Effects of aging on the susceptibility to the toxic effects of cyclosporin A in rats. Changes in liver glutathione and antioxidant enzymes

[EN] Free radicals are involved in aging and cyclosporin A-induced toxicity. The age-related changes in the liver oxidative status of glutathione, lipid peroxidation, and the activity of the enzymatic antioxidant defense system, as well as the influence of aging on the susceptibility to the hepatotoxic effects of cyclosporin (CyA) were investigated in rats of different ages (1, 2, 4, and 24 months). The hepatic content of reduced glutathione (GSH) increased with aging, peaked at 4 months, and decreased in senescent rats. By contrast, glutathione disulfide (GSSG) and thiobarbituric acid-reactive substances (TBARS) concentrations and superoxide dismutase, catalase, and glutathione peroxidase activities were higher in the oldest than in the youngest rats. CyA treatment, besides inducing the well-known cholestatic syndrome, increased liver GSSG and TBARS contents and the GSSG/GSH molar ratio, and altered the nonenzymatic and enzymatic antioxidant defense systems. The CyA-induced cholestasis and hepatic depletion of GSH, and the increases in the GSSG/GSH ratio, and in GSSG and TBARS concentrations were higher in the older than the mature rats. Moreover, superoxide dismutase and catalase activities were found to be significantly decreased only in treated senescent rats. The higher CyA-induced oxidative stress, lipoperoxidation, and decreases in the antioxidant defense systems in the aged animals render them more susceptible to the hepatotoxic effects of cyclosporin. © 2001 Elsevier Science Inc

Glutathione Metabolism In Cyclosporine A‐Treated Rats: Dose‐ And Time‐Related Changes In Liver And Kidney

[EN] 1. We investigated the simultaneous effects of cyclosporine A (CsA) treatment in rats on glutathione metabolism, oxidative status and their interorgan relationship in the liver and kidney. 2. Reduced and oxidized glutathione (GSH and GSSG, respectively), lipid peroxidation and the activity of several enzymes of the glutathione cycle were evaluated in adult Wistar rats treated daily (i.p.) with saline, CsA vehicle (olive oil) or CsA (10 and 20 mg/kg per day) for either 1 or 4 weeks (short- and long-term treatments, respectively). 3. Cyclosporine A treatment elicited a significant depletion in liver GSH content and a decrease in the GSH/GSSG ratio that was unrelated to either the time of treatment or the dose used; these effects were already evident after I week of treatment. Renal GSH levels remained unaffected or increased, while those of GSSG increased markedly in all CsA-treated rats, leading to decreases in the GSH/GSSG ratio, except in rats treated in the short term with the lower dose of CsA. These changes in the GSH/GSSG ratio were time and dose dependent. Short-term CsA treatment using the higher dose and long-term treatment with both doses of CsA progressively enhanced lipid peroxidation, which was reflected by increased levels of thiobarbituric acid-reactive substances in both hepatic and renal homogenates. Hepatic γ-glutamylcysteine synthetase activity was increased after long-term treatment with both doses of CsA, whereas the activity of GSH hepatic peroxidase and GSH transferase was not significantly modified in any of the experimental groups. In contrast, renal γ-glutamyl transpeptidase activity decreased in a progressive fashion, with the magnitude of this decrease being dose and time dependent. The plasma levels of total glutathione increased only in rats treated in the long term, regardless of the dose of CsA used, and remained unaltered in animals treated in the short term. 4. In summary, the data collected indicate that CsA treatment alters the interorgan homeostasis of glutathione and the oxidative status of the rat liver and kidney, which is associated with increases in lipid peroxidation in both organs, and also induces modifications in the activity of some enzyme related to the glutathione cycle

Effects of S-adenosylmethionine on intrabiliary glutathione degradation induced by long-term administration of cyclosporin A in the rat

[EN] We investigate the ability of S-adenosylmethionine (SAMe) to antagonize the cyclosporine A (CyA)-induced inhibition of biliary glutathione efflux induced by long-term administration of CyA (10 mg/kg per day-CyA10 or 20 mg/kg per day-CyA20 for 4 weeks) in rats. CyA treatment reduced the liver content of total glutathione and caused a significant increase in the oxidized-to-reduced glutathione ratio and the thiobarbituric acid-reactive substances (TBARS) concentration. When the rats were concurrently treated with SAMe (10 mg/kg twice daily) and CyA, all these parameters did not significantly differ from control values. Treatment with CyA induced a significant increase in liver GGT activity that was attenuated by coadministration of SAMe. Biliary efflux of total glutathione was significantly reduced in animals treated with CyA. These changes were abolished by SAMe administration. Following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates increased to a lesser extent in animals cotreated with SAMe when compared to those receiving only CyA. The significant decrease in biliary efflux of oxidized glutathione induced by CyA was totally (S+CyA10) or partially (S+CyA20) prevented by coadministration of SAMe. Our observations confirm that SAMe cotreatment in rats antagonizes CyA-induced inhibition in the biliary efflux of glutathione and suggest that protection against intrabiliary glutathione degradation plays a major role in this protective effect

Effects of aging and cyclosporin treatment on the hepatobiliary efflux of glutathione

[EN] The aim of this study was to investigate the effects of cyclosporin (CyA) treatment on biliary glutathione efflux in rats of different ages (1, 2, 4, and 24 months). CyA treatment reduced the liver content of total glutathione in 1-, 2- and 24 month old rats ( 30%, 43% and 30%, respectively). By contrast, oxidized glutathione (GSSG) concentration in liver tended to increase, although non significantly, in the rats aged 4 and 24 month ( + 36% and + 28%, respectively). The oxidized-to-reduced glutathione ratio was significantly increased in 2-, 4- and 24 month old animals ( + 23%, + 36% and >100%, respectively). Regarding biliary glutathione, our data indicate that efflux rates of total glutathione in control (untreated) rats increased to a maximum at 4 months, and decreased ( 56%) in 24 month old rats, although values were still higher than those from young animals. CyA treatment significantly reduced biliary glutathione secretion except in 24 month old rats ( 98%, 66% and 32%, at 1, 2 and 4 month, respectively). In addition, following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates into bile were significantly reduced by the drug only in 1- and 2 month old rats ( 29% and 55%, respectively) and even tended to increase, although non significantly, in oldest animals. Our data indicate that inhibition of biliary glutathione efflux by CyA was greater in younger rats and support the view that increased intrabiliary catabolism of the tripeptide and inhibition of its canalicular transport could contribute to the decline in biliary glutathione secretion induced by the drug

Vertical characterization of fine and coarse dust particles during an intense Saharan dust outbreak over the Iberian Peninsula in springtime 2021

An intense and long-lasting Saharan dust outbreak crossed the Iberian Peninsula (IP) from the southwest (SW) to the northeast (NE) from 25 March until 7 April 2021. This work aims to assess the optical and mass contribution of both fine and coarse dust particles along their transport. Five Iberian lidar stations were monitoring the transport and evolution of the Saharan dust particles, i.e. El Arenosillo/Huelva, Granada, Torrejon/Madrid and Barcelona in Spain, and evora in Portugal. The particular meteorological conditions determined the aerosol scenario along the overall dust event, differing in the first part of the event (25-31 March), in which the strongest dust incidence occurred on 29-31 March at the south and central stations and 1 April at Barcelona, from the second one (1-7 April). The use of the two-step POLIPHON algorithm showed the relevance of using polarized lidar measurements for separating the aerosol properties of dust fine and coarse particles as an added value. Both the fine dust (Df) and coarse dust (Dc) components of the total particle backscatter coefficient (total dust, DD = Dc + Df) were separately derived. The dust plume was well-mixed with height and no significant differences were found in the vertical structure of both the Dc and Df particle backscatter coefficients. From the beginning of the dust outbreak until 1 April, the vertical Df / DD mass ratio was nearly constant in time at each station and also in altitude with values of & SIM; 10 %. Moreover, the mean dust optical depth at 532 nm was decreasing along that dust pathway, reporting values from SW to NE stations of 0.34 at El Arenosillo/Huelva, 0.28 at Granada, 0.20 at evora, 0.28 at Torrejon/Madrid, and 0.14 at Barcelona, although its Df / DD ratio remained almost constant (28 %-30 %). A similar pattern was found for the total dust mass loading and its Df / DD ratio, i.e. mostly decreasing mean mass values were reported, being constant in its Df / DD ratio (& SIM; 10 %) along the SW-NE dust pathway. In addition, the episode-mean centre-of-mass height increased with latitude overall, showing a high variability, being greater than 0.5 km at the southern sites (El Arenosillo/Huelva, Granada, evora) and & SIM; 1.0 km at Torrejon/Madrid and Barcelona. However, despite the relatively high intensity of the dust intrusion, the expected ageing of the dust particles was hardly observed, by taking into account the minor changes found in the contribution and properties of the coarse and fine dust particles. This is on the basis that the IP is relatively close to the Saharan dust sources and then, under certain dust transport conditions, any potential ageing processes in the dust particles remained unappreciated. The following must be highlighted: the different relative contribution of the fine dust particles to the total dust found for their optical properties (& SIM; 30 %) associated with the radiative effect of dust, with respect to that for the mass features (& SIM; 10 %) linked to air quality issues, along the overall dust event by crossing the IP.Ministry of Science and Innovation, Spain (MICINN) Spanish Government PID2019-104205GB-C21/AEI/10.13039/50110001103

Susceptibility to the toxic effects of cyclosporin in the rat: effects of aging

[ES] Sumario de la revista Journal of Hepatology: Susceptibilidad a los efectos tóxicos de la ciclosporina en la rata: efectos del envejecimiento

Circulating neutrophil counts and mortality in septic shock

Producción CientíficaPolynuclear neutrophils can play dual roles in sepsis: on the one hand they mediate major antimicrobial activities and on the other hand they can contribute to the development of multiple organ failure [1]. Nonetheless, in spite of the importance of these cells in sepsis, the influence of the circulating neutrophil count (CNC) on the prognosis of septic patients with this pathology has not been properly evaluated. We analyzed the association between CNC and outcome in two cohorts of patients with diagnostic criteria of septic shock (SS) [2]: the first was recruited in the context of a single center study (EXPRESS study, discovery cohort, n = 195; Table 1), and the second in the context of a multi-centric study (GRECIA study, validation cohort, n = 194; Table 2). Written informed consent was obtained from each patient or their legal representative. The two studies were approved by the Research Ethics Committee of the Hospital Clínico Universitario, Valladolid, Spain (for the EXPRESS study) and Hospital Universitario Río Hortega, Valladolid, Spain (coordinating center for the GRECIA study).Instituto de Salud Carlos III (grant PI 10/01362)Junta de Castilla y León (grant BOCYL-D-26072010

Semantic inference using chemogenomics data for drug discovery

<p>Abstract</p> <p>Background</p> <p>Semantic Web Technology (SWT) makes it possible to integrate and search the large volume of life science datasets in the public domain, as demonstrated by well-known linked data projects such as LODD, Bio2RDF, and Chem2Bio2RDF. Integration of these sets creates large networks of information. We have previously described a tool called WENDI for aggregating information pertaining to new chemical compounds, effectively creating evidence paths relating the compounds to genes, diseases and so on. In this paper we examine the utility of automatically inferring new compound-disease associations (and thus new links in the network) based on semantically marked-up versions of these evidence paths, rule-sets and inference engines.</p> <p>Results</p> <p>Through the implementation of a semantic inference algorithm, rule set, Semantic Web methods (RDF, OWL and SPARQL) and new interfaces, we have created a new tool called Chemogenomic Explorer that uses networks of ontologically annotated RDF statements along with deductive reasoning tools to infer new associations between the query structure and genes and diseases from WENDI results. The tool then permits interactive clustering and filtering of these evidence paths.</p> <p>Conclusions</p> <p>We present a new aggregate approach to inferring links between chemical compounds and diseases using semantic inference. This approach allows multiple evidence paths between compounds and diseases to be identified using a rule-set and semantically annotated data, and for these evidence paths to be clustered to show overall evidence linking the compound to a disease. We believe this is a powerful approach, because it allows compound-disease relationships to be ranked by the amount of evidence supporting them.</p

Vascular and root tip GPT2 expression mediates the PGI1-independent response of Arabidopsis to small microbial volatiles

Resumen del trabajo presentado en el XVI Meeting of Plant Molecular Biology, celebrado en Sevilla (España), del 14 al 16 de septiembre de 2022Microorganisms emit a plethora of volatile compounds (VCs) that promote plant growth and photosynthesis as well as strong developmental and metabolic changes. In Arabidopsis, the plastidial isoform of phosphoglucose isomerase PGI1 mediates photosynthesis, metabolism and development, probably due to its involvement in the synthesis of isoprenoid-derived signals in vascular tissues (Bahaji et al., 2015; Bahaji et al., 2018). Like in wild-type (WT) plants, microbial VCs promote growth and photosynthesis as well as starch and CK accumulation in PGI1-lacking pgi1-2 plants (Sánchez-López et al. 2016). A striking alteration in the transcriptome of leaves of small fungal VC-treated plants involves strong up-regulation of levels of transcripts of GPT2 (At1g61800), a gene that codes for a plastidial G6P/Pi transporter. We hypothesized that the PGI1-independent response to microbial volatile emissions involves GPT2 action. To test this hypothesis, we characterized responses of WT, GPT2-null gpt2-1, PGI1-null pgi1-2 and pgi1- 2gpt2-1 plants to small fungal VCs. In addition, we characterized responses of pgi1-2gpt2-1 plants expressing GPT2 under the control of a vascular tissue- and root tip-specific promoter to small fungal VCs. Results presented in this work provide evidence that, under conditions in which PGI1 activity is reduced, long-distance action of GPT2 plays an important role in the response of plants to small VCs through mechanisms involving resetting of the photosynthesis-related proteome in leaves and complex GPT2 regulation.This work was supported by the Ministerio de Ciencia e Innovación (MCIN) and Agencia Estatal de Investigación (AEI) / 10.13039/501100011033/ (grants BIO2016-78747-P, PID2019-104685GB-100 and PID2019-107657RB-C22) and the Ministry of Education, Youth and Sport of the Czech Republic and ERDF project entitled “Plants as a tool for sustainable global development” (No. CZ.02.1.01/0.0/0.0/16_019/0000827)

Cross-cultural validation of the patient-practitioner orientation scale among primary care professionals in Spain

In recent decades, many self-report instruments have been developed to assess the extent to which patients want to be informed and involved in decisions about their health as part of the concept of person-centred care (PCC). The main objective of this research was to translate, adapt and validate the Patient-Practitioner Orientation Scale (PPOS) using a sample of primary care health-care professionals in Spain. Baseline analysis of PPOS scores for 321 primary care professionals (general practitioners and nurses) from 63 centres and 3 Spanish regions participating in a randomized controlled trial. We analysed missing values, distributions and descriptive statistics, item-to-scale correlations and internal consistency. Performed were confirmatory factor analysis (CFA) of the 2-factor model (sharing and caring dimensions), scale depuration and principal component analysis (PCA). Low inter-item correlations were observed, and the CFA 2-factor model only obtained a good fit to the data after excluding 8 items. Internal consistency of the 10-item PPOS was acceptable (0.77), but low for individual subscales (0.70 and 0.55). PCA results suggest a possible 3-factor structure. Participants showed a patient-oriented style (mean = 4.46, SD = 0.73), with higher scores for caring than sharing. Although the 2-factor model obtained empirical support, measurement indicators of the PPOS (caring dimension) could be improved. Spanish primary care health-care professionals overall show a patient-oriented attitude, although less marked in issues such as patients' need for and management of medical information