Cross-validation of methods used for analysis of MTBE and other gasoline components in groundwater.

Head space gas chromatography with flame-ionization detection (HS-GC-FID), ancl purge and trap gas chromatography-mass spectrometry (P&T-GC-MS) have been used to determine methyl-tert-butyl ether (MTBE) and benzene, toluene, and the ylenes (BTEX) in groundwater. In the work discussed in this paper measures of quality, e.g. recovery (94-111%), precision (4.6 - 12.2%), limits of detection (0.3 - 5.7 I~g L 1 for HS and 0.001 I~g L 1 for PT), and robust-ness, for both methods were compared. In addition, for purposes of comparison, groundwater samples from areas suffering from odor problems because of fuel spillage and tank leakage were analyzed by use of both techniques. For high concentration levels there was good correlation between results from both methods

JNK isoforms control adult mammal hippocampal neurogenesis

[eng] In mammals, the term "Adult Neurogenesis” (AN) defines the process through which, throughout adulthood, new neurons are produced from neural stem cells (NSC). These NSC are located in a specific niche, concretely, in the subventricular zone (SVZ), lining the lateral ventricles, and in the subgranular zone (SGZ) in the dentate gyrus (DG) of the hippocampus. Controversially, new data have questioned the existence of this AN in the human brain seeing how only populations of immature neurons (IN), broadly dispersed within SGZ, have been detected. Either way, neurogenic activity in the hippocampus has been correlated with learning, memory formation and behavioral responses to stress, just like with the pathophysiology of many brain diseases and mood disorders. Various extracellular and intracellular stimuli have been shown to modulate survival, proliferation, and differentiation of adult-born cells in the hippocampus, especially through conserved stimuli-response mechanisms like the JNKs. In the present review, the JNK pathway and their control of adult hippocampal neurogenesis are described, evidencing the critical role of isoform JNK1.[cat] En mamíferos, el término “Neurogenesis Adulta (NA)”, se define como el proceso a través del cual, en adultos, se producen nuevas neuronas granulares a partir de células madre neurales (CMN). Estas CMN estan ubicadas en microambientes específicos, en concreto en la zona subventicular (ZSV), recubriendo los ventriculos laterales, y en la zona subgranular (ZSG) del giro dentado del hipocampo (GD). Sin embargo, nuevas informaciones han cuestionado la existencia de este proceso de neurogenesis adulta en el cerebro humano, ya que solamente se han detectado poblaciones de neuronas inmaduras (NI) dispersas a lo largo de la ZSG. Independientemente, la existencia de una actividad neurogénica en el hipocampo adulto se ha correlacionado con el aprendizaje, la formación de memoria y en el comportamiento ante situaciones de estrés, así como en la patofisiologia de diferentes patologías del cerebro, incluso en casos de alteraciones del estado de ánimo. Se ha demostrado que diferentes estímulos extracelulares e intracelulares controlan la supervivencia, la proliferación y la diferenciación de las nuevas neuronas del hipocampo, especialmente a través de mecanismos conservados de respuesta a estímulos como las JNKs. En la presente revisión se describe las JNK y su control de la neurogénesis hipocampal adulta, evidenciando el papel crucial de la isoforma JNK1

The Preclinical discovery and development of opicapone for the treatment of Parkinson's Disease

Introduction: Opicapone (OPC) is a well-established catechol-O-methyltransferase (COMT) inhibitor that is approved for the treatment of Parkinson's disease (PD) associated with L-DOPA / L-amino acid decarboxylase inhibitor (DDI) therapy allowing for prolonged activity due to a more continuous supply of L-DOPA in the brain. Thus, OPC decreases fluctuation in L-DOPA plasma levels and favours more constant central dopaminergic receptor stimulation, thus improving PD symptomatology. Areas covered: This review evaluates the preclinical development, pharmacology, pharmacokinetics and safety profile of OPC. Data were extracted from published preclinical and clinical studies published on PUBMED and SCOPUS (Search period: 2000-2019). Clinical and post-marketing data were also evaluated. Expert opinion: OPC is a third generation COMT inhibitor with a novel structure. It has an efficacy and tolerability superior to its predecessors, tolcapone (TOL) and entacapone (ENT). It also provides a safe and simplified drug regimen that allows neurologists to individually adjust the existing daily administration of L-DOPA. OPC is indicated as an adjunctive therapy to L-DOPA/DDI in patients with PD and end-of-dose motor fluctuations who cannot be stabilised on those combinations. Abbreviations: 3-OMD, 3-O-methyldopa; 6-OHDA, 6-hydroxydopamine; BG, basal ganglia; COMT, Catechol-O-methyltransferase; DDI, decarboxylase inhibitors; ENT, Entacapone; FDA, Food and Drug Administration; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OPC, Opicapone; PD, Parkinson's disease; TOL, Tolcapone; GDNF, Glial cell-line-derived neurotrophic factor; NTN, neurturin; ICV, Intracerebroventricular; PDUFA, Prescription Drug User Fees Act; EMA, European Medicine Administration; AE, Adverse event BG, Basal ganglia. QD, once a day

The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer's Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet

The most common type of dementia is Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology

Neoinnervation and neovascularization of acellular pericardial-derived scaffolds in myocardial infarcts

Engineered bioimplants for cardiac repair require functional vascularization and innervation for proper integration with the surrounding myocardium. The aim of this work was to study nerve sprouting and neovascularization in an acellular pericardial-derived scaffold used as a myocardial bioimplant. To this end, 17 swine were submitted to a myocardial infarction followed by implantation of a decellularized human pericardial-derived scaffold. After 30 days, animals were sacrificed and hearts were analyzed with hematoxylin/eosin and Masson's and Gallego's modified trichrome staining. Immunohistochemistry was carried out to detect nerve fibers within the cardiac bioimplant by using βIII tubulin and S100 labeling. Isolectin B4, smooth muscle actin, CD31, von Willebrand factor, cardiac troponin I, and elastin antibodies were used to study scaffold vascularization. Transmission electron microscopy was performed to confirm the presence of vascular and nervous ultrastructures. Left ventricular ejection fraction (LVEF), cardiac output (CO), stroke volume, end-diastolic volume, end-systolic volume, end-diastolic wall mass, and infarct size were assessed by using magnetic resonance imaging (MRI). Newly formed nerve fibers composed of several amyelinated axons as the afferent nerve endings of the heart were identified by immunohistochemistry. Additionally, neovessel formation occurred spontaneously as small and large isolectin B4-positive blood vessels within the scaffold. In summary, this study demonstrates for the first time the neoformation of vessels and nerves in cell-free cardiac scaffolds applied over infarcted tissue. Moreover, MRI analysis showed a significant improvement in LVEF (P = 0.03) and CO (P = 0.01) and a 43 % decrease in infarct size (P = 0.007)

Dexibuprofen prevents neurodegeneration and cognitive decline in APPswe/PS1dE9 through multiple signaling pathways.

The aim of the present study is to elucidate the neuronal pathways associated to NSAIDs causing a reduction of the risk and progression of Alzheimer's disease. The research was developed administering the active enantiomer of ibuprofen, dexibuprofen (DXI), in order to reduce associated gastric toxicity. DXI was administered from three to six-month-old female APPswe/PS1dE9 mice as a model of familial Alzheimer's disease. DXI treatment reduced the activation of glial cells and the cytokine release involved in the neurodegenerative process, especially TNFα. Moreover, DXI reduced soluble β-amyloid (Aβ1-42) plaque deposition by decreasing APP, BACE1 and facilitating Aβ degradation by enhancing insulin-degrading enzyme. DXI also decreased TAU hyperphosphorylation inhibiting c-Abl/CABLES/p-CDK5 activation signal pathway and prevented spatial learning and memory impairment in transgenic mice. Therefore, chronic DXI treatment could constitute a potential AD-modifying drug, both restoring cognitive functions and reversing multiple brain neuropathological hallmarks

Benzodiazepines and Related Drugs as a Risk Factor in Alzheimer's Disease Dementia.

Benzodiazepines (BZDs) and Z-drugs are compounds widely prescribed in medical practice due to their anxiolytic, hypnotic, and muscle relaxant properties. Yet, their chronic use is associated with cases of abuse, dependence, and relapse in many patients. Furthermore, elderly people are susceptible to alterations in pharmacodynamics, pharmacokinetics as well as to drug interaction due to polypharmacy. These situations increase the risk for the appearance of cognitive affectations and the development of pathologies like Alzheimer's disease (AD). In the present work, there is a summary of some clinical studies that have evaluated the effect of BZDs and Z-drugs in the adult population with and without AD, focusing on the relationship between their use and the loss of cognitive function. Additionally, there is an assessment of preclinical studies focused on finding molecular proof on the pathways by which these drugs could be involved in AD pathogenesis. Moreover, available data (1990-2019) on BZD and Z-drug use among elderly patients, with and without AD, was compiled in this work. Finally, the relationship between the use of BZD and Z-drugs for the treatment of insomnia and the appearance of AD biomarkers was analyzed. Results pointed to a vicious circle that would worsen the condition of patients over time. Likewise, it put into relevance the need for close monitoring of those patients using BZDs that also suffer from AD. Consequently, future studies should focus on optimizing strategies for insomnia treatment in the elderly by using other substances like melatonin agonists, which is described to have a much more significant safety profile

The Implication of the Brain Insulin Receptor in Late Onset Alzheimer's Disease Dementia

Alzheimer's disease (AD) is progressive neurodegenerative disorder characterized by brain accumulation of the amyloid β peptide (Aβ), which form senile plaques, neurofibrillary tangles (NFT) and, eventually, neurodegeneration and cognitive impairment. Interestingly, epidemiological studies have described a relationship between type 2 diabetes mellitus (T2DM) and this pathology, being one of the risk factors for the development of AD pathogenesis. Information as it is, it would point out that, impairment in insulin signalling and glucose metabolism, in central as well as peripheral systems, would be one of the reasons for the cognitive decline. Brain insulin resistance, also known as Type 3 diabetes, leads to the increase of Aβ production and TAU phosphorylation, mitochondrial dysfunction, oxidative stress, protein misfolding, and cognitive impairment, which are all hallmarks of AD. Moreover, given the complexity of interlocking mechanisms found in late onset AD (LOAD) pathogenesis, more data is being obtained. Recent evidence showed that Aβ42 generated in the brain would impact negatively on the hypothalamus, accelerating the 'peripheral' symptomatology of AD. In this situation, Aβ42 production would induce hypothalamic dysfunction that would favour peripheral hyperglycaemia due to down regulation of the liver insulin receptor. The objective of this review is to discuss the existing evidence supporting the concept that brain insulin resistance and altered glucose metabolism play an important role in pathogenesis of LOAD. Furthermore, we discuss AD treatment approaches targeting insulin signalling using anti-diabetic drugs and mTOR inhibitors

A metabolic perspective of late onset Alzheimer's disease

After decades of research, the molecular neuropathology of Alzheimer's disease (AD) is still one of the hot topics in biomedical sciences. Some studies suggest that soluble amyloid β (Aβ) oligomers act as causative agents in the development of AD and could be initiators of its complex neurodegenerative cascade. On the other hand, there is also evidence pointing to Aβ oligomers as mere aggravators, with an arguable role in the origin of the disease. In this line of research, the relative contribution of soluble Aβ oligomers to neuronal damage associated with metabolic disorders such as Type 2 Diabetes Mellitus (T2DM) and obesity is being actively investigated. Some authors have proposed the endoplasmic reticulum (ER) stress and the induction of the unfolded protein response (UPR) as important mechanisms leading to an increase in Aβ production and the activation of neuroinflammatory processes. Following this line of thought, these mechanisms could also cause cognitive impairment. The present review summarizes the current understanding on the neuropathological role of Aβ associated with metabolic alterations induced by an obesogenic high fat diet (HFD) intake. It is believed that the combination of these two elements has a synergic effect, leading to the impairement of ER and mitochondrial functions, glial reactivity status alteration and inhibition of insulin receptor (IR) signalling. All these metabolic alterations would favour neuronal malfunction and, eventually, neuronal death by apoptosis, hence causing cognitive impairment and laying the foundations for late-onset AD (LOAD). Moreover, since drugs enhancing the activation of cerebral insulin pathway can constitute a suitable strategy for the prevention of AD, we also discuss the scope of therapeutic approaches such as intranasal administration of insulin in clinical trials with AD patients