Neurotoxidad inducida por ifosfamida / Ifosfamide-induced neurotoxicity

Introducción: La ifosfamida es un agente alquilante utilizado para el tratamiento de enfermedades oncohematológicas. Entre sus eventos adversos agudos se encuentra la neurotoxicidad. Esta puede presentarse desde el inicio de la infusión hasta tres días después. El tratamiento consiste en suspender la administración y asegurar una adecuada hidratación. Objetivo: Describir eventos neurológicos asociados al uso de ifosfamida en pacientes pediátricos con enfermedades oncohematológicas. Materiales y métodos: Estudio observacional, descriptivo, retrospectivo y transversal. Los datos se obtuvieron de historias clínicas de pacientes internados en el Hospital Garrahan que infundieron ifosfamida y desarrollaron síntomas neurológicos. Se analizaron edad, diagnóstico de base, dosis de ifosfamida, síntomas neurológicos y su relación con la infusión, tratamiento instaurado, exámenes complementarios y posibles factores de riesgo asociados. Resultados: Se registraron un total de catorce eventos neurológicos en doce pacientes, sin diferencia de sexo, con una mediana de edad de 9,5 años. La enfermedad de base más prevalente fue osteosarcoma. Las convulsiones fueron el síntoma más frecuente (50%), seguido de somnolencia y paresias. La combinación de ifosfamida y etopósido con/sin carboplatino se asoció en un 36% cada uno. El 64% desarrolló neurotoxicidad dentro de las primeras cuatro horas. Ningún paciente presentó alteraciones en los exámenes complementarios. Todos presentaron recuperación ad integrum. Conclusión: Este estudio brinda información acerca del tiempo de aparición de esta complicación, lo cual facilitará su detección precoz y tratamiento oportuno (AU)

Introduction: Ifosfamide is an alkylating agent used for the treatment of cancer. Among its acute adverse events is neurotoxicity. This can occur from the beginning of the infusion up to three days afterwards. Treatment consists of discontinuing administration and ensuring adequate hydration. Objective: To describe neurological events associated with the use of ifosfamide in children with cancer. Materials and methods: Observational, descriptive, retrospective, and cross-sectional study. Data were obtained from clinical records of patients admitted to the Garrahan Hospital who received ifosfamide infusion and developed neurological symptoms. Age, baseline diagnosis, ifosfamide dose, neurological symptoms and their relationship with the infusion, treatment, complementary tests, and possible associated risk factors were analyzed. Results: A total of fourteen neurological events were recorded in twelve patients, without difference in sex and with a median age of 9.5 years. The most prevalent underlying disease was osteosarcoma. Seizures were the most frequent symptom (50%), followed by drowsiness and paresis. The combination of ifosfamide and etoposide with/without carboplatin was associated in 36% each. Sixty-four percent developed neurotoxicity within the first four hours. None of the patients presented with abnormalities in the complementary examinations. All recovered ad integrum. Conclusion: This study provides information about the time of onset of this complication, which will facilitate its early detection and timely treatment (AU)

Encefalitis por inhibidores del punto de control inmunitario / Encephalitis associated to immune checkpoint inhibitors

Resumen Los inhibidores del punto de control inmunitario han demostrado mejorar el pronóstico de múltiples enfer medades oncológicas. Recientemente se han reportado eventos adversos relacionados a la inmunoterapia. La to xicidad neurológica es poco frecuente. Se presenta el caso de un paciente con encefalitis relacionada con inhibido res del punto de control inmunitario.

Abstract Immune checkpoint inhibitors have been shown to improve the prognosis of multiple oncological diseases. Recently, adverse events related to immunotherapy have been reported. Neurologic toxicity is infrequent. We pre sent the case of a patient with encephalitis associated to immune checkpoint inhibitors.

Lead Toxicity in Children: Health Effects, Policies and Recommendations

Lead is a dangerous element that exists naturally in the Earth's crust. Any kind of lead causes a detrimental response in the human body. It is discharged into the environment during the manufacturing of batteries, foundries, ammunition, lead paint, water pipes, and other manufactured goods. It can enter the body through a variety of pathways, including those in the air, water, soil, food, and dust. Concern is raised since there is no amount of lead that is safe for the human body. The problem persists despite several prevention measures that the state and the federal governments have put in place. This review assesses the effects of lead exposure on children as well as suggested solutions to the issue.

Successful stem cell transplantation after nelarabine, pegylated asparaginase, vincristine, doxorubicin, and prednisone in refractory early T-cell precursor acute lymphoblastic leukemia: A case report

Early T-cell precursor Acute Lymphoblastic Leukemia (ALL) has a dismal prognosis. Nelarabine is a purine nucleoside analog that increases the apoptosis rate in T-cell lymphoblasts. We present a 30-year-old patient diagnosed with T-cell ALL. He was a high-risk patient because of an early precursor phenotype and a complex karyotype that had been refractory to three previous lines of treatment. He started a course of nelarabine (1500 mg/m for three days), pegylated-asparaginase, doxorubicin, vincristine, and prednisone (Nelarabine Peg-Asp AdmVP). He reached complete remission and received an allogeneic sibling hematopoietic stem cell transplant with fludarabine, total body irradiation, and cyclophosphamide as the conditioning regimen. He developed a pulmonary mycosis, which resolved, and grade-2 neurotoxicity in his upper and lower limbs. He was discharged after 40 days and to date remains with 23 months of complete remission. The Nelarabine Peg-Asp AdmVP regimen seems to be effective and safe. Further research is needed to establish it as an induction treatment in refractory early T-cell precursor acute lymphoblastic leucemia.

Neurotoxicidad subaguda por metotrexato en pacientes con enfermedad oncohematológica. Reporte de tres casos / Subacute methotrexate neurotoxicity in patients with oncohematological disease. A report of 3 cases

El metotrexato es un fármaco análogo del ácido fólico ampliamente utilizado en el tratamiento de enfermedades autoinmunes, leucemias y linfomas. Su uso puede ocasionar la aparición de múltiples efectos adversos entre los que se encuentran aquellos relacionados con la presencia de toxicidad neurológica, que puede presentarse de forma aguda, subaguda o crónica. La neurotoxicidad subaguda es aquella que ocurre típicamente entre los 2 y los 14 días posteriores a la administración y puede manifestarse con una amplia gama de síntomas neurológicos. En la mayoría de los casos, no recurre con futuras exposiciones al medicamento. Presentamos tres casos de neurotoxicidad subaguda por metotrexato con manifestaciones clínicas diferentes en pacientes oncohematológicos que se internaron entre los años 2018 y 2020. Dos de ellos presentaron recurrencia frente a la nueva administración del fármaco y todos evidenciaron lesiones en resonancia magnética nuclear.

Methotrexate is a folic acid analogue widely used in the treatment of autoimmune diseases, leukemias, and lymphomas. Methotrexate use may cause multiple adverse effects, including those related to the presence of neurological toxicity, which may be acute, subacute, or chronic. Subacute neurotoxicity typically occurs between 2 and 14 days after administration and may present as a wide range of neurological symptoms. In most cases, it does not recur with future exposures to the drug. Here we describe 3 cases of subacute methotrexate neurotoxicity with different clinical manifestations in patients with oncohematological disease who were hospitalized between 2018 and 2020. Two of them showed recurrence with a new drug administration. Lesions were observed in the magnetic resonance imaging tests of all of them.

Neurotoxicity mechanism of aconitine in HT22 cells studied by microfluidic chip-mass spectrometry / 药物分析学报

Aconitine,a common and main toxic component of Aconitum,is toxic to the central nervous system.However,the mechanism of aconitine neurotoxicity is not yet clear.In this work,we had the hypothesis that excitatory amino acids can trigger excitotoxicity as a pointcut to explore the mechanism of neurotoxicity induced by aconitine.HT22 cells were simulated by aconitine and the changes of target cell metabolites were real-time online investigated based on a microfluidic chip-mass spectrometry system.Meanwhile,to confirm the metabolic mechanism of aconitine toxicity on HT22 cells,the levels of lactate dehydrogenase,intracellular Ca2+,reactive oxygen species,glutathione and superoxide dismutase,and ratio of Bax/Bcl-2 protein were detected by molecular biotechnology.Integration of the detected results revealed that neurotoxicity induced by aconitine was associated with the process of excitotoxicity caused by glutamic acid and aspartic acid,which was followed by the accumulation of lactic acid and reduction of glucose.The surge of extracellular glutamic acid could further lead to a series of cascade reactions including intracellular Ca2+overload and oxidative stress,and eventually result in cell apoptosis.In general,we illustrated a new mechanism of aconitine neurotoxicity and presented a novel analysis strategy that real-time online monitoring of cell metabolites can provide a new approach to mechanism analysis.

Research progress on material basis for neurotoxicity of traditional Chinese medicine and its mechanism / 中国药房

In recent years， neurotoxicity caused by traditional Chinese medicine （TCM） has frequently occurred and has become one of the important factors restricting the development and application of TCM. TCM contains active components and its dosage-effect relationship is the key to determine its pharmacological activity and toxic effects. Among them， the endogenous toxic components include alkaloids， glycosides， diterpenoids， animal and plant toxic proteins and heavy metals， and so on； exogenous toxic components mainly refer to some harmful elements and pesticide residues during the cultivation， processing， transportation and storage of medicinal materials that are not synthesized by themselves. Effect on the processes such as oxidative stress， inflammation， ion exchange， and energy metabolism may be important mechanisms of TCM-induced neurotoxicity. Neural cells， myelin cells， axons and neurotransmitter systems are common targets of TCM-induced neurotoxicity. In the future， we can use modern research methods and big data mining means to establish a safety evaluation mode of “toxic symptoms-poisoning dose-toxic original agent-detoxification scheme” with the basic component group of toxic substances as the core， so as to provide support for development and clinical intervention of neurotoxic traditional Chinese medicine.

Methamphetamine: Mechanism of Action and Chinese Herbal Medicine Treatment for Its Addiction / 中国结合医学杂志

With the proliferation of synthetic drugs, research on the mechanism of action of addictive drugs and treatment methods is of great significance. Among them, methamphetamine (METH) is the most representative amphetamine synthetic drug, and the treatment of METH addiction has become an urgent medical and social problem. In recent years, the therapeutic effects of Chinese herbal medicines on METH addiction have gained widespread attention because of their non-addictiveness, multiple targets, low side effects, low cost, and other characteristics. Previous studies have identified a variety of Chinese herbal medicines with effects on METH addiction. Based on the research on METH in recent years, this article summarizes the mechanism of action of METH as the starting point and briefly reviews the Chinese herbal medicine-based treatment of METH.

Caracterización del uso de emulsiones lipídicas como terapia antidotal en intoxicaciones diferentes a anestésicos locales en un centro de alta complejidad en Medellín / Characterization of the use of lipid emulsions as antidotal therapy in intoxications other than local anesthetics in a high complexity center in Medellin

Introducción. Las emulsiones lipídicas intravenosas (ELI) son unas emulsiones grasas no tóxicas con fosfolípidos, actualmente aprobadas para su uso en el tratamiento de intoxicaciones, específicamente en las producidas por anestésicos locales. El propósito de este estudio es la caracterización del uso de ELI en pacientes mayores de 18 años, que presentaron intoxicación por sustancias y medicamentos diferentes a anestésicos locales, en un hospital de alta complejidad de la ciudad de Medellín, durante el periodo comprendido entre 2015 y 2020. Metodología. Se realizó un estudio descriptivo, retrospectivo, de casos que recibieron ELI como tratamiento para su intoxicación. Se hizo revisión de las historias clínicas de la población objeto de estudio. Se recolectó información acerca de variables sociodemográficas, clínicas y paraclínicas, y de atención. Se hizo análisis univariado de las variables de interés. Resultados. Del total de 1.966 intoxicaciones, se incluyeron 51 (2,6 %) casos de intoxicación por sustancias y medicamentos diferentes a anestésicos locales, que recibieron la terapia con ELI entre 2015 y 2020. La mediana de edad de los participantes fue de 27 años. Un 74,5 % de los participantes presentó intoxicación por medicamentos. El promedio de la dosis de ELI recibida fue de 1.036 mL en 24 horas, dosis inferior a la calculada por kilo de peso que debían recibir, de 1.149 mL en promedio. Un 86,3 % (n=44) de los casos presentaron neurotoxicidad, y 76,5 % (n=39) presentaron cardiotoxicidad. La neurotoxicidad mejoró en el 34,7 % y la cardiotoxicidad en el 59,1 % de los individuos que recibieron terapia con ELI. Conclusión. La aplicación de las ELI se hizo en personas en su mayoría intoxicadas por antipsicóticos, hombres, jóvenes; menos de la mitad tenía compromiso de la ventilación, y hubo mejoría en la cardiotoxicidad y neurotoxicidad. Hubo una diferencia entre la dosis recibida y la que debían recibir ajustada por el peso

Introduction. Intravenous lipid emulsions (IVLE) are non-toxic fatty emulsions with phospholipids, currently approved for use in the treatment of poisoning, specifically those produced by local anesthetics. The purpose of this study is to characterize the use of IVLE in patients over 18 years of age, who presented intoxication by substances and medications other than local anesthetics, in a high complexity hospital in the city of Medellín, during the period between 2015 and 2020. Methodology. A retrospective descriptive study was carried out on cases that received IVLE as a treatment for their poisoning. The clinical records of the study population were reviewed. Information was collected about sociodemographic, clinical and paraclinical variables, and care. Univariate analysis of the variables of interest was performed. Results. Of the total of 1,966 poisonings, 51 (2.6%) cases caused by substances and medications other than local anesthetics, received ELI therapy between 2015 and 2020 and were included in the study. The median age of the participants was 27 years. 74.5% of the participants presented drug poisoning. The average IVLE dose received was 1,036 mL in 24 hours, a lower dose than the one calculated per kilo of weight, which had been on average 1,149 mL. 86.3% (n=44) of the cases presented neurotoxicity, and 76.5% (n=39) presented cardiotoxicity. Neurotoxicity improved in 34.7% and cardiotoxicity in 59.1% of individuals receiving ELI therapy. Conclusion. The application of IVLE was made in people mostly poisoned by antipsychotics, men, young people, less than half had compromised ventilation, and there was improvement in cardiotoxicity and neurotoxicity. There was a difference between the dose received and the one they should have received adjusted for weight

Study of the potential toxicity of adrenaline to neurons, using the SH-SY5Y human cellular model

Abstract Prolonged overexposure to catecholamines causes toxicity, usually credited to continuous adrenoceptor stimulation, autoxidation, and the formation of reactive pro-oxidant species. Non-differentiated SH-SY5Y cells were used to study the possible contribution of oxidative stress in adrenaline (ADR)-induced neurotoxicity, as a model to predict the toxicity of this catecholamine to peripheral nerves. Cells were exposed to several concentrations of ADR (0.1, 0.25, 0.5 and 1mM) and two cytotoxicity assays [lactate dehydrogenase (LDH) release and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) reduction] were performed at several time-points (24, 48, and 96h). The cytotoxicity of ADR was concentration- and time-dependent in both assays, since the lowest concentration tested (0.1mM) also caused significant cytotoxicity at 96h. N-acetyl-cysteine (1mM), a precursor of glutathione synthesis, prevented ADR-induced toxicity elicited by 0.5mM and 0.25mM ADR following a 96-h exposure, while the antioxidant Tiron (100µM) was non-protective. In conclusion, ADR led to mitochondrial distress and ultimately cell death in non-differentiated SH-SY5Y cells, possibly because of ADR oxidation products. The involvement of such processes in the catecholamine-induced peripheral neuropathy requires further analysis.

Advances on mechanisms of regulated cell death in neurotoxicity of aluminum / 环境与职业医学

Aluminum is a light metal which is rich in the earth's crust and widely used. Recently, the adverse health effects of environmental and occupational aluminum exposure on human have attracted more and more attention. Aluminum exposure has toxic effects on the central nervous system and is believed to be closely related to the development and progression of Alzheimer's disease. The neurotoxic mechanism of aluminum is complex, especially the role of regulated cell death (RCD) in aluminum-induced neuronal death remains to be further studied. RCD refers to all modes of cell death regulated by multiple intracellular signal transduction pathways under physiological and pathological conditions, including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis. This review summarized the morphological characteristics and mechanisms of each RCD mode in the process of aluminum-induced neuronal death, and discussed the relationship and transformation between different RCD modes, providing a new scientific basis for future studies on the treatment and intervention of neurotoxicity induced by aluminum exposure.

Relationship of cytokines to adverse reaction of chimeric antigen receptor T cell immunotherapy and targeted drug intervention / 中国生物制品学杂志

@#Chimeric antigen receptor T cell(CAR-T)immunotherapy is the most potential adoptive immunotherapy for malignant tumors,which needs no antigen presenting cells(APC)and is not limited by major histocompatibiliy complex(MHC). CAR-T immunotherapy not only recognizes and kills tumor cells directly,but also forms memory T cells and establishs long-term anti-tumor mechanism,of which the effect in leukemia,multiple myeloma and other non-solid tumors as well as the great potential in solid tumors have been widely verified. However,a variety of adverse reactions such as cytokine release syndrome(CRS),neurotoxicity(NT)and miss target effect are produced during CAR-T immunotherapy,of which the occurrence of CRS and NT may be related to the abnormal level of cytokines. Remarkable increase of cytokine level is a major characteristics of CRS. However,the increase of cytokines is neither the root cause nor the only result of CAR-T adverse reaction. CAR-T immunotherapy has a high incidence of adverse reaction which may even endanger the life of patients. Cytokine targeted drugs such as Anakinra and Tocilizumab may decrease the incidence of adverse reaction and improve the prognosis of patients. This paper reviews the correlation of cytokines with CRS and NT in CAR-T immunotherapy and the effect of cytokine targeting drugs,so as to provide a reference for the basic research,quality control and clinical application of CAR-T immunotherapy.

Stress-another possible mechanism of neurotoxicity in neurodegenerative diseases

Theliteratureassociatesoxidativestresswiththeproductionoffreeradicals,whichleadtoneurodegeneration.Theypresentinnumerablehypotheses,amongwhichareabnormalitiesinthefunctioningofthehypothalamic-pituitary-adrenalaxis,neurotoxiceffectsandneuronaloxidativedamage.ClinicalobservationhasshownthatinneurodegenerativediseasessuchasMultipleSclerosis(MS)andAmyotrophicLateralSclerosis(ALS)thereisareportofprolonged or violent emotionalstressprecedingthesymptoms.Aims:UsingtheCarilloComplexSystemsModel,presentsomepossibilitiesonhowstresscancontributetoneurodegeneration.Methodology:NinecasesofALSandsixcasesofMSwereevaluated,pathologiesalreadyclassifiedasbelongingtosyphilinism.Literaturereviewonstressandneurotoxicitycarriedout.Resultsanddiscussion:Syphilinism is instability with a predominantly intrinsicorigin to the system with a chronic caracter.This diathesis is characterized by a dissipative deficiency, predominantly hepatic, to the processing of certain elements or potentially toxic substances with exogenous origin or endogenous Such non-processed substances are unstable factors in the system, with greater affinity for certain tissues,like the nervous system. Among the toxins, we find alcohol, esters, formaldehyde, aloe, ketones, aldehydes, etc. The final hepatic metabolism of cortisol results in cortic acids and cortol, which use the same enzymatic system as alcohol, and can be considered syphilinic toxins. Ethanol can act directly at the circadian rhythm, disrupting it and generating stressful substances such as cortisol, regardless of an external event, increasing the toxin level. The inflammatory process generated by the production of free radicals and metabolic abnormalities, including the reduction of neuropeptide Y that modulates inflammatory activity in the nervous system, leads to changes that can result in neurodegeneration. Conclusion: Inflammation caused by toxins from prolonged/violent emotional stress can lead to several changes in syphilinic individuals, due to failure in the dissipative process, including neurodegeneration.

Efectos patogénicos de la acrilamida para la salud. Una revisión

RESUMEN En abril de 2002, un grupo de investigadores suecos dio a conocer que algunos alimentos ricos en almidón y pobres en proteínas, sometidos a procesos con temperaturas mayores a 120 °C (fritura, horneado, asado y tostado) contenían el procancerígeno conocido como acrilamida, un "probable carcinógeno para los humanos" -mutágeno de categoría 2 y tóxico para la reproducción de categoría 3 según la Unión Europea-, comportándose como neurotóxico tras exposiciones agudas. La revisión tiene como objetivo mostrar una actualización de los avances en investigaciones sobre la toxicidad de la acrilamida como un aspecto preocupante en el tema alimentario, y exponer los mecanismos de la formación de este compuesto en los alimentos, sus efectos tóxicos, los métodos analíticos usados en su determinación, los niveles detectados en distintos alimentos y estudios recientes sobre su ingesta. Para ello se realizaron búsquedas en las bases de datos PubMed, SciELO, LILACS y ClinicalKey. Los estudios epidemiológicos llevan poco tiempo, y en su mayoría son inconsistentes respecto al cáncer en humanos, no obstante, se complementan con el empleo de biomarcadores, donde se obtienen resultados en cuanto a la toxicidad cancerígena y no cancerígena más fiables, con menor margen de error. Por el momento, la única recomendación para mitigar su exposición es la divulgación sobre los riesgos del consumo excesivo de alimentos fritos, demasiado tostados o procesados, y seguir una dieta equilibrada y saludable.

ABSTRACT In April 2002, a group of Swedish researchers revealed that some foods rich in starch and poor in protein, subjected to processes with temperatures above 120 °C (frying, baking, roasting and toasting) contained the procancerogen known as acrylamide, a "probable carcinogen for human"-mutagen of category 2 and toxic to category 3 reproduction according to European Union-behaving as neurotoxic after acute exposures. The review aims to show an update of the advances in research on the toxicity of acrylamide as a worrying aspect in the food issue, and to expose the mechanisms of formation of this compound in food, its toxic effects, the analytical methods used in its determination, the levels detected in different foods, and recent studies on its intake. For that, searches were conducted in PubMed, SciELO, LILACS and ClinicalKey. Epidemiological studies take a short time, and are mostly inconsistent with respect to cancer in human. However, they are complemented using biomarkers where results are obtained in terms of the most reliable carcinogenic and non-carcinogenic toxicity, with less margins of error. For now, the only recommendation to mitigate exposition is to divulge the risk of excessive consumption of fried, very roasted or processed foods, and to follow an equilibrated and healthy diet.

Compositional and toxicological investigation of pooled venom from farm-raised Naja atra

Background: Naja atra is a venomous snake species medically relevant in China. In the current study, we evaluated the composition and toxicological profile of venom collected from farm-raised N. atra. Methods: Venom was collected from third-generation captive bred N. atra on a snake farm in Hunan Province, China. The venom was analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis and nano-liquid chromatography with electrospray ionization tandem mass spectrometry. In addition, hemolytic activity, median lethal dose, serum biochemical and histopathological parameters were accessed. Results: N. atra venom proteome was dominated by phospholipase A2 (46.5%) and three-finger toxins (41.4 %), and a set of common low relative abundance proteins, including cysteine-rich secretory proteins (4.7%), NGF-beta (2.4%), snake venom metalloproteinase (1.5%), glutathione peroxidase (0.6%), vespryn (0.3%), and 5ʹ-nucleotidases (0.2%) were also found. Furthermore, the venom exhibited direct hemolytic activity, neurotoxicity, myotoxicity, and high lethal potency in mice, with a subcutaneous median lethal dose of 1.02 mg/kg. Histopathological analysis and serum biochemical tests revealed that venom caused acute hepatic, pulmonary and renal injury in mice. Conclusion: This study revealed the composition and toxicity of venom collected from farm-raised N. atra, thereby providing a reference for the analysis of venom samples collected from captive-born venomous snakes in the future.(AU)

Bioinformatics study on role of IL-17 signaling in manganese poisoning and manganese-related neurodegenerative diseases / 环境与职业医学

Background Manganese (Mn) is one of the environmental factors of Parkinson's disease (PD), and long-term exposure to Mn can cause nerve damage. It is important to explore the common mechanism of neurotoxic effects of Mn and neurodegenerative diseases (NDD), especially PD, for early diagnosis of the disease. Objective To comprehensively analyze the core messenger RNA (mRNA)-microRNAs (miRNAs) co-expressed in frontal cortex of NDD patients and neuronal cells exposed to Mn via bioinformatics, and to reveal the potential common mechanism between Mn-induced neurotoxicity and NDD, especially PD. Methods Difference of the mRNAs from frontal cortex of NDD patients (GSE150696) and human neuroblastoma (SH-SY5Y) cells exposed to Mn were analyzed by R software; Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was performed on the overlapping differentially expressed genes (DEGs). The miRNAs were predicted using the miRNet database, mRNA-miRNA interactions were identified by the starBase and miRTarBase databases, and mRNA-miRNA regulatory networks were constructed with Cytoscape software. The core miRNAs associated with PD (GSE77667) were incorporated into Weighted Gene Co-Expression Network Analysis (WGCNA) and the mRNA-miRNA regulatory network was comparatively analyzed. Results A total of 34 overlapping DEGs were identified in the frontal cortical of NDD patients and the neuronal cells exposed to Mn, mainly enriched in interleukin-17 (IL-17) signaling pathway, cyclic adenosine monophosphate (cAMP) signaling pathway, and primary immunodeficiency. Based on the results of database prediction, 52 miRNAs with 71 pairs of interaction relationships were finally included to construct the miRNA-mRNA regulatory network. Six core miRNAs were screened by WGCNA: hsa-let-7i-5p, hsa-mir-155-5p, hsa-mir-219-2-3p, hsa-mir-221-3p, hsa-mir-485-3p, and hsa-mir-509-3-5p, among which hsa-let-7i-5p interacted with the target gene FBXW2 and hsa-mir-155-5p interacted with the target gene CCL2. The results of the KEGG analysis indicated that CCL2 was closely related to the IL-17 signaling pathway. Conclusion There are similar molecular regulatory mechanisms involved in the neurotoxicity of Mn and NDD, and the IL-17 signaling pathway may play a role in Mn-related NDD through CCL2 and hsa-mir-155-5p.

Effects of chronic lead acetate exposure on neurobehavior and serum metabolomics in mice / 环境与职业医学

Background Chronic low-level exposure to lead can damage the central nervous system and cause anxiety-like behavior. However, whether changes of blood metabolites occur in this process and its relationship with lead-induced neurobehavioral disorder remain unclear. Objective To explore the effects of chronic lead acetate (PbAc) exposure at different concentrations on anxiety-like behavior and serum metabolites and their relationships in mice, as well as the mechanism of lead exposure on neurobehavioral injury in mice from the perspective of metabolomics. Methods A total of 64 healthy 4-week-old C57BL/6J mice, half male and half female, were randomly divided into four groups: control group (normal drinking water), 20 mg·L−1 PbAc group, 100 mg·L−1 PbAc group, and 500 mg·L−1 PbAc group. After 10 weeks of free drinking of water containing designed concentrations of PbAc, the mice were tested for anxiety-like behavioral changes by open field experiment. After the mice were anesthetized, blood was collected from the eyes, the serum was separated, and the effects of designed doses of lead exposure on metabolites in the serum of mice were compared by liquid chromatography with tandem mass spectrometry combined with principal component analysis and partial least squares discrimination analysis. Results The results of the open field experiment showed that the reductions in movement time spent in central area in the 100 mg·L−1 and 500 mg·L−1 PbAc groups compared with the control group were of statistical significance (P<0.05); the reduction in crossing times of central region in the 500 mg·L−1 PbAc group was statistically significant compared with the control group (P<0.05); the increases in defecation frequency in the 100 mg·L−1 and 500 mg·L−1 PbAc groups were statistically significant compared to the control group (P<0.05). In both positive and negative ion modes, compared with the control group, 157 differential metabolites were screened out in the 20 mg·L−1 PbAc group, of which 80 were up-regulated and 77 were down-regulated; 172 differential metabolites were screened out in the 100 mg·L−1 PbAc group, of which 57 were up-regulated and 115 were down-regulated; 119 differential metabolites were screened out in the 500 mg·L−1 PbAc group, of which 42 were up-regulated and 77 were down-regulated. The results of the KEGG enrichment analysis on the differential metabolites revealed alterations in metabolic pathways mainly involving primary bile acid biosynthesis, bile secretion, and cholesterol metabolism. Among the differential metabolites, norethisterone was positively correlated with the number of central region crossings (r=0.406, P<0.05); dihydrothymine was negatively correlated with the number of central region crossings (r=−0.346, P<0.05); lysophosphatidylcholine 22∶1 and lysophospholipid 14∶0 were negatively correlated with time spent in central region (r=−0.429, P<0.05; r=−0.374, P<0.05). Conclusion Chronic lead exposure induces anxiety-like behavior in mice, and this altered behavior is associated with altered metabolites in serum, with differential metabolites enriched primarily in the metabolic pathways of primary bile acid biosynthesis, bile acid secretion, and cholesterol metabolism.

Compositional and toxicological investigation of pooled venom from farm-raised Naja atra

Abstract Background: Naja atra is a venomous snake species medically relevant in China. In the current study, we evaluated the composition and toxicological profile of venom collected from farm-raised N. atra. Methods: Venom was collected from third-generation captive bred N. atra on a snake farm in Hunan Province, China. The venom was analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis and nano-liquid chromatography with electrospray ionization tandem mass spectrometry. In addition, hemolytic activity, median lethal dose, serum biochemical and histopathological parameters were accessed. Results: N. atra venom proteome was dominated by phospholipase A2 (46.5%) and three-finger toxins (41.4 %), and a set of common low relative abundance proteins, including cysteine-rich secretory proteins (4.7%), NGF-beta (2.4%), snake venom metalloproteinase (1.5%), glutathione peroxidase (0.6%), vespryn (0.3%), and 5-nucleotidases (0.2%) were also found. Furthermore, the venom exhibited direct hemolytic activity, neurotoxicity, myotoxicity, and high lethal potency in mice, with a subcutaneous median lethal dose of 1.02 mg/kg. Histopathological analysis and serum biochemical tests revealed that venom caused acute hepatic, pulmonary and renal injury in mice. Conclusion: This study revealed the composition and toxicity of venom collected from farm-raised N. atra, thereby providing a reference for the analysis of venom samples collected from captive-born venomous snakes in the future.

Neurotoxicidades apresentadas por pacientes submetidos ao transplante de células-tronco hematopoéticas: uma revisão de escopo / Neurotoxicidades en pacientes sometidos al trasplante de células madre hematopoyéticas: una revisión de alcance / Neurotoxicity presented by patients undergoing hematopoietic stem cell transplantation: a scoping review

Resumo Objetivo Mapear os tipos de neurotoxicidades apresentadas por pacientes submetidos ao Transplante de Células-Tronco Hematopoéticas. Métodos Trata-se de uma Scoping Review, orientada a partir do método proposto pelo Joanna Briggs Institute, e seguiu as recomendações do Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews. A busca pelos estudos foi realizada entre os meses de julho e agosto de 2020 e ocorreu nas bases de dados e em portais de teses e dissertações nacionais e internacionais. Resultados A amostra final foi composta por 71 artigos científicos, todos na língua Inglesa. Houve destaque para o ano de 2018 com 14 (19%) publicações. Observou-se prevalência de estudos realizados nos Estados Unidos da América com 29 (40,8%). No tocante a população, todos (100%) os artigos são sobre pacientes submetidos ao transplante de células-tronco hematopoéticas que apresentaram neurotoxicidades. Acerca dos quimioterápicos utilizados no regime de condicionamento pré-transplante de células-tronco hematopoéticas sete (9,8%) utilizaram a combinação de Fludarabina e Ciclofosfamida, seguida da Ciclosporina e Tacrolimus em seis (8,4%), ciclosporina em quatro (5,6%), Fludarabina em três (4,2%). Quanto às neurotoxicidades apresentadas em pacientes submetidos ao transplante, evidenciou-se a síndrome de encefalopatia reversível posterior em 19 (26,7%) estudos. Cabe ressaltar que outros estudos identificaram essa síndrome, porém relataram sintomas diferentes. Conclusão As neurotoxicidades apresentadas por pacientes submetidos ao transplante de células-tronco hematopoéticas, são encefalopatia reversível posterior, leucoencefalopatia reversível posterior, encefalopatia de Wernicke, encefalopatia hipertensiva, encefalopatia metabólica, encefalopatia límbica, complicações hemorrágicas e convulsões.

Resumen Objetivo Mapear los tipos de neurotoxicidades en pacientes sometidos al trasplante de células madre hematopoyéticas. Métodos Se trata de una Scoping Review, orientada a partir del método propuesto por el Joanna Briggs Institute, que siguió las recomendaciones del Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews. La búsqueda de los estudios se realizó entre los meses de julio y agosto de 2020 y ocurrió en las bases de datos y en portales de tesis de doctorado y maestría nacionales e internacionales. Resultados La muestra final estuvo compuesta por 71 artículos científicos, todos en lengua inglesa. Se destacó el año 2018 con 14 publicaciones (19 %). Se observó una prevalencia de estudios realizados en Estados Unidos de América con 29 (40,8 %). En lo que se refiere a la población, todos los artículos (100 %) tratan sobre pacientes sometidos al trasplante de células madre hematopoyéticas que presentaron neurotoxicidades. Sobre los quimioterápicos utilizados en el régimen de acondicionamiento previo al trasplante de células madre hematopoyéticas, siete (9,8 %) utilizaron la combinación de Fludarabina y Ciclofosfamida, seguida de la Ciclosporina y Tacrolimus en seis (8,4 %), ciclosporina en cuatro (5,6 %), Fludarabina en tres (4,2 %). Con relación a las neurotoxicidades en pacientes sometidos al trasplante, se evidenció el síndrome de encefalopatía reversible posterior en 19 estudios (26,7 %). Cabe destacar que otros estudios identificaron ese síndrome, pero refirieron síntomas distintos. Conclusión Las neurotoxicidades presentadas por pacientes sometidos al trasplante de células madre hematopoyéticas son encefalopatía reversible posterior, leuco encefalopatía reversible posterior, encefalopatía de Wernicke, encefalopatía hipertensiva, encefalopatía metabólica, encefalopatía límbica, complicaciones hemorrágicas y convulsiones.

Abstract Objective To map the types of neurotoxicity presented by patients undergoing Hematopoietic Stem Cell Transplantation. Methods This is a scoping review, guided by the method proposed by the Joanna Briggs Institute, and followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews recommendations. The search for studies was carried out between the months of July and August 2020 and took place in databases and in national and international theses and dissertations portals. Results The final sample consisted of 71 scientific articles, all in English. There was a highlight for the year 2018 with 14 (19%) publications. There was a prevalence of studies carried out in the United States of America with 29 (40.8%). Regarding the population, all (100%) articles are about patients undergoing hematopoietic stem cell transplantation who presented neurotoxicity. Regarding the chemotherapeutic agents used in the pre-transplantation regimen of hematopoietic stem cells, seven (9.8%) used the combination of Fludarabine and Cyclophosphamide, followed by Cyclosporine and Tacrolimus in six (8.4%), Cyclosporine in four (5.6%), Fludarabine in three (4.2%). As for the neurotoxicity presented in patients undergoing transplantation, the posterior reversible encephalopathy syndrome was evidenced in 19 (26.7%) studies. It should be noted that other studies have identified this syndrome, but have reported different symptoms. Conclusion The neurotoxicity presented by patients undergoing hematopoietic stem cell transplantation are posterior reversible encephalopathy, posterior reversible leukoencephalopathy, Wernicke's encephalopathy, hypertensive encephalopathy, metabolic encephalopathy, limbic encephalopathy, hemorrhagic complications and seizures.

Cadmium and Mercury Exposure: Oxidative, Neurobehavioural and Histological Alterations to the Cerebellum of Wistar Rats

Background: The unprecedented increase in metal exposure has been aided by modern industrialization and anthropogenic activities. Cadmium and mercury are recognized as two of the most common heavy metals with destructive impacts on most organ systems. The present study was designed to investigate and improve existing literature on the possible deleterious effects of cadmium and mercury exposure. Methods: Adult Wistar rats were treated with cadmium chloride (5 mg/kg/day) and mercury chloride (4 mg/kg/day) for 14 days. Body, brain and cerebellar weights, motor deficits, antioxidant and lipid peroxidation activities as well as histological alterations to the cerebellum were evaluated at the end of the experiment. Results: Findings showed a significant reduction in body and brain weights, dysregulation of antioxidant enzymes activity and impaired locomotion and exploratory activity in treated rats. Also, an increase in lipid peroxidation and degeneration of Purkinje cells of the cerebellum was observed in treated rats. Conclusion: Overall, these results corroborate previous findings that cadmium and mercury induce deleterious effects on the cerebellum and central nervous system. In addition, this study helps to provide an anatomical perspective and information on the exact cerebellar changes induced by cadmium and mercury in Wistar rats.