RESUMEN
Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD), and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives, and society. However, the underlying pathomechanisms are poorly understood, and current therapies mostly aim at supporting patients in their daily lives. This illustrates the urgent need to elucidate the pathogenesis and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modeling of cognitive disorders in CKD. We discuss the use of mice, rats, and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving the therapy of people with CKD and MCI.
Asunto(s)
Disfunción Cognitiva , Modelos Animales de Enfermedad , Insuficiencia Renal Crónica , Animales , Insuficiencia Renal Crónica/fisiopatología , Insuficiencia Renal Crónica/psicología , Insuficiencia Renal Crónica/complicaciones , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/psicología , Humanos , Ratones , Pez Cebra , Cognición , Ratas , Riñón/fisiopatología , Riñón/metabolismoRESUMEN
AIMS: CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia. METHODS: The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride. RESULTS: CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice. CONCLUSIONS: Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
Asunto(s)
Enfermedades Cerebelosas , Enfermedades Neurodegenerativas , Humanos , Ratones , Animales , Adolescente , Ratones Transgénicos , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Ataxia/metabolismo , Ataxia/patología , Cerebelo/patología , Enfermedades Cerebelosas/patología , Enfermedades Neurodegenerativas/patología , Atrofia/patología , Modelos Animales de EnfermedadRESUMEN
In the framework of wastewater treatment plants, sewage sludge can be directed to biochar production, which when coupled with an external iron source has the potential to be used as a carbon-iron composite material for treating various organic pollutants in advanced oxidation processes. In this research, "green" synthesized nano zero-valent iron (nZVI) supported on sewage sludge-based biochar (BC)-nZVI-BC was used in the Fenton process for the degradation of the recalcitrant organic molecule. In this way, the circular economy principles were supported within wastewater treatment with immediate loop closing; unlike previous papers, where only the water treatment was assessed, the authors proposed a new approach to wastewater treatment, combining solutions for both water and sludge. The following phases were implemented: synthesis and characterization of nano zero-valent iron supported on sewage sludge-based biochar (nZVI-BC); optimization of organic pollutant removal (Reactive Blue 4 as the model pollutant) by nZVI-BC in the Fenton process, using a Definitive Screening Design (DSD) model; reuse of the obtained Fenton sludge, as an additional catalytic material, under previously optimized conditions; and assessment of the exhausted Fenton sludge's ability to be used as a source of nutrients. nZVI-BC was used in the Fenton treatment for the degradation of Reactive Blue 4-a model substance containing a complex and stable anthraquinone structure. The DSD model proposes a high dye-removal efficiency of 95.02% under the following optimal conditions: [RB4] = 50 mg/L, [nZVI] = 200 mg/L, [H2O2] = 10 mM. pH correction was not performed (pH = 3.2). Afterwards, the remaining Fenton sludge, which was thermally treated (named FStreated), was applied as a heterogeneous catalyst under the same optimal conditions with a near-complete organic molecule degradation (99.56% ± 0.15). It could be clearly noticed that the cumulative amount of released nutrients significantly increased with the number of leaching experiments. The highest cumulative amounts of released K, Ca, Mg, Na, and P were therefore observed at the fifth leaching cycle (6.40, 1.66, 1.12, 0.62, 0.48 and 58.2 mg/g, respectively). According to the nutrient release and toxic metal content, FStreated proved to be viable for agricultural applications; these findings illustrated that the "green" synthesis of nZVI-BC not only provides innovative and efficient Fenton catalysts, but also constitutes a novel approach for the utilization of sewage sludge, supporting overall process sustainability.
Asunto(s)
Contaminantes Ambientales , Contaminantes Químicos del Agua , Purificación del Agua , Hierro/química , Aguas del Alcantarillado , Peróxido de Hidrógeno , Contaminantes Químicos del Agua/química , Carbón OrgánicoRESUMEN
Kidney dysfunction can profoundly influence many organ systems, and recent evidence suggests a potential role for increased albuminuria in the development of mild cognitive impairment (MCI) or dementia. Epidemiological studies conducted in different populations have demonstrated that the presence of increased albuminuria is associated with a higher relative risk of MCI or dementia both in cross-sectional analyses and in studies with long-term follow-up. The underlying pathophysiological mechanisms of albuminuria's effect are as yet insufficiently studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. Both the kidney and the brain have microvascular similarities that make them sensitive to endothelial dysfunction involving different mechanisms, including oxidative stress and inflammation. The exact substrate of MCI and dementia is still under investigation, however available experimental data indicate that elevated albuminuria and low glomerular filtration rate are associated with significant neuroanatomical declines in hippocampal function and grey matter volume. Thus, albuminuria may be critical in the development of cognitive impairment and its progression to dementia. In this review, we summarize the available evidence on albuminuria's link to MCI and dementia, point to existing gaps in our knowledge and suggest actions to overcome them. The major question of whether interventions that target increased albuminuria could prevent cognitive decline remains unanswered. Our recommendations for future research are aimed at helping to plan clinical trials and to solve the complex conundrum outlined in this review, with the ultimate goal of improving the lives of patients with chronic kidney disease.
Asunto(s)
Disfunción Cognitiva , Demencia , Albuminuria/complicaciones , Disfunción Cognitiva/etiología , Estudios Transversales , Demencia/complicaciones , Demencia/etiología , Progresión de la Enfermedad , Humanos , Factores de RiesgoRESUMEN
Chronic kidney disease (CKD) perturbs the crosstalk with others organs, with the interaction between the kidneys and the heart having been studied most intensively. However, a growing body of data indicates that there is an association between kidney dysfunction and disorders of the central nervous system. In epidemiological studies, CKD is associated with a high prevalence of neurological complications, such as cerebrovascular disorders, movement disorders, cognitive impairment and depression. Along with traditional cardiovascular risk factors (such as diabetes, inflammation, hypertension and dyslipidaemia), non-traditional risk factors related to kidney damage (such as uraemic toxins) may predispose patients with CKD to neurological disorders. There is increasing evidence to show that uraemic toxins, for example indoxyl sulphate, have a neurotoxic effect. A better understanding of factors responsible for the elevated prevalence of neurological disorders among patients with CKD might facilitate the development of novel treatments. Here, we review (i) the potential clinical impact of CKD on cerebrovascular and neurological complications, (ii) the mechanisms underlying the uraemic toxins' putative action (based on pre-clinical and clinical research) and (iii) the potential impact of these findings on patient care.
Asunto(s)
Trastornos Cerebrovasculares , Insuficiencia Renal Crónica , Uremia , Humanos , Indicán , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/terapia , Uremia/complicaciones , Tóxinas UrémicasRESUMEN
Metabolic acidosis, defined as a plasma or serum bicarbonate concentration <22 mmol/L, is a frequent consequence of chronic kidney disease (CKD) and occurs in ~10-30% of patients with advanced stages of CKD. Likewise, in patients with a kidney transplant, prevalence rates of metabolic acidosis range from 20% to 50%. CKD has recently been associated with cognitive dysfunction, including mild cognitive impairment with memory and attention deficits, reduced executive functions and morphological damage detectable with imaging. Also, impaired motor functions and loss of muscle strength are often found in patients with advanced CKD, which in part may be attributed to altered central nervous system (CNS) functions. While the exact mechanisms of how CKD may cause cognitive dysfunction and reduced motor functions are still debated, recent data point towards the possibility that acidosis is one modifiable contributor to cognitive dysfunction. This review summarizes recent evidence for an association between acidosis and cognitive dysfunction in patients with CKD and discusses potential mechanisms by which acidosis may impact CNS functions. The review also identifies important open questions to be answered to improve prevention and therapy of cognitive dysfunction in the setting of metabolic acidosis in patients with CKD.
Asunto(s)
Acidosis , Disfunción Cognitiva , Trastornos Motores , Insuficiencia Renal Crónica , Acidosis/etiología , Bicarbonatos , Disfunción Cognitiva/etiología , Humanos , Trastornos Motores/complicacionesRESUMEN
Kidney function has two important elements: glomerular filtration and tubular function (secretion and reabsorption). A persistent decrease in glomerular filtration rate (GFR), with or without proteinuria, is diagnostic of chronic kidney disease (CKD). While glomerular injury or disease is a major cause of CKD and usually associated with proteinuria, predominant tubular injury, with or without tubulointerstitial disease, is typically non-proteinuric. CKD has been linked with cognitive impairment, but it is unclear how much this depends on a decreased GFR, altered tubular function or the presence of proteinuria. Since CKD is often accompanied by tubular and interstitial dysfunction, we explore here for the first time the potential role of the tubular and tubulointerstitial compartments in cognitive dysfunction. To help address this issue we selected a group of primary tubular diseases with preserved GFR in which to review the evidence for any association with brain dysfunction. Cognition, mood, neurosensory and motor disturbances are not well characterized in tubular diseases, possibly because they are subclinical and less prominent than other clinical manifestations. The available literature suggests that brain dysfunction in tubular and tubulointerstitial diseases is usually mild and is more often seen in disorders of water handling. Brain dysfunction may occur when severe electrolyte and water disorders in young children persist over a long period of time before the diagnosis is made. We have chosen Bartter and Gitelman syndromes and nephrogenic diabetes insipidus as examples to highlight this topic. We discuss current published findings, some unanswered questions and propose topics for future research.
Asunto(s)
Enfermedades Renales , Nefritis Intersticial , Insuficiencia Renal Crónica , Encéfalo , Niño , Preescolar , Tasa de Filtración Glomerular , Humanos , Enfermedades Renales/diagnóstico , Nefritis Intersticial/complicaciones , Proteinuria/etiología , Insuficiencia Renal Crónica/complicacionesRESUMEN
Magnesium (Mg), is not only a modulator of the glutamatergic NMDA receptors' affinity, it also prevents HPA axis hyperactivity, thus possibly being implicated in neurobiological features of mood disorders. Further uncovering of molecular mechanisms underlying magnesium's proposed effects is needed due to the recent shift in research of treatment resistant depression (TRD) towards glutamatergic pathways. Here, we applied Mg via drinking water for 28â¯days (50â¯mg/kg/day), in ACTH-treated rats, an established animal model of depression resistant to tricyclic antidepressants. Using this model in male rats we measured (1) changes in hippocampal neurogenesis and behavioral alterations, (2) adrenal hormones response to acute stress challenge and (3) levels of biometals involved in regulation of monoamines turnover in rat prefrontal cortex. Our results support beneficial behavioral impact of Mg in TRD model together with increased hippocampal neurogenesis and BDNF expression. Furthermore, Mg prevented ACTH-induced disruption in HPA axis function, by normalizing the levels of plasma ACTH, corticosterone and interleukin-6, and by increasing the peripheral release of adrenaline, noradrenaline and serotonin after the acute stress challenge. Finally, the influence on copper/zinc ratio suggested probable magnesium's involvement in monoamine turnover in PFC. Our findings provide further insights into the possible pathways implicated in the behavioral modulation effects of Mg, as well as its central and peripheral effects in ACTH-induced TRD model. Thus, further investigation of molecular signaling related to the glutamatergic transmission and role of Mg, could reveal prospects to novel treatment strategies that could be of particular importance for patients suffering from TRD.
Asunto(s)
Antidepresivos Tricíclicos/uso terapéutico , Conducta Animal/efectos de los fármacos , Depresión , Magnesio/farmacología , Sistemas Neurosecretores/efectos de los fármacos , Hormona Adrenocorticotrópica , Animales , Corticosterona/sangre , Depresión/inducido químicamente , Depresión/tratamiento farmacológico , Depresión/patología , Modelos Animales de Enfermedad , Resistencia a Medicamentos/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Magnesio/administración & dosificación , Masculino , Neurogénesis/efectos de los fármacos , Sistemas Neurosecretores/fisiología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Ratas , Ratas Wistar , Factores de Tiempo , Insuficiencia del TratamientoRESUMEN
BACKGROUND: The effects of anesthetic drugs on postoperative cognitive function in children are not well defined and have not been experimentally addressed. AIMS: The present study aimed to examine the influence of propofol anesthesia exposure on nonaversive hippocampus-dependent learning and biochemical changes involved in memory process in the dorsal hippocampus, in peripubertal rats as the rodent model of periadolescence. METHODS: The intersession spatial habituation and the novel object recognition tasks were used to assess spatial and nonspatial, nonaversive hippocampus-dependent learning. The exposure to anesthesia was performed after comparably long acquisition phases in both tasks. Behavioral testing lasted for 2 consecutive days (24-hour retention period). Changes in the expression of molecules involved in memory retrieval/reconsolidation were examined in the dorsal hippocampus by Western blot and immunohistochemistry, at the time of behavioral testing. RESULTS: Exposure to propofol anesthesia resulted in inappropriate assessment of spatial novelty at the beginning of the test session and affected continuation of acquisition in the spatial habituation test. The treatment did not affect recognition of the novel object at the beginning of the test session but it attenuated overall preference to novelty, reflecting retrieval of a weak memory. The expression of phosphorylated extracellular signal-regulated kinase 2 (involved in memory retrieval) was decreased while the level of phosphorylated Ca2+ /calmodulin-dependent protein kinase IIα and early growth response protein 1 (involved in memory reconsolidation) was increased in the dorsal hippocampus. The level of Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog B (neuronal activity indicator) was increased in the dorsal dentate gyrus. Enhanced exploratory activity was still evident in the propofol anesthesia exposure (PAE) group 48 hour after the treatment in both tasks. CONCLUSION: In peripubertal rats, propofol anesthesia exposure affects memory retrieval and acquisition of new learning in the spatial and nonspatial, nonaversive learning tasks 24 hour after the treatment, along with the expression of molecules that participate in memory retrieval/reconsolidation in the dorsal hippocampus. These results may have clinical implications, favoring control of basic cognitive functions in older children after the propofol exposure.
Asunto(s)
Hipocampo/efectos de los fármacos , Hipocampo/patología , Hipnóticos y Sedantes/efectos adversos , Trastornos de la Memoria/inducido químicamente , Propofol/efectos adversos , Animales , Conducta Animal/efectos de los fármacos , Western Blotting , Modelos Animales de Enfermedad , Inmunohistoquímica , Masculino , Memoria/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The aim of this study was to establish correlation of chemical composition and antioxidant activity of bilberry plants from Montenegro. Total phenolic, tannin, flavonoid, procyanidin and anthocyanin contents were determined in fruits and leaves extracts using spectrophotometric methods, while the measurements of metal content was carried out in an Inductively Coupled Atomic Emission Spectrometer. Qualitative and quantitative analyses of major phenolics were achieved by HPLC. In the investigated extracts, the most abundant phenolic was chlorogenic acid, followed by protocatechuic acid, while resveratrol, isoquercetin, quecetin and hyperoside were also present in significant quantities. Antioxidant potential was evaluated using two in vitro assays-FRAP and DPPH-being in the accordance with the cyclic voltammetry tests, performed as well. The results revealed that all the investigated extracts were rich in phenolic and essential mineral constituents, with significant antioxidant activity, depending on the polyphenolic and mineral contents, which was confirmed by principal component analysis.
Asunto(s)
Antocianinas/química , Antocianinas/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Suplementos Dietéticos , Vaccinium myrtillus/química , Cromatografía Líquida de Alta Presión , Minerales/química , Montenegro , Fenoles/análisis , Fenoles/química , Fitoquímicos/química , Fitoquímicos/farmacología , Extractos VegetalesRESUMEN
BACKGROUND: Propofol is commonly used in modern anesthesiology. Some findings suggest that it is highly addictive. AIM: In this study it was examined whether propofol anesthesia exposure was able to induce behavioral alterations and brain molecular changes already described in addictive drug usage in peripubertal rats, during the onset of mid/periadolescence as a developmental period with increasing vulnerability to drug addiction. METHODS: The expression of D1 dopamine receptor, a dopamine, and cAMP-regulated phosphoprotein with a Mr 32 000; Ca2+ /calmodulin-dependent protein kinase IIα; and Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog-B was examined in peripubertal rats 4, 24, and 48 hour after propofol anesthesia exposure by Western blot and immunohistochemistry. Brain regions of interest were the medial prefrontal cortex, the striatum, and the thalamus. Anxiety and behavioral cross-sensitization to d-amphetamine were examined as well. RESULTS: Significant increase in the expression of dopamine and cAMP-regulated phosphoprotein with a Mr 32 000 phosphorylated at threonine 34, a postsynaptic marker of dopaminergic neurotransmission, and Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog-B, a marker of neuronal activity, was detected in the thalamus of experimental animals 4-24 hour after the treatment, with the accent on the paraventricular thalamic nucleus. Significant increase in the expression of Ca2+ /calmodulin-dependent protein kinase IIα phosphorylated at threonine 286, a sensor of synaptic activity, was observed in the prefrontal cortex and the striatum 24 hour after propofol anesthesia exposure. It was accompanied by a significant decrease in Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog-B expression in the striatum. Decreased behavioral inhibition in aversive environment and increased motor response to d-amphetamine in a context-independent manner were observed as well. CONCLUSION: In peripubertal rats, propofol anesthesia exposure induces transient molecular and behavioral response that share similarities with those reported previously for addictive drugs. In the absence of additional pharmacological manipulation, all detected effects receded within 48 hour after the treatment.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Propofol/farmacología , Animales , Western Blotting , Encéfalo/metabolismo , Dopamina/metabolismo , Masculino , Modelos Animales , Fosfoproteínas/efectos de los fármacos , Fosfoproteínas/metabolismo , Ratas , Ratas WistarRESUMEN
Preclinical Research The emergence of rapid-acting antidepressants such as ketamine has motivated studies aiming to reveal the molecular mechanism of the ketamine antidepressant effect and to enable the clinical application of rapid-acting antidepressants. Here, we provide an overview of studies addressing the antidepressant effects of ketamine in depressed patients and animal models of depression and we compare the reduction of depressive symptoms in humans with the reduction in immobility time in the forced swim test in rodents after acute ketamine treatment. We also discuss different theories and potential biochemical pathways involved in the rapid antidepressant response to ketamine including the modulation of glutamatergic neurotransmission and intracellular hub-kinase activation. Finally, we summarize recent brain-region specific studies and we suggest that the activation of the ventral hippocampus-medial prefrontal cortex-dorsal raphae nuclei (vHC-mPFC-DRN) neuronal pathway may mediate the antidepressant effect of ketamine. Although substantial progress has been made, further brain-region specific animal studies and longitudinal clinical trials are necessary for the understanding and successful application of novel rapid-acting antidepressants. Drug Dev Res 77 : 414-422, 2016. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Ketamina/farmacología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Depresión/fisiopatología , Modelos Animales de Enfermedad , Humanos , Natación , Factores de TiempoRESUMEN
Surface sediments were subject to systematic long-term monitoring (2002-2014) in the Republic of Serbia (Province of Vojvodina). Eight heavy metals (Ni, Zn, Cd, Cr, Cu, Pb, As and Hg), mineral oils (total petroleum hydrocarbons), 16 EPA PAHs, selected pesticides and polychlorinated biphenyls (PCB) were monitored. As part of this research, this paper presents a sediment contamination spatial and temporal trend study of diverse pollution sources and the ecological risk status of the alluvial sediments of Carska Bara at three representative sampling sites (S1S3), in order to establish the status of contamination and recommend substances of interest for more widespread future monitoring. Multivariate statistical methods including factor analysis of principal component analysis (PCA/FA), Pearson correlation and several synthetic indicators were used to evaluate the extent and origin of contamination (anthropogenic or natural, geogenic sources) and potential ecological risks. Hg, Cd, As, mineral oils and PAHs (dominated by dibenzo(a,h)anthracene and benzo(a)pyrene, contributing 85.7% of the total) are derived from several anthropogenic sources, whereas Ni, Cu, Cr and Zn are convincingly of geogenic origin, and exhibit dual origins. Cd and Hg significantly raise the levels of potential ecological risk for all sampling locations, demonstrating the effect of long-term bioaccumulation and biomagnification. Pb is isolated from the other parameters, implying unique sources. This research suggests four heavy metals (Zn, Cr, Cu and As) and dibenzo(a,h)anthracene be added to the list of priority pollutants within the context of the application of the European Water Framework Directive (WFD), in accordance with significant national and similar environmental data from countries in the region.
Asunto(s)
Monitoreo del Ambiente/métodos , Sedimentos Geológicos/química , Metales Pesados/química , Compuestos Orgánicos/química , Contaminantes Químicos del Agua/química , Conservación de los Recursos Naturales , Humanos , Análisis de Componente Principal , Medición de Riesgo , Serbia , Naciones UnidasRESUMEN
Chemoresistance and invasion properties are severe limitations to efficient glioma therapy. Therefore, development of glioma in vivo models that more accurately resemble the situation observed in patients emerges. Previously, we established RC6 rat glioma cell line resistant to DNA damaging agents including antiglioma approved therapies such as 3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and temozolomide (TMZ). Herein, we evaluated the invasiveness of RC6 cells in vitro and in a new orthotopic animal model. For comparison, we used C6 cells from which RC6 cells originated. Differences in cell growth properties were assessed by real-time cell analyzer. Cells' invasive potential in vitro was studied in fluorescently labeled gelatin and by formation of multicellular spheroids in hydrogel. For animal studies, fluorescently labeled cells were inoculated into adult male Wistar rat brains. Consecutive coronal and sagittal brain sections were analyzed 10 and 25 days post-inoculation, while rats' behavior was recorded during three days in the open field test starting from 25th day post-inoculation. We demonstrated that development of chemoresistance induced invasive phenotype of RC6 cells with significant behavioral impediments implying usefulness of orthotopic RC6 glioma allograft in preclinical studies for the examination of new approaches to counteract both chemoresistance and invasion of glioma cells.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Daño del ADN/efectos de los fármacos , Resistencia a Antineoplásicos , Glioma/genética , Glioma/patología , Animales , Conducta Animal/efectos de los fármacos , Neoplasias Encefálicas/tratamiento farmacológico , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Glioma/tratamiento farmacológico , Humanos , Actividad Motora/efectos de los fármacos , Invasividad Neoplásica , RatasRESUMEN
Dietary restriction (DR) exerts significant beneficial effects in terms of aging and age-related diseases in many organisms including humans. The present study aimed to examine the influence of long-term DR on the BDNF system at the transcriptional and translational levels in the cortex and hippocampus of middle-aged (12-month-old) and aged (24-month-old) male Wistar rats. The obtained results revealed that the DR upregulated the expression of exon-specific BDNF transcripts in both regions, followed by elevated levels of mBDNF only in the cortex in middle-aged animals. In aged animals, DR modulated BDNF protein levels by increasing proBDNF and by declining mBDNF levels. Additionally, elevated levels of the full-length TrkB accompanied by a decreased level of the less-glycosylated TrkB protein were observed in middle-aged rats following DR, while in aged rats, DR amplified only the expression of the less-glycosylated form of TrkB. The levels of phosphorylated TrkB(Y816) were stable during aging regardless of feeding. Reduced levels of p75(NTR) were detected in both regions of middle-aged DR-fed animals, while a significant increase was measured in the cortex of aged DR-fed rats. These findings shed additional light on DR as a modulator of BDNF system revealing its disparate effects in middle-aged and aged animals. Given the importance of the proBDNF/BDNF circuit-level expression in different brain functions and various aspects of behavior, it is necessary to further elucidate the optimal duration of the applied dietary regimen with regard to the animal age in order to achieve its most favorable effects.
Asunto(s)
Envejecimiento/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Restricción Calórica , Corteza Cerebral/metabolismo , Hipocampo/metabolismo , Receptor trkB/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal/fisiología , Factor Neurotrófico Derivado del Encéfalo/genética , Masculino , Modelos Animales , Proteínas Tirosina Quinasas/metabolismo , ARN Mensajero/metabolismo , Ratas Wistar , Receptor de Factor de Crecimiento Nervioso/metabolismo , Receptor trkB/genética , Factores de TiempoRESUMEN
Previously we observed that prolonged exposure to propofol anesthesia causes caspase-3- and calpain-mediated neuronal death in the developing brain. The present study examines the effects of propofol anesthesia on the expression of tumor necrosis factor-α (TNFα), pro-nerve growth factor (NGF), and their receptors in the cortex and the thalamus. We also investigated how propofol influences the expression of Akt and X-linked inhibitor of apoptosis (XIAP) expression, proteins that promote prosurvival pathways. Seven-day-old rats (P7) were exposed to propofol anesthesia lasting 2, 4, or 6 hr and killed 0, 4, 16, or 24 hr after anesthesia termination. The relative levels of mRNA and protein expression were estimated by RT-PCR and Western blot analysis, respectively. The treatments caused marked activation of TNFα and its receptor TNFR-1 and pro-NGF and p75(NTR) receptor expression. In parallel with the induction of these prodeath signals, we established that propofol anesthesia promotes increased expression of the prosurvival molecules pAkt and XIAP during the 24-hr postanesthesia period. These results show that different brain structures respond to propofol anesthesia with a time- and duration of exposure-dependent increase in proapoptotic signaling and with concomitant increases in activities of prosurvival proteins. We hypothesized that the fine balance between these opposing processes sustains homeostasis in the immature rat brain and prevents unnecessary damage after exposure to an injurious stimulus. The existence of this highly regulated process provides a time frame for potential therapeutic intervention directed toward suppressing the deleterious component of propofol anesthesia.
Asunto(s)
Anestésicos Intravenosos/farmacología , Encéfalo/efectos de los fármacos , Factor de Crecimiento Nervioso/metabolismo , Proteína Oncogénica v-akt/metabolismo , Propofol/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X/metabolismo , Análisis de Varianza , Animales , Animales Recién Nacidos , Encéfalo/crecimiento & desarrollo , Regulación de la Expresión Génica/efectos de los fármacos , Masculino , Proteínas del Tejido Nervioso , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Receptores de Factores de Crecimiento , Receptores de Factor de Crecimiento Nervioso/genética , Receptores de Factor de Crecimiento Nervioso/metabolismoRESUMEN
The purpose of this study is investigation of electrocoagulation (EC) as a treatment of municipal wastewater, integrating life cycle impact assessment (LCIA) for assessing its environmental performance of investigated treatment. The study evaluated the effectiveness of EC in removing physico-chemical and microbial parameters using aluminum (Al) and iron (Fe) electrodes in monopolar and bipolar modes. Bipolar arrangement of Al(-)/Al/Al/Al(+) electrodes achieved the highest removals: 70% COD, 72% BOD5 followed by complete elimination of total phosphorous, turbidity and microbial parameters. This treatment was subject to investigation of the influence of reaction time (t = 10-60 min) on removals at higher current density (CD = 3.33 mA/cm2). In order to reduce energy consumption, the same reaction time range was used with a reduced CD = 2.33 mA/cm2. Following removal efficiencies obtained: 47-72% COD (higher CD) and 53-78% (lower CD); 69-75% BOD5 (higher CD) and 55-74% CD (lower CD); 12-21% NH4- (higher CD) and 7-22% NH4- (lower CD). Total P, NO3- and NO2- compounds showed the same removals regardless the CD. Decrease in current density did not influence removals of total suspended matter, turbidity, salinity as well as microbial parameters. The bipolar arrangement of Al(-)/Al/Al/Al(+) electrodes, assuming a lower CD = 2.33 mA/cm2 and t = 30 min, was assessed with the Recipe 2016Midpoint (H) and USEtox v.2 LCIA methods to explore the environmental justification of using EC for wastewater treatment. The LCIA results revealed that the EC process significantly reduces water eutrophication and toxicity for freshwater and marine ecosystems, but has higher impacts in global warming, fossil fuel consumption, human toxicity, acidification, and terrestrial ecotoxicity due to high energy consumption. This can be mainly explained by the assumption in the study that the EC precipitate is dispersed to agricultural soil without any pre-treatment and material recovery, along with relatively high energy consumption during the process.
Asunto(s)
Eliminación de Residuos Líquidos , Aguas Residuales , Humanos , Eliminación de Residuos Líquidos/métodos , Ecosistema , Electrocoagulación/métodos , Hierro , Electrodos , Aluminio , Residuos Industriales/análisisRESUMEN
The relationship between chronic kidney disease (CKD) and cognitive function has received increased attention in recent years. Antibacterial agents (ABs) represent a critical component of therapy regimens in patients with CKD due to increased susceptibility to infections. Following our reviewing work on the neurocognitive impact of long-term medications in patients with CKD, we propose to focus on AB-induced direct and indirect consequences on cognitive function. Patients with CKD are predisposed to adverse drug reactions (ADRs) due to altered drug pharmacokinetics, glomerular filtration decline, and the potential disruption of the blood-brain barrier. ABs have been identified as a major cause of ADRs in vulnerable patient populations. This review examines the direct neurotoxic effects of AB classes (e.g. beta-lactams, fluoroquinolones, aminoglycosides, and metronidazole) on the central nervous system (CNS) in patients with CKD. We will mainly focus on the acute effects on the CNS associated with AB since they are the most extensively studied effects in CKD patients. Moreover, the review describes the modulation of the gut microbiota by ABs, potentially influencing CNS symptoms. The intricate brain-gut-kidney axis emerges as a pivotal focus, revealing the interplay between microbiota alterations induced by ABs and CNS manifestations in patients with CKD. The prevalence of antibiotic-associated encephalopathy in patients with CKD undergoing intravenous AB therapy supports the use of therapeutic drug monitoring for ABs to reduce the number and seriousness of ADRs in this patient population. In conclusion, elucidating AB-induced cognitive effects in patients with CKD demands a comprehensive understanding and tailored therapeutic strategies that account for altered pharmacokinetics and the brain-gut-kidney axis.
RESUMEN
Oxidative stress, arising from disrupted balance between reactive oxygen/nitrogen species (ROS/RNS) and antioxidant defences, has been implicated in the pathogenesis of stress-related disorders. There is a growing body of evidence that supports the relationship between the activity of the hypothalamic-pituitary-adrenal (HPA) stress system, oxidative stress and magnesium (Mg) homeostasis. The present study aimed to explore the gap in our current understanding of antigenotoxic and protective effects of Mg supplementation against excessive ROS production in male rats during chronic treatment with adrenocorticotropic hormone (ACTH). Our findings show that exposure to exogenous ACTH (10 µg/day, s.c., for 21 days), as one of the key mediators of the HPA axis and stress response, produced an increase in superoxide anion levels and a decrease in superoxide dismutase activity in plasma. We observed that Mg supplementation, starting seven days prior to ACTH treatment and lasting 28 days (300 mg/L of drinking water, per os), abolished these effects in experimental animals. Moreover, our study reveals that ACTH increased the susceptibility of peripheral blood lymphocytes to ex vivo H2O2-induced total and high-level oxidative DNA damage, while Mg completely reversed these effects. Collectively, these results highlight the promising role of Mg in stress-related conditions accompanied by increased oxidative stress in animals and support further investigation using human dietary trials.
Asunto(s)
Peróxido de Hidrógeno , Magnesio , Humanos , Animales , Ratas , Masculino , Magnesio/farmacología , Especies Reactivas de Oxígeno , Sistema Hipotálamo-Hipofisario , Sistema Hipófiso-Suprarrenal , Estrés Oxidativo , Hormona Adrenocorticotrópica/farmacología , Daño del ADN , Trastornos PsicofisiológicosRESUMEN
Background: Breech presentation (BP) results from at random filling of the intrauterine cavity, with an equal probability for a BP or cephalic presentation (CP). Each fetus in BP has its "pair" in CP randomly assumed CP. Direct comparison of BP and CP makes bias to less expressed differences between these two groups. It is therefore necessary to subtract the number of fetuses/newborns from the CP set that are identical to the number of fetuses/newborns in the BP set, with identical characteristics, and add this group to the BP set before comparing them to the rest of the CP fetuses/newborns in the matching process. Methods: The procedure encompasses nine variables in pregnancies with a congenitally malformed uterus (CMU) identified at the Department of Obstetrics (1985-2014): gestational age, birth mass, birth length, head circumference, shoulders circumference, umbilical length, placental weight, newborn mass/newborn length ratio, and newborn mass/placental mass ratio. Firstly, the probability of BP was determined and its relation to gestational age, physical characteristics, and previous presentations. Then direct comparison as well as case-control matching of the CP and BP were performed. Case-control matching was based on either a single specific variable (M1) or all combined variables (M2). Findings: 462 deliveries were identified with CMU. In 81 cases of multiparity, a fetal presentation was found to be an independent event regardless of the previous presentation, gestational age, and newborn physical characteristics. In four types of CMU with 337 deliveries (Bicornuate, Didelphys, Unicornuate, Arcuate), 9 variables with 36 instances of comparison were observed. M1 in 10 instances and M2 in 6 instances showed a statistically significant lower value of breech/random presentation compared with CP. CP have lower value in 2 instances in M1 and 1 in M2. Statistically significant differences were absent without the matching process. Interpretations: The study confirms the maximum probability for the BP is 50%. The case-control matching procedure shows that it is able to detect the difference between the breech/random presentation and CP, while the classic method of direct comparison was unable to detect any differences. The outcome of the breech/random presentation in CMU should be evaluated with the described case-control matching procedure.