative diseases. This is the first study in the literature to investigate the neutralizing potency of NRF2 overexpressed neural EVs against cisplatin-induced neurotoxicity.


Assuntos
Antineoplásicos , Cisplatino , Vesículas Extracelulares , Fator 2 Relacionado a NF-E2 , Células-Tronco Neurais , Transdução de Sinais , Cisplatino/toxicidade , Fator 2 Relacionado a NF-E2/metabolismo , Vesículas Extracelulares/efeitos dos fármacos , Vesículas Extracelulares/metabolismo , Animais , Antineoplásicos/toxicidade , Antineoplásicos/farmacologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Síndromes Neurotóxicas/prevenção & controle , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/etiologia , Elementos de Resposta Antioxidante/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Células Cultivadas
13.
J Hazard Mater ; 478: 135611, 2024 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-39173387

RESUMO

Per- and polyfluoroalkyl substances (PFAS) have been called "forever chemicals" due to their inherent chemical stability. Their potential toxic effects on aquatic animals and health risk assessments have not been fully elucidated. In this study, we investigated the toxic effects of PFASs at environmentally relevant concentrations (200 ng/L) on crucian carp (Carassius auratus). The results showed that PFAS reduced the comfort behaviour of crucian carp and was associated with reduced levels of acetylcholinesterase and dopamine in the brain. PFAS exposure also decreased the activities of total superoxide dismutase, catalase and glutathione peroxidase, while increasing the levels of malondialdehyde. PFAS caused over-expression of the pro-inflammatory cytokines TNF-α, IFN-γ and stress-related genes Caspase-3, HSP-70 in the fish brain. Pathological staining showed that PFAS caused multifocal demyelination and perineural vacuolization in brain, intestinal tissue also showed reduced villus length and focal damage. PFASs altered the composition of the gut microbiota of crucian carp, significantly increasing the abundance of potentially pathogenic bacteria and the potential pathogenicity of the microbiota. It is suggested that PFASs may cause varying degrees of tissue damage by destabilising the gut microbiota. These results provide insights for assessing the toxicity of PFAS contaminants at aquatic environmental concentrations.


Assuntos
Encéfalo , Disbiose , Fluorocarbonos , Microbioma Gastrointestinal , Carpa Dourada , Poluentes Químicos da Água , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Poluentes Químicos da Água/toxicidade , Disbiose/induzido quimicamente , Fluorocarbonos/toxicidade , Acetilcolinesterase/metabolismo , Carpas , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/etiologia , Citocinas/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Dopamina/metabolismo , Comportamento Animal/efeitos dos fármacos
14.
BMC Infect Dis ; 24(1): 862, 2024 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-39187812

RESUMO

BACKGROUND: The study aimed to compare polymyxin B with colistimethate sodium (CMS) regarding neurotoxicity, nephrotoxicity and 30-day mortality in patients with MDR Gram-negatives. METHODS: All adult patients who received polymyxin B or CMS for at least 24 h for the treatment of MDR microorganisms were evaluated retrospectively. RESULTS: Among 413 initially screened patients, 147 patients who were conscious and able to express their symptoms were included in the neurotoxicity analysis. 13 of 77 patients with polymyxin B and 1 of 70 with CMS had neurotoxic adverse events, mainly paresthesias. All events were reversible after drug discontinuation. Among 290 patients included in nephrotoxicity analysis, the incidence of acute kidney injury (AKI) was 44.7% and 40.0% for polymyxin B and CMS, respectively (p = 0.425). AKI occurred two days earlier with colistin than polymyxin B without statistical significance (median (IQR): 5 (3-11) vs. 7 (3-12), respectively, p = 0.701). Polymyxin therapy was withdrawn in 41.1% of patients after AKI occurred and CMS was more frequently withdrawn than polymyxin B (p = 0.025). AKI was reversible in 91.6% of patients with CMS and 79% with polymyxin B after the drug withdrawal. Older age, higher baseline serum creatinine and the use of at least two nephrotoxic drugs were independent factors associated with AKI (OR 1.05, p < 0.001; OR 2.99, p = 0.022 and OR 2.45, p = 0.006, respectively). Septic shock, mechanical ventilation, presence of a central venous catheter and Charlson comorbidity index (OR 2.13, p = 0.004; OR 3.37, p < 0.001; OR 2.47, p = 0.004 and OR 1.21, p p < 0.001, respectively) were the independent predictors of mortality. The type of polymyxin was not related to mortality. CONCLUSIONS: Neurotoxicity is a relatively common adverse event that leads to drug withdrawal during polymyxins, particularly polymyxin B. Nephrotoxicity is very common during polymyxin therapy and the two polymyxins display similar nephrotoxic events with high reversibility rates after drug withdrawal. Close monitoring of AKI is crucial during polymyxin therapy, particularly, for elderly patients, patients who have high baseline creatinine, and using other nephrotoxic drugs.


Assuntos
Injúria Renal Aguda , Antibacterianos , Colistina , Polimixina B , Humanos , Colistina/efeitos adversos , Colistina/análogos & derivados , Polimixina B/efeitos adversos , Polimixina B/uso terapêutico , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Antibacterianos/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Adulto , Farmacorresistência Bacteriana Múltipla , Idoso de 80 Anos ou mais , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/epidemiologia
15.
J Hematol Oncol ; 17(1): 61, 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39107847

RESUMO

Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count < 150 G/L, a C-reactive protein (CRP) level > 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets (< 150 G/L), use of axi-cel and no bridging therapy or SD/PD after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel.


Assuntos
Antígenos CD19 , Síndrome da Liberação de Citocina , Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Antígenos CD19/imunologia , Prognóstico , Linfoma Difuso de Grandes Células B/terapia , Linfoma Difuso de Grandes Células B/imunologia , Síndrome da Liberação de Citocina/etiologia , Idoso , Adulto , Síndromes Neurotóxicas/etiologia , Produtos Biológicos/uso terapêutico , Produtos Biológicos/efeitos adversos , França , Idoso de 80 Anos ou mais , Receptores de Antígenos de Linfócitos T
16.
Biomolecules ; 14(8)2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39199372

RESUMO

Pregnancy is a particularly vulnerable period for the growing fetus, when exposure to toxic agents, especially in the early phases, can decisively harm embryo development and compromise the future health of the newborn. The inclusion of various chemical substances in personal care products (PCPs) and cosmetic formulations can be associated with disruption and damage to the nervous system. Microplastics, benzophenones, parabens, phthalates and metals are among the most common chemical substances found in cosmetics that have been shown to induce neurotoxic mechanisms. Although cosmetic neurotoxin exposure is believed to be minimal, different exposure scenarios of cosmetics suggest that these neurotoxins remain a threat. Special attention should be paid to early exposure in the first weeks of gestation, when critical processes, like the migration and proliferation of the neural crest derived cells, start to form the ENS. Importantly, cosmetic neurotoxins can cross the placental barrier and affect the future embryo, but they are also secreted in breast milk, so babies remain exposed for longer periods, even after birth. In this review, we explore how neurotoxins contained in cosmetics and PCPs may have a role in the pathogenesis of various neurodevelopmental disorders and neurodegenerative diseases and, therefore, also in congenital enteric aganglionosis as well as in postnatal motility disorders. Understanding the mechanisms of these chemicals used in cosmetic formulations and their role in neurotoxicity is crucial to determining the safety of use for cosmetic products during pregnancy.


Assuntos
Cosméticos , Humanos , Feminino , Gravidez , Cosméticos/efeitos adversos , Neurotoxinas/toxicidade , Síndromes Neurotóxicas/etiologia , Ácidos Ftálicos/toxicidade , Animais
18.
Intensive Care Med ; 50(9): 1459-1469, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39172238

RESUMO

The use of chimeric antigen receptor T (CAR-T) cells is a significant therapeutic improvement increasing the prognosis for patients with a variety of hematological malignancies. However, this therapy has also sometimes life-threatening, complications. Therefore, knowledge of the treatment and management of these complications, especially in treatment centers and intensive care units, respectively, is of outstanding importance. This review provides recommendations for the diagnosis, management, and treatment of CAR-T cell-associated complications such as cytokine release syndrome, immune effector cell associated neurotoxicity syndrome, hematotoxicity, hypogammaglobulinemia, and CAR-T cell-induced pseudo-progression amongst others for physicians treating patients with CAR-T cell-associated complications and intensivists.


Assuntos
Síndrome da Liberação de Citocina , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/uso terapêutico , Receptores de Antígenos Quiméricos/imunologia , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/terapia , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/imunologia , Síndromes Neurotóxicas/etiologia
19.
Toxicol Lett ; 400: 81-92, 2024 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-39147216

RESUMO

T-2 toxin is one of the mycotoxins widely distributed in human food and animal feed. Our recent work has shown that microglial activation may contribute to T-2 toxin-induced neurotoxicity. However, the molecular mechanisms involved need to be further clarified. To address this, we employed high-throughput transcriptome sequencing and found altered B cell translocation gene 2 (BTG2) expression levels in microglia following T-2 toxin treatment. It has been shown that altered BTG2 expression is involved in a range of neurological pathologies, but whether it's involved in the regulation of microglial activation is unclear. The aim of this study was to investigate the role of BTG2 in T-2 toxin-induced microglial activation. The results of animal experiments showed that T-2 toxin caused neurobehavioral disorders and promoted the expression of microglial BTG2 and pro-inflammatory activation of microglia in hippocampus and cortical, while microglial inhibitor minocycline inhibited these changes. The results of in vitro experiments showed that T-2 toxin enhanced BTG2 expression and pro-inflammatory microglial activation, and inhibited BTG2 expression weakened T-2 toxin-induced microglial activation. Moreover, T-2 toxin activated PI3K/AKT and its downstream NF-κB signaling pathway, which could be reversed after knock-down of BTG2 expression. Meanwhile, the PI3K inhibitor LY294002 also blocked this process. Therefore, BTG2 may be involved in T-2 toxin's ability to cause microglial activation through PI3K/AKT/NF-κB pathway.


Assuntos
Proteínas Imediatamente Precoces , Microglia , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Toxina T-2 , Microglia/efeitos dos fármacos , Microglia/metabolismo , Animais , Proteínas Proto-Oncogênicas c-akt/metabolismo , Toxina T-2/toxicidade , Transdução de Sinais/efeitos dos fármacos , Proteínas Imediatamente Precoces/metabolismo , Proteínas Imediatamente Precoces/genética , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Camundongos , Fosfatidilinositol 3-Quinases/metabolismo , Masculino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Fosfatidilinositol 3-Quinase/metabolismo
20.
Sci Total Environ ; 951: 175681, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39173756

RESUMO

Manganese (Mn) is an environmental pollutant, and overexposure can cause neurodegenerative disorders similar to Alzheimer's disease and Parkinson's disease that are characterized by ß-amyloid (Aß) overexpression, Tau hyperphosphorylation and neuroinflammation. However, the mechanisms of Mn neurotoxicity are not clearly defined. In our study, a knockout mouse model of Mn exposure combined with gut flora-induced neurotoxicity was constructed to investigate the effect of gut flora on Mn neurotoxicity. The results showed that the levels of Tau, p-Tau and Aß in the hippocampus of C57BL/6 mice were greater than those in the hippocampus of control mice after 5 weeks of continuous exposure to manganese chloride (Mn content of 200 mg/L). Transplanted normal and healthy fecal microbiota from mice significantly downregulated Tau, p-Tau and Aß expression and ameliorated brain pathology. Moreover, Mn exposure activated the cGAS-STING pathway and altered the cecal microbiota profile, characterized by an increase in Clostridiales, Pseudoflavonifractor, Ligilactobacillus and Desulfovibrio, and a decrease in Anaerotruncus, Eubacterium_ruminantium_group, Fusimonas and Firmicutes, While fecal microbiome transplantation (FMT) treatment inhibited this pathway and restored the microbiota profile. FMT alleviated Mn exposure-induced neurotoxicity by inhibiting activation of the NLRP3 inflammasome triggered by overactivation of the cGAS-STING pathway. Deletion of the cGAS and STING genes and FMT altered the gut microbiota composition and its predictive function. Phenotypic prediction revealed that FMT markedly decreased the abundances of anaerobic and stress-tolerant bacteria and significantly increased the abundances of facultative anaerobic bacteria and biofilm-forming bacteria after blocking the cGAS-STING pathway compared to the Mn-exposed group. FMT from normal and healthy mice ameliorated the neurotoxicity of Mn exposure, possibly through alterations in the composition and function of the microbiome associated with the cGAS-STING/NLRP3 pathway. This study provides a prospective direction for future research on the mechanism of Mn neurotoxicity.


Assuntos
Transplante de Microbiota Fecal , Microbioma Gastrointestinal , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Microbioma Gastrointestinal/fisiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas de Membrana/metabolismo , Manganês/toxicidade , Síndromes Neurotóxicas , Camundongos Knockout , Transdução de Sinais , Nucleotidiltransferases
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