RÉSUMÉ
Environmental pollutants' (EPs) amount and diversity have increased in recent years due to anthropogenic activity. Several neurodegenerative diseases (NDs) are theorized to be related to EPs, as their incidence has increased in a similar way to human EPs exposure and they reproduce the main ND hallmarks. EPs induce several neurotoxic effects, including accumulation and gradual deposition of misfolded toxic proteins, producing neuronal malfunction and cell death. Cells possess different mechanisms to eliminate these toxic proteins, including heat shock proteins (HSPs) and the proteasome system. The accumulation and deleterious effects of toxic proteins are induced through HSPs and disruption of proteasome proteins' homeostatic function by exposure to EPs. A therapeutic approach has been proposed to reduce accumulation of toxic proteins through treatment with recombinant HSPs/proteasome or the use of compounds that increase their expression or activity. Our aim is to review the current literature on NDs related to EP exposure and their relationship with the disruption of the proteasome system and HSPs, as well as to discuss the toxic effects of dysfunction of HSPs and proteasome and the contradictory effects described in the literature. Lastly, we cover the therapeutic use of developed drugs and recombinant proteasome/HSPs to eliminate toxic proteins and prevent/treat EP-induced neurodegeneration.
RÉSUMÉ
The widely used plasticizer bisphenol-A (BPA) is well-known for producing neurodegeneration and cognitive disorders, following acute and long-term exposure. Although some of the BPA actions involved in these effects have been unraveled, they are still incompletely known. Basal forebrain cholinergic neurons (BFCN) regulate memory and learning processes and their selective loss, as observed in Alzheimer's disease and other neurodegenerative diseases, leads to cognitive decline. In order to study the BPA neurotoxic effects on BFCN and the mechanisms through which they are induced, 60-day old Wistar rats were used, and a neuroblastoma cholinergic cell line from the basal forebrain (SN56) was used as a basal forebrain cholinergic neuron model. Acute treatment of rats with BPA (40 µg/kg) induced a more pronounced basal forebrain cholinergic neuronal loss. Exposure to BPA, following 1- or 14-days, produced postsynaptic-density-protein-95 (PSD95), synaptophysin, spinophilin, and N-methyl-D-aspartate-receptor-subunit-1 (NMDAR1) synaptic proteins downregulation, an increase in glutamate content through an increase in glutaminase activity, a downregulation in the vesicular-glutamate-transporter-2 (VGLUT2) and in the WNT/ß-Catenin pathway, and cell death in SN56 cells. These toxic effects observed in SN56 cells were mediated by overexpression of histone-deacetylase-2 (HDAC2). These results may help to explain the synaptic plasticity, cognitive dysfunction, and neurodegeneration induced by the plasticizer BPA, which could contribute to their prevention.
RÉSUMÉ
Cadmium (Cd) produces cognition decline following single and repeated treatment, although the complete mechanisms are still unrevealed. Basal forebrain (BF) cholinergic neurons innervate the cortex and hippocampus, regulating cognition. Cd single and repeated exposure induced BF cholinergic neuronal loss, partly through thyroid hormones (THs) disruption, which may cause the cognition decline observed following Cd exposure. However, the mechanisms through which THs disruption mediate this effect remain unknown. To research the possible mechanisms through which Cd-induced THs deficiency may mediate BF neurodegeneration, Wistar male rats were treated with Cd for 1- (1 mg/kg) or 28-days (0.1 mg/kg) with or without triiodothyronine (T3, 40 µg/kg/day). Cd exposure promoted neurodegeneration, spongiosis, gliosis and several mechanisms related to these alterations (increased H202, malondialdehyde, TNF-α, IL-1ß, IL-6, BACE1, Aß and phosphorylated-Tau levels, and decreased phosphorylated-AKT and phosphorylated-GSK-3ß levels). T3 supplementation partially reversed the effects observed. Our results show that Cd induces several mechanisms that may be responsible for the neurodegeneration, spongiosis and gliosis observed in the rats' BF, which are partially mediated by a reduction in THs levels. These data may help to explain the mechanisms through which Cd induces BF neurodegeneration, possibly leading to the cognitive decline observed, providing new therapeutic tools to prevent and treat these damages.
Sujet(s)
Prosencéphale basal , Cadmium , Animaux , Mâle , Rats , Amyloid precursor protein secretases/métabolisme , Aspartic acid endopeptidases/métabolisme , Prosencéphale basal/métabolisme , Cadmium/toxicité , Gliose/induit chimiquement , Glycogen synthase kinase 3 beta/métabolisme , Inflammation , Rat Wistar , Espèces réactives de l'oxygène , Protéines tau/métabolisme , Hormones thyroïdiennesRÉSUMÉ
Bisphenol-A (BPA), a polymer component extensively used, produces memory and learning alterations after acute and long-term exposure. However, the mechanisms are not well known. Cortex and hippocampus neuronal networks control cognitive functions, which are innervated by basal forebrain cholinergic neurons (BFCN), and their neurodegeneration induces cognitive dysfunctions. Wild type or protein tyrosine phosphatase 1B (PTP1B), histone deacetylase 2 (HDAC2), tau or ß amyloid precursor protein (ßAPP) silenced SN56 cells treated with BPA (0.001 µM-100 µM) with or without N-acetylcysteine (NAC; 1 mM), following 1 and 14 days, were used, as a model of BFCN to determine the insulin pathway dysfunction, oxidative stress (OS) generation and amyloid-ß (Aß) and tau proteins accumulation involvement in the BCFN cell death induction, as a possible mechanism that could produce the cognitive disorders reported. BPA-induced BFCN cell death, after 24 h and 14 days of treatment, through insulin pathway dysfunction, OS generation, mediated by NRF2 pathway downregulation, and Aß and tau proteins accumulation, which were in turn induced by HDAC2 and PTP1B overexpression. This is relevant information to explain the BFCN neurodegeneration mechanisms that could trigger the neurodegeneration in the rest of the regions innerved by them, leading to cognitive disorders.
Sujet(s)
Insulines , Protéines tau , Protéines tau/métabolisme , Espèces réactives de l'oxygène/métabolisme , Histone Deacetylase 2/métabolisme , Phosphoric monoester hydrolases/métabolisme , Peptides bêta-amyloïdes/métabolisme , Neurones cholinergiques/métabolisme , Apoptose , Agents cholinergiques/métabolisme , Insulines/métabolismeRÉSUMÉ
Acute and long-term paraquat (PQ) exposure produces hippocampal neurodegeneration and cognition decline. Although some mechanisms involved in these effects were found, the rest are unknown. PQ treatment, for 1 and 14 days, upregulated interferon-gamma signaling, which reduced insulin levels and downregulated the insulin pathway through phosphorylated-c-Jun N-terminal-kinase upregulation, increasing glucose levels and the production of Aß1-42 and phosphorylated-tau, by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) overexpression and phosphorylated-GSK3ß (p-GSK3ß; ser9) level reduction, respectively, which induced primary hippocampal neuronal loss. This novel information on the PQ mechanisms leading to hippocampal neurodegeneration could help reveal the PQ actions that lead to cognition dysfunction.
Sujet(s)
Paraquat , Protéines tau , Protéines tau/métabolisme , Paraquat/toxicité , Paraquat/métabolisme , Amyloid precursor protein secretases/métabolisme , Amyloid precursor protein secretases/pharmacologie , Glycogen synthase kinase 3 beta/métabolisme , Glycogen synthase kinase 3 beta/pharmacologie , Insuline/métabolisme , Régulation positive , Aspartic acid endopeptidases/métabolisme , Aspartic acid endopeptidases/pharmacologie , Peptides bêta-amyloïdes/métabolisme , Hippocampe , Mort cellulaireRÉSUMÉ
OBJECTIVE: This study aims to investigate the relationship between the pre-operative indocyanine green (ICG) test, the chemotherapy-associated liver injury (CALI), and the development of severe post-operative complications (POC) in patients operated of colorectal liver metastases (CRLMs). MATERIALS AND METHODS: Sixty-nine patients previously treated with chemotherapy and submitted to liver resection for CRLM were retrospectively studied. Two pathologists independently reviewed the pathological specimens and assessed the presence of CALI. The correlation between ICG clearance and specific pathological features was analyzed. In addition, a logistic regression analysis was performed to seek for pre-operative factors associated with severe complications. RESULTS: After a mean of 10.6 (± 7.5) chemotherapy cycles, 44 patients (63.8%) developed CALI. ICG retention rate at 15 min (ICG-R15) was not statistically different between patients with and without CALI and it could only discriminate the presence of centrilobular fibrosis. Rate of severe complications was almost 6-fold in patients with CALI compared to patients without CALI (p = 0.024). ICG-R15 ≥ 10% was the only independent risk factor associated with severe POC at multivariable logistic regression (OR = 4.075 95% CI: 1.077-15.422, p = 0.039). CONCLUSIONS: Pre-operative ICG clearance test, although not useful to identify patients with hepatic drug toxicity, is a strong predictor for the development of severe post-hepatectomy complications.
OBJETIVO: Investigar la relación entre el test de aclaramiento del verde de indocianina (ICG) preoperatorio, las alteraciones patológicas derivadas de la quimioterapia (CALI) y el desarrollo de complicaciones posoperatorias en los pacientes sometidos a resección hepática por metástasis de cáncer colorrectal (MCCR). MATERIAL Y MÉTODOS: Sesenta y nueve pacientes previamente tratados con quimioterapia y operados de MCCR se estudiaron de manera retrospectiva. Dos patólogas revisaron independientemente el parénquima hepático no tumoral de los especímenes y determinaron la presencia de daño quimio-inducido. Se analizó la correlación entre el aclaramiento de ICG y las diferentes alteraciones anatomo-patológicas encontradas. Además, se realizó un análisis de regresión logística para identificar los factores preoperatorios asociados con las complicaciones posoperatorias. RESULTADOS: Tras una media de 10.6 (± 7.5) ciclos de quimioterapia, 44 pacientes (63.8%) desarrollaron CALI. La tasa de retención de ICG a los 15 minutos (ICG-R15) no fue estadísticamente diferente entre los pacientes con y sin CALI y solo pudo discriminar la presencia de fibrosis centrolobulillar. La tasa de complicaciones severas posoperatorias fue 6 veces superior en los pacientes con CALI, comparada con aquella de los pacientes sin CALI (p = 0.024). Un ICG-R15 ≥ 10% fue el único factor de riesgo independiente asociado a complicaciones severas (OR = 4.075 95% CI: 1.077-15.422, p = 0.039). CONCLUSIONES: La prueba preoperatoria de aclaramiento del ICG, a pesar de no identificar eficazmente los pacientes con daño por quimioterapia, es un fuerte predictor de desarrollo de complicaciones severas posoperatorias.
Sujet(s)
Tumeurs colorectales , Hépatite , Tumeurs du foie , Tumeurs colorectales/complications , Tumeurs colorectales/traitement médicamenteux , Tumeurs colorectales/chirurgie , Humains , Vert indocyanine/usage thérapeutique , Tumeurs du foie/traitement médicamenteux , Tumeurs du foie/secondaire , Tumeurs du foie/chirurgie , Complications postopératoires/étiologie , Études rétrospectivesRÉSUMÉ
Cadmium (Cd) single and repeated exposure produces cognitive dysfunctions. Basal forebrain cholinergic neurons (BFCN) regulate cognitive functions. BFCN loss or cholinergic neurotransmission dysfunction leads to cognitive disabilities. Thyroid hormones (THs) maintain BFCN viability and functions, and Cd disrupts their levels. However, Cd-induced BFCN damages and THs disruption involvement was not studied. To research this we treated male Wistar rats intraperitoneally with Cd once (1 mg/kg) or repetitively for 28 days (0.1 mg/kg) with/without triiodothyronine (T3, 40 µg/kg/day). Cd increased thyroid-stimulating-hormone (TSH) and decreased T3 and tetraiodothyronine (T4). Cd altered cholinergic transmission and induced a more pronounced neurodegeneration on BFCN, mediated partially by THs reduction. Additionally, Cd antagonized muscarinic 1 receptor (M1R), overexpressed acetylcholinesterase S variant (AChE-S), downregulated AChE-R, M2R, M3R and M4R, and reduced AChE and choline acetyltransferase activities through THs disruption. These results may assist to discover cadmium mechanisms that induce cognitive disabilities, revealing a new possible therapeutic tool.
Sujet(s)
Prosencéphale basal/effets des médicaments et des substances chimiques , Chlorure de cadmium/toxicité , Neurones cholinergiques/effets des médicaments et des substances chimiques , Acetylcholinesterase/métabolisme , Animaux , Mâle , Rat Wistar , Récepteur muscarinique de type M1/effets des médicaments et des substances chimiques , Thyréostimuline/sang , Thyroxine/sang , Tri-iodothyronine/administration et posologie , Tri-iodothyronine/sangRÉSUMÉ
Bisphenol-A (BPA), a widely used plasticizer, induces cognitive dysfunctions following single and repeated exposure. Several studies, developed in hippocampus and cortex, tried to find the mechanisms that trigger and mediate these dysfunctions, but those are still not well known. Basal forebrain cholinergic neurons (BFCN) innervate hippocampus and cortex, regulating cognitive function, and their loss or the induction of cholinergic neurotransmission dysfunction leads to cognitive disabilities. However, no studies were performed in BFCN. We treated wild type or histone deacetylase (HDAC2), P75NTR or acetylcholinesterase (AChE) silenced SN56 cholinergic cells from BF with BPA (0.001 µM-100 µM) with or without recombinant nerve growth factor (NGF) and with or without acetylcholine (ACh) for one- and fourteen days in order to elucidate the mechanisms underlying these effects. BPA induced cholinergic neurotransmission disruption through reduction of ChAT activity, and produced apoptotic cell death, mediated partially through AChE-S overexpression and NGF/TrkA/P75NTR signaling dysfunction, independently of cholinergic neurotransmission disruption, following one- and fourteen days of treatment. BPA mediates these alterations, in part, through HDAC2 overexpression. These data are relevant since they may help to elucidate the neurotoxic mechanisms that trigger the cognitive disabilities induced by BPA exposure, providing a new therapeutic approach.
Sujet(s)
Apoptose/effets des médicaments et des substances chimiques , Composés benzhydryliques/toxicité , Neurones cholinergiques/effets des médicaments et des substances chimiques , Histone Deacetylase 2/métabolisme , Facteur de croissance nerveuse/métabolisme , Phénols/toxicité , Récepteur trkA/métabolisme , Récepteurs facteur croissance nerf/métabolisme , Transduction du signal/effets des médicaments et des substances chimiques , Transmission synaptique/effets des médicaments et des substances chimiques , Acétylcholine/métabolisme , Animaux , Composés benzhydryliques/administration et posologie , Lignée cellulaire tumorale/effets des médicaments et des substances chimiques , Techniques de knock-down de gènes , Souris , Neuroblastome , Phénols/administration et posologie , Réaction de polymérisation en chaine en temps réelRÉSUMÉ
Paraquat (PQ) produces hippocampal neuronal cell death and cognitive dysfunctions after unique and continued exposure, but the mechanisms are not understood. Primary hippocampal wildtype or ßAPP-Tau silenced cells were co-treated with PQ with or without E2, N-acetylcysteine (NAC), NS-398 (cyclooxygenase-2 inhibitor), MF63 (PGES-1 inhibitor) and/or recombinant brain-derived neurotrophic factor (BDNF) during one- and fourteen-days to studied PQ effect on prostaglandin E2 (PGE2) and BDNF signaling and their involvement in hyperphosphorylated Tau (pTau) and amyloid-beta (Aß) protein formation, and oxidative stress generation, that lead to neuronal cell loss through estrogenic disruption, as a possible mechanism of cognitive dysfunctions produced by PQ. Our results indicate that PQ overexpressed cyclooxygenase-2 that leads to an increase of PGE2 and alters the expression of EP1-3 receptor subtypes. PQ induced also a decrease of proBDNF and mature BDNF levels and altered P75NTR and tropomyosin receptor kinase B (TrkB) expression. PQ induced PGE2 and BDNF signaling dysfunction, mediated through estrogenic disruption, leading to Aß and pTau proteins synthesis, oxidative stress generation and finally to cell death. Our research provides relevant information to explain PQ hippocampal neurotoxic effects, indicating a probable explanation of the cognitive dysfunction observed and suggests new therapeutic strategies to protect against PQ toxic effects.
Sujet(s)
Facteur neurotrophique dérivé du cerveau/métabolisme , Mort cellulaire/effets des médicaments et des substances chimiques , Dinoprostone/métabolisme , Oestrogènes/métabolisme , Herbicides/pharmacologie , Hippocampe/effets des médicaments et des substances chimiques , Neurones/effets des médicaments et des substances chimiques , Paraquat/pharmacologie , Transduction du signal , Animaux , Cellules cultivées , Femelle , Hippocampe/cytologie , Hippocampe/métabolisme , Neurones/métabolisme , Stress oxydatif/effets des médicaments et des substances chimiques , Grossesse , Rats , Rat WistarRÉSUMÉ
Manganese (Mn) produces cholinergic neuronal loss in basal forebrain (BF) region that was related to cognitive dysfunction induced after single and repeated Mn treatment. All processes that generate cholinergic neuronal loss in BF remain to be understood. Mn exposure may produce the reduction of BF cholinergic neurons by increasing amyloid beta (Aß) and phosphorylated Tau (pTau) protein levels, altering heat shock proteins' (HSPs) expression, disrupting proteasome P20S activity and generating oxidative stress. These mechanisms, described to be altered by Mn in regions different than BF, could lead to the memory and learning process alteration produced after Mn exposure. The research performed shows that single and repeated Mn treatment of SN56 cholinergic neurons from BF induces P20S inhibition, increases Aß and pTau protein levels, produces HSP90 and HSP70 proteins expression alteration, and oxidative stress generation, being the last two effects mediated by NRF2 pathway alteration. The increment of Aß and pTau protein levels was mediated by HSPs and proteasome dysfunction. All these mechanisms mediated the cell decline observed after Mn treatment. Our results are relevant because they may assist to reveal the processes leading to the neurotoxicity and cognitive alterations observed after Mn exposure.
Sujet(s)
Peptides bêta-amyloïdes/métabolisme , Prosencéphale basal/effets des médicaments et des substances chimiques , Neurones cholinergiques/effets des médicaments et des substances chimiques , Polluants environnementaux/toxicité , Protéines du choc thermique HSP70/métabolisme , Protéines du choc thermique HSP90/métabolisme , Manganèse/toxicité , Proteasome endopeptidase complex/métabolisme , Protéines tau/métabolisme , Animaux , Prosencéphale basal/métabolisme , Prosencéphale basal/anatomopathologie , Lignée cellulaire tumorale , Survie cellulaire/effets des médicaments et des substances chimiques , Neurones cholinergiques/métabolisme , Neurones cholinergiques/anatomopathologie , Relation dose-effet des médicaments , Polluants environnementaux/métabolisme , Manganèse/métabolisme , Souris , Stress oxydatif/effets des médicaments et des substances chimiquesRÉSUMÉ
BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA. OBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients. METHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction. RESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001). CONCLUSIONS: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.
Sujet(s)
ADN mitochondrial/génétique , Mitochondries/génétique , Maladies mitochondriales/génétique , Paraplégie/génétique , Paraplégie spasmodique héréditaire/génétique , Adolescent , Adulte , Enfant , Femelle , Humains , Mâle , Adulte d'âge moyen , Mutation/génétique , Syndromes parkinsoniens/génétique , Phénotype , Jeune adulteRÉSUMÉ
Manganese (Mn) induces cognitive disorders and basal forebrain (BF) cholinergic neuronal loss, involved on learning and memory regulation, which could be the cause of such cognitive disorders. However, the mechanisms through which it induces these effects are unknown. We hypothesized that Mn could induce BF cholinergic neuronal loss through oxidative stress generation, cholinergic transmission and AChE variants alteration that could explain Mn cognitive disorders. This study shows that Mn impaired cholinergic transmission in SN56 cholinergic neurons from BF through alteration of AChE and ChAT activity and CHT expression. Moreover, Mn induces, after acute and long-term exposure, AChE variants alteration and oxidative stress generation that leaded to lipid peroxidation and protein oxidation. Finally, Mn induces cell death on SN56 cholinergic neurons and this effect is independent of cholinergic transmission alteration, but was mediated partially by oxidative stress generation and AChE variants alteration. Our results provide new understanding of the mechanisms contributing to the harmful effects of Mn on cholinergic neurons and their possible involvement in cognitive disorders induced by Mn.
Sujet(s)
Acetylcholinesterase/métabolisme , Prosencéphale basal/effets des médicaments et des substances chimiques , Neurones cholinergiques/effets des médicaments et des substances chimiques , Peroxyde d'hydrogène/métabolisme , Manganèse/toxicité , Animaux , Apoptose/effets des médicaments et des substances chimiques , Caspase-3/métabolisme , Caspase-7/métabolisme , Lignée cellulaire tumorale , Survie cellulaire/effets des médicaments et des substances chimiques , Peroxydation lipidique/effets des médicaments et des substances chimiques , Souris , Stress oxydatif/effets des médicaments et des substances chimiques , Carbonylation des protéines/effets des médicaments et des substances chimiquesRÉSUMÉ
INTRODUCTION: The term "Small-for-Flow" reflects the pathogenetic relevance of hepatic hemodynamics for the "Small-For-Size" syndrome and posthepatectomy liver failure. We aimed to characterize a large-animal model for studying the "Small-for-Flow" syndrome. METHODS: We performed subtotal (90%) hepatectomies in 10 female MiniPigs using a simplified transection technique with a tourniquet. Blood tests, hepatic and systemic hemodynamics, and hepatic function and histology were assessed before (Bas), 15 min (t-15 min) and 24 h (t-24 h) after the operation. Some pigs underwent computed tomography (CT) scans for hepatic volumetry (n = 4) and intracranial pressure (ICP) monitoring (n = 3). Postoperative care was performed in an intensive care unit environment. RESULTS: All hepatectomies were successfully performed, and hepatic volumetry confirmed liver remnant volumes of 9.2% [6.2-11.2]. The hepatectomy resulted in characteristic hepatic hemodynamic alterations, including portal hyperperfusion, relative decrease of hepatic arterial blood flow, and increased portal pressure (PP) and portal-systemic pressure gradient. The model reproduced major diagnostic features including the development of cholestasis, coagulopathy, encephalopathy with increased ICP, ascites, and renal failure, hyperdynamic circulation, and hyperlactatemia. Two animals (20%) died before t-24 h. Histological liver damage was observed at t-15 min and at t-24 h. The degree of histological damage at t-24 h correlated with intraoperative PP (r = 0.689, p = 0.028), hepatic arterial blood flow (r = 0.655, p = 0.040), and hepatic arterial pulsatility index (r = 0.724, p = 0.066). All animals with intraoperative PP > 20 mmHg presented liver damage at t-24 h. CONCLUSION: The present 90% hepatectomy porcine experimental model is a feasible and reproducible model for investigating the "Small-for-Flow" syndrome.
Sujet(s)
Hépatectomie/effets indésirables , Artère hépatique/physiopathologie , Circulation hépatique/physiologie , Défaillance hépatique/chirurgie , Régénération hépatique/physiologie , Foie/chirurgie , Pression portale/physiologie , Animaux , Modèles animaux de maladie humaine , Femelle , Foie/vascularisation , Défaillance hépatique/physiopathologie , Suidae , Porc miniature , SyndromeRÉSUMÉ
Cadmium, a neurotoxic environmental compound, produces cognitive disorders, although the mechanism remains unknown. Cadmium induces a more pronounced cell death on cholinergic neurons from basal forebrain (BF), mediated, in part, by increase in Aß and total and phosphorylated Tau protein levels, which may explain cadmium effects on learning and memory processes. Cadmium downregulates the expression of heat shock proteins (HSPs) HSP 90, HSP70 and HSP27, and of HSF1, the master regulator of the HSP pathway. HSPs proteins reduce the production of Aß and phosphorylated Tau proteins and avoid cell death pathways induction. Thus, we hypothesized that cadmium induced the production of Aß and Tau proteins by HSP pathway disruption through HSF1 expression alteration, leading to BF cholinergic neurons cell death. Our results show that cadmium downregulates HSF1, leading to HSP90, HSP70 and HSP27 gene expression downregulation in BF SN56 cholinergic neurons. In addition, cadmium induced Aß and total and phosphorylated Tau proteins generation, mediated partially by HSP90, HSP70 and HSP27 disruption, leading to cell death. These results provide new understanding of the mechanisms contributing to cadmium harmful effects on cholinergic neurons.
Sujet(s)
Peptides bêta-amyloïdes/métabolisme , Cadmium/toxicité , Mort cellulaire/effets des médicaments et des substances chimiques , Neurones cholinergiques/effets des médicaments et des substances chimiques , Protéines du choc thermique/métabolisme , Protéines tau/métabolisme , Animaux , Caspase-3/génétique , Caspase-3/métabolisme , Caspase-7/génétique , Caspase-7/métabolisme , Lignée cellulaire tumorale , Survie cellulaire/effets des médicaments et des substances chimiques , Neurones cholinergiques/métabolisme , Régulation de l'expression des gènes/effets des médicaments et des substances chimiques , Techniques de knock-down de gènes , Humains , Souris , Composés du phosphore , Réaction de polymérisation en chaine en temps réelRÉSUMÉ
Chlorpyrifos (CPF) is an organophosphate insecticide described to induce cognitive disorders, both after acute and repeated administration. However, the mechanisms through which it induces these effects are unknown. CPF has been reported to produce basal forebrain cholinergic neuronal cell death, involved on learning and memory regulation, which could be the cause of such cognitive disorders. Neuronal cell death was partially mediated by oxidative stress generation, P75NTR and α7-nAChRs gene expression alteration triggered through acetylcholinesterase (AChE) variants disruption, suggesting other mechanisms are involved. In this regard, CPF induces Aß and tau proteins production and activation of GSK3ß enzyme and alters glutamatergic transmission, which have been related with basal forebrain cholinergic neuronal cell death and development of cognitive disorders. According to these data, we hypothesized that CPF induces basal forebrain cholinergic neuronal cell death through induction of Aß and tau proteins production, activation of GSK-3ß enzyme and disruption of glutamatergic transmission. We evaluated this hypothesis in septal SN56 basal forebrain cholinergic neurons, after 24â¯h and 14â¯days CPF exposure. This study shows that CPF increases glutamate levels, upregulates GSK-3ß gene expression, and increases the production of Aß and phosphorylated tau proteins and all these effects reduced cell viability. CPF increases glutaminase activity and upregulates the VGLUT1 gene expression, which could mediate the disruption of glutamatergic transmission. Our present results provide new understanding of the mechanisms contributing to the harmful effects of CPF, and its possible relevance in the pathogenesis of neurodegenerative diseases.
Sujet(s)
Peptides bêta-amyloïdes/biosynthèse , Chlorpyriphos/toxicité , Acide glutamique/métabolisme , Glycogen synthase kinase 3 beta/biosynthèse , Neurones/métabolisme , Protéines tau/biosynthèse , Animaux , Mort cellulaire/effets des médicaments et des substances chimiques , Mort cellulaire/physiologie , Lignée cellulaire tumorale , Survie cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/physiologie , Relation dose-effet des médicaments , Insecticides/toxicité , Souris , Neurones/effets des médicaments et des substances chimiques , Transmission synaptique/effets des médicaments et des substances chimiques , Transmission synaptique/physiologie , Facteurs tempsRÉSUMÉ
Cadmium, an environmental neurotoxic compound, produces cognitive disorders, although the mechanism remains unknown. Previously, we described that cadmium induces a more pronounced cell death on cholinergic neurons from basal forebrain (BF). This effect, partially mediated by M1 receptor blockade, triggering it through AChE splices variants alteration, may explain cadmium effects on learning and memory processes. Cadmium has been also reported to induce oxidative stress generation leading to M2 and M4 muscarinic receptors alteration, in hippocampus and frontal cortex, which are necessary to maintain cell viability and cognitive regulation, so their alteration in BF could also mediate this effect. Moreover, it has been reported that antioxidant treatment could reverse cognitive disorders, muscarinic receptor and AChE variants alterations induced by cadmium. Thus, we hypothesized that cadmium induced cell death of BF cholinergic neurons is mediated by oxidative stress generation and this mechanism could produce this effect, in part, through AChE variants altered by muscarinic receptors disruption. To prove this, we evaluated in BF SN56 cholinergic neurons, whether cadmium induces oxidative stress and alters muscarinic receptors, and their involvement in the induction of cell death through alteration of AChE variants. Our results show that cadmium induces oxidative stress, which mediates partially the alteration of AChE variants and M2 to M4 muscarinic receptors expression and blockage of M1 receptor. In addition, cadmium induced oxidative stress generation by M1 and M3 receptors alteration through AChE variants disruption, leading to cell death. These results provide new understanding of the mechanisms contributing to cadmium harmful effects on cholinergic neurons.
Sujet(s)
Acetylcholinesterase/métabolisme , Chlorure de cadmium/toxicité , Neurones cholinergiques/effets des médicaments et des substances chimiques , Espèces réactives de l'oxygène/métabolisme , Récepteur muscarinique de type M1/métabolisme , Récepteur muscarinique de type M2/métabolisme , Animaux , Lignée cellulaire , Survie cellulaire/effets des médicaments et des substances chimiques , Neurones cholinergiques/métabolisme , Neurones cholinergiques/anatomopathologie , Peroxydation lipidique/effets des médicaments et des substances chimiques , Mémoire/effets des médicaments et des substances chimiques , Souris , Maladies neurodégénératives/induit chimiquement , Maladies neurodégénératives/métabolisme , Maladies neurodégénératives/anatomopathologie , Stress oxydatif/effets des médicaments et des substances chimiques , Prosencéphale/effets des médicaments et des substances chimiques , Prosencéphale/métabolisme , Prosencéphale/anatomopathologieRÉSUMÉ
Paraquat (PQ) is a widely used non-selective contact herbicide shown to produce memory and learning deficits after acute and repeated exposure similar to those induced in Alzheimer's disease (AD). However, the complete mechanisms through which it induces these effects are unknown. On the other hand, cholinergic and glutamatergic systems, mainly in the hippocampus, are involved on learning, memory and cell viability regulation. An alteration of hippocampal cholinergic or glutamatergic transmissions or neuronal cell loss may induce these effects. In this regard, it has been suggested that PQ may induce cell death and affect cholinergic and glutamatergic transmission, which alteration could produce neuronal loss. According to these data, we hypothesized that PQ could induce hippocampal neuronal loss through cholinergic and glutamatergic transmissions alteration. To prove this hypothesis, we evaluated in hippocampal primary cell culture, the PQ toxic effects after 24h and 14 consecutive days exposure on neuronal viability and the cholinergic and glutamatergic mechanisms related to it. This study shows that PQ impaired acetylcholine levels and induced AChE inhibition and increased CHT expression only after 14days exposure, which suggests that acetylcholine levels alteration could be mediated by these actions. PQ also disrupted glutamate levels through induction of glutaminase activity. In addition, PQ induced, after 24h and 14days exposure, cell death on hippocampal neurons that was partially mediated by AChE variants alteration and cholinergic and gultamatergic transmissions disruption. Our present results provide new view of the mechanisms contributing to PQ neurotoxicity and may explain cognitive dysfunctions observed after PQ exposure.
Sujet(s)
Acétylcholine/métabolisme , Acetylcholinesterase/métabolisme , Acide glutamique/métabolisme , Herbicides/toxicité , Hippocampe/effets des médicaments et des substances chimiques , Neurones/effets des médicaments et des substances chimiques , Paraquat/toxicité , Transmission synaptique/effets des médicaments et des substances chimiques , Acetylcholinesterase/génétique , Animaux , Comportement animal/effets des médicaments et des substances chimiques , Mort cellulaire/effets des médicaments et des substances chimiques , Survie cellulaire/effets des médicaments et des substances chimiques , Cellules cultivées , Choline O-acetyltransferase/génétique , Choline O-acetyltransferase/métabolisme , Cognition/effets des médicaments et des substances chimiques , Relation dose-effet des médicaments , Protéines liées au GPI/génétique , Protéines liées au GPI/métabolisme , Âge gestationnel , Glutaminase/génétique , Glutaminase/métabolisme , Hippocampe/enzymologie , Hippocampe/anatomopathologie , Hippocampe/physiopathologie , Protéines de transport membranaire/génétique , Protéines de transport membranaire/métabolisme , Neurones/enzymologie , Neurones/anatomopathologie , Culture de cellules primaires , Interférence par ARN , Rat Wistar , Facteurs temps , TransfectionRÉSUMÉ
BACKGROUND: Portal vein embolization is performed weeks before extended hepatic resections to increase the future liver remnant and prevent posthepatectomy liver failure. Portal vein embolization performed closer to the operation also could be protective, but worsening of portal hyper-perfusion is a major concern. We determined the hepatic hemodynamic effects of a portal vein embolization performed 24 hours prior to hepatic operation. METHODS: An extended (90%) hepatectomy was performed in swine undergoing (portal vein embolization) or not undergoing (control) a portal vein embolization 24 hours earlier (n = 10/group). Blood tests, hepatic and systemic hemodynamics, hepatic function (plasma disappearance rate of indocyanine green), liver histology, and volumetry (computed tomographic scanning) were assessed before and after the hepatectomy. Hepatocyte proliferating cell nuclear antigen expression and hepatic gene expression also were evaluated. RESULTS: Swine in the control and portal vein embolization groups maintained stable systemic hemodynamics and developed similar increases of portal blood flow (302 ± 72% vs 486 ± 92%, P = .13). Portal pressure drastically increased in Controls (from 9.4 ± 1.3 mm Hg to 20.9 ± 1.4 mm Hg, P < .001), while being markedly attenuated in the portal vein embolization group (from 11.4 ± 1.5 mm Hg to 16.1 ± 1.3 mm Hg, P = .061). The procedure also improved the preservation of the hepatic artery blood flow, liver function, and periportal edema. These effects occurred in the absence of hepatocyte proliferation or hepatic growth and were associated with the induction of the vasoprotective gene Klf2. CONCLUSION: Portal vein embolization preconditioning represents a potential hepato-protective strategy for extended hepatic resections. Further preclinical studies should assess its medium-term effects, including survival. Our study also supports the relevance of hepatic hemodynamics as the main pathogenetic factor of post-hepatectomy liver failure.