A metabolomic approach shows sphingosine 1-phosphate and lysophospholipids as mediators of the therapeutic effect of liver growth factor in emphysema.

Tobacco smoke exposure is the principal cause of lung tissue destruction, which in turn results in emphysema that leads into shortness of breath. Liver growth factor (LGF, a cell and tissue regenerating factor with therapeutic activity in several organs) has antifibrotic and antioxidant properties that could be useful to promote lung tissue regenerating capacity in damaged lungs. The current study has examined differences in metabolite profiles (fingerprints) of plasma from mice (strain C57BL/6J, susceptible to develop emphysema) exposed to tobacco smoke during six months. One group of mice received a treatment with Liver Growth Factor (LGF) after emphysema was established, whereas the other group did not receive the treatment. Age and sex-matched mice not exposed to smoke were also maintained with or without treatment as controls. Metabolic fingerprints (untargeted analysis) of plasma after protein precipitation were obtained by LC-QTOF-MS. The signals were processed and a large number of possible metabolites were found (23944). Multivariate data analysis provided models that highlighted the differences between control and smoke exposed mice in both conditions. Accurate masses of features (possible compounds) representing significant differences were searched using online public databases. Lipid mediators, related to intracellular signaling in inflammation, were found among the metabolites putatively identified as markers of the different conditions and among them, sphingosine, sphingosine 1-phosphate and lysophospholipids point at the relevance of such metabolites in the regulation of the processes related to tissue regeneration mediated by LGF. These results also suggest that metabolomic fingerprinting could potentially guide the characterization of relevant metabolites leading the regeneration of lungs in emphysema disease.

Improving the cadmium-induced centriacinar emphysema model in rats by concomitant anti-oxidant treatment.

1. The aim of the present study was to perform an evolutionary analysis of the morphometrical, biochemical and functional parameters of centriacinar emphysema induced by cadmium chloride (CdCl2) in rats and to determine the effects of concomitant N-acetylcysteine (NAC) administration. 2. Male Wistar rats were instilled orotracheally with either CdCl2 (n = 24) or saline (n = 24). One group of rats, consisting of both CdCl2- and saline-treated rats, was fed a normal diet (n = 24), whereas the other group received NAC (n = 24). 3. Changes in inspiratory capacity (IC), lung compliance (CL), expiratory flow at 75% (F75), forced vital capacity (FVC) and hydroxyproline content were assessed 2, 8, 21 and 45 days after instillation. Polymorphonuclear cells were evaluated 2 and 8 days after instillation and the mean linear intercept (Lm) was determined at 21 and 45 days. 4. Over time, CdCl2 instillation causes several changes that are bound up with centriacinar emphysema. The concomitant administration of NAC to CdCl2-treated rats partially reversed Lm at 21 days compared with CdCl2 alone (115 +/- 2 vs 127 +/- 2, respectively; P < 0.05). However, 45 days after instillation, NAC improved lung function in CdCl2-treated rats compared with that in the saline-treated control group (IC 14.64 vs 15.25, respectively (P = 0.054); FVC 16.94 vs 16.28, respectively (P = 0.052), F75 31.41 vs 32.48, respectively (P = 0.062)). In addition, 45 days after instillation, NAC reduced lung collagen content in both the saline-treated control (100 vs 81% alone and in the presence of NAC, respectively) and CdCL2-treated groups (213 vs 161% alone and in the presence of NAC, respectively). In addition, although the results were not significant, NAC tended to reduce Lm and enhance CL in NAC + CdCl2-treated rats. 5. In conclusion, NAC partially improved emphysematous changes and reduced collagen deposition, which diminished the CdCl2-induced fibrotic component of centriacinar emphysema.

Magnetic resonance methods and applications in pharmaceutical research.

This review presents an overview of some recent magnetic resonance (MR) techniques for pharmaceutical research. MR is noninvasive, and does not expose subjects to ionizing radiation. Some methods that have been used in pharmaceutical research MR include magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) methods, among them, diffusion-weighted MRI, perfusion-weighted MRI, functional MRI, molecular imaging and contrast-enhance MRI. Some applications of MR in pharmaceutical research include MR in metabonomics, in vivo MRS, studies in cerebral ischemia and infarction, degenerative joint diseases, oncology, cardiovascular disorders, respiratory diseases and skin diseases. Some of these techniques, such as cardiac and joint imaging, or brain fMRI are standard, and are providing relevant data routinely. Skin MR and hyperpolarized gas lung MRI are still experimental. In conclusion, considering the importance of finding and characterizing biomarkers for improved drug evaluation, it can be expected that the use of MR techniques in pharmaceutical research is going to increase in the near future.

Neurotransmitter amino acid in cerebrospinal fluid of patients with dementia with Lewy bodies.

The purpose of the present study was to compare neurotransmitter amino acid concentrations in the cerebrospinal fluid (CSF) and CSF/plasma ratios in 21 patients with dementia with Lewy bodies (DLB) and 26 matched controls. To this purpose, we used an ion-exchange chromatographic method. DLB patients exhibit higher CSF concentrations of asparagine (+25%) and glycine (+21%) compared to a control group, whereas no differences in CSF/plasma ratios were found between both groups. On the other hand, no alterations in concentrations of glutamate, aspartate and GABA were detected in CSF of patients compared to a control group. There was no correlation among amino acid levels and CSF/plasma ratios with age, age of onset, body mass index, duration of the disease or scores of the Mini Mental State Examination, UPDRS and Hoehn and Yahr stage. These results suggest a possible role of glycine and asparagine in the pathogenic mechanism of dementia with Lewy bodies.

Neurobiología de la dependencia alcohólica / Neurobiology of alcohol dependence

Objetivo: El proceso de dependencia al alcohol implica modificaciones funcionales en la neurotransmisión cerebral alterando de esta manera el equilibrio homeostático entre neurotransmisores inhibidores y excitadores en diferentes circuitos cerebrales relacionados con el refuerzo inducido por sustancias. Material y métodos: Se revisa la neurobiología de la dependencia al alcohol. Resultados: Un gran número de resultados experimentales sugieren que el alcohol ejerce efectos muy variados sobre los principales sistemas de neurotransmisión dependiendo del tiempo y el patrón de ingesta de la bebida. Así, el consumo de alcohol a corto plazo potencia la neurotransmisión inhibitoria (por inhibición de la transmisión glutamatérgica, y activación de neuronas GABAérgicas), mientras que a largo plazo se produce tolerancia, lo que tiende a desplazar estas alteraciones neuroquímicas hacia valores normales. Por el contrario, si el consumo de alcohol es discontinuo o se reduce bruscamente, se produce activación de la neurotransmisión glutamatérgica e inhibición de la neurotransmisión GABAérgica, entre otras muchas alteraciones neuroquímicas, lo que desencadena síndrome de abstinencia y consiguiente comportamiento de búsqueda y deseo irrefrenable de consumir alcohol. Conclusiones: Los efectos del alcohol están regulados por distintos sistemas de neurotransmisión y neuromodulación, entre los que se puede destacar los sistemas de la dopamina (DA), noradrenalina (NA), factor liberador de corticotropina (CRF), neuropéptido Y (NPY), sistema opioide y el sistema cannabinoide endógeno, de forma que no se pueden explicar muchos de los efectos farmacológicos y comportamentales del alcohol sin entender sus acciones sobre estos sistemas (AU)