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This article presents the results of atmospheric deposition from a 15-sites network which cover remote, agricultural, urban and industrial areas in the Iberian Peninsula and the Balearic Islands, with the aim of exploring geographical, climatic and natural vs anthropogenic gradients. Annual average fluxes of global deposition, discriminating insoluble (3,5-20,7 g m -2  year -1 ) and soluble-inorganic (7,1-45,5 g m -2  year -1 ) aerosols are discussed, seasonal patterns are regarded, and an attempt to estimate the impact of the main sources is presented. The wide range of atmospheric deposition fluxes (DF) regarding soluble (DF SOL ) and insoluble (DF INS ) has been investigated taking into consideration the contribution from nearby to long-distance sources, such as African dust, or regional-to-nearby ones, which include agricultural dust in the Ebro Valley, industrial emissions at different parts, urban dust at all cities, or saline dust resuspension from a dissicated lake bed. DF SOL is made up of marine aerosols, prevailing in coastal areas, with few exceptions in the Ebro Valley; nitrogen-species, homogeneously distributed across the network, with few exceptions due to agricultural sources; mineral dust, enhanced in the Ebro Valley owing to regional and agricultural emissions; and phospathe, displaying comparable values to other studies in general, but three hotspots at regional background environments have been identified. DF INS particles followed the aridity pattern, especially where anthropogenic emissions take place. Our estimates indicate that the regional dust to DF INS in the Ebro Valley represented 23-30%, overpassing 50% at intensive agricultural areas. Similarly, urban-metropolitan contributions accounted for 37-45% at the four cities, and 55% at the industrial one. African dust deposition was enhanced in the Central Pyrenees (75-80%) as a result of the magnification of atmospheric washout processes, and in south-eastern Iberia (69%) owing to the higher frequency of dust outbreaks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Previous studies demonstrated that peptides produced by the hydrolysis of olive seed proteins using Alcalase enzyme showed in vitro multifunctional lipid-lowering capability. This work presents a deeper insight into the hypolipidemic effect of olive seed peptides. The capability of olive seed peptides to inhibit endogenous cholesterol biosynthesis through the inhibition of HMG-CoA reductase enzyme was evaluated observing a 38 ± 7% of inhibition. Two in vivo assays using different peptides concentrations (200 and 400 mg/kg/day) were designed to evaluate the hypolipidemic effect of olive seed peptides in male and female mice. A low concentration of hydrolysate reduced total cholesterol in male mice in a 20% after 11 weeks compared to the mice feeding with hypercholesterolemic diet. A higher hydrolysate concentration showed a greater reduction in total cholesterol (25%). The analysis of the olive seed hydrolysate by reverse phase high-performance liquid chromatography mass spectrometry (RP-HPLC-MS) enabled the identification of peptides that could be responsible for this hypolipidemic effect.

A peptide fraction with molecular masses below 3 kDa (PSH-3 kDa) from a peach seed hydrolysate demonstrated high angiotensin converting enzyme (ACE) inhibitory activity (concentration to inhibit 50% ACE (IC 50 ) = 16.4 μg/mL) in our previous work. This work proposes a further study of this highly active fraction. RP-HPLC enabled two fractions (F3 and F4) with high inhibitory activity (IC 50 = 2.0 ± 0.5 and 1.2 ± 0.2 μg/mL, respectively) to be isolated. Peptide analysis by LC-Q-TOF-MS/MS using reverse-phase and hydrophilic interaction chromatography enabled 33 peptides within both fractions to be identified. Among them, peptide isoleucine-tyrosine-serine-proline-histidine (IYSPH) showed the highest capacity. The lack of cytotoxicity of peptides was demonstrated in three different cell lines (HeLa, HT-29, and HK-2). Oral administration of PSH-3 kDa fraction or peptide IYSPH caused a significant systolic blood pressure reduction (-30 mmHg) on spontaneously hypertensive rats after 3-6 h treatment.

Directive 2010/63/EU introduced requirements for the classification of the severity of procedures to be applied during the project authorisation process to use animals in scientific procedures and also to report actual severity experienced by each animal used in such procedures. These requirements offer opportunities during the design, conduct and reporting of procedures to consider the adverse effects of procedures and how these can be reduced to minimize the welfare consequences for the animals. Better recording and reporting of adverse effects should also help in highlighting priorities for refinement of future similar procedures and benchmarking good practice. Reporting of actual severity should help inform the public of the relative severity of different areas of scientific research and, over time, may show trends regarding refinement. Consistency of assignment of severity categories across Member States is a key requirement, particularly if re-use is considered, or the safeguard clause is to be invoked. The examples of severity classification given in Annex VIII are limited in number, and have little descriptive power to aid assignment. Additionally, the examples given often relate to the procedure and do not attempt to assess the outcome, such as adverse effects that may occur. The aim of this report is to deliver guidance on the assignment of severity, both prospectively and at the end of a procedure. A number of animal models, in current use, have been used to illustrate the severity assessment process from inception of the project, through monitoring during the course of the procedure to the final assessment of actual severity at the end of the procedure (Appendix 1).

Sterile inflammation is considered critical in the pathogenesis of diabetic nephropathy (DN). Here we show that Fetuin-A (FetA) or lipopolysaccharide (LPS) exacerbate palmitic acid-induced podocyte death, which is associated with a strong induction of monocyte chemoattractant protein-1 (MCP-1) and keratinocyte chemoattractant (KC). Moreover, blockage of TLR4 prevents MCP-1 and KC secretion and attenuates podocyte death induced by palmitic acid alone or combined with FetA. In addition, inhibition of interleukin-1 (IL-1) signaling by anakinra, a recombinant human IL-1Ra, or a murinized anti-IL-1 β antibody attenuates the inflammatory and ultimate cell death response elicited by FetA alone or combined with palmitic acid. In vivo short-term therapy of diabetic DBA/2J mice with an anti-IL1- β antibody for 4 weeks prevented an increase in serum FetA and considerably decreased urinary tumor necrosis alpha (TNF- α ), a known risk factor for DN progression. In summary, our results suggest that FetA similarly to LPS leads to an inflammatory response in podocytes, which exacerbates palmitic acid-induced podocyte death and our data imply a critical role for IL-1 β signaling in this process. The study offers the rational for prolonged in vivo studies aimed at testing anti-IL-1 β therapy for prevention and treatment of DN., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Background: Emerging evidence suggests that by affecting mineral balance, aluminum (Al) may enhance some events associated with neurodegenerative diseases., Aim: To examine the effect of Al(NO3)3 exposure on brain Al, cooper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), silicon (Si), and zinc (Zn) levels, and the metal-change implication in brain oxidant and inflammatory status., Methods: Four groups of six-week-old male NMRI mice were treated for three months: i) controls, administrated with deionized water; ii) Al, which received Al(NO3)3; iii) Al+silicic acid, which were given Al(NO3)3 plus silicic acid; and iv) Al+beer, which received Al(NO3)3 plus beer., Results: Brain Al and TBARS levels and TNFα and GPx expressions increased, while Cu, Mn, and Zn levels, and catalase and CuZn-SOD expression decreased (at least, p < 0.05) in Al versus control animals. Al, Si, and TBARS levels and TNFα expression decreased (p < 0.05) in Al+silicic acid and Al+beer specimens while Cu, Mn, and Zn levels and antioxidant expression increased versus the Al group. Brain Al levels correlated negatively with those of Cu, Fe, Mn, and Zn, and catalase, CuZn-SOD, and GPx enzyme expressions but positively with Si and TBARS levels and TNFα expression. Two components of the principal component analysis (PCA) explained 71.2% of total data variance (p < 0.001). PCA connected the pro-oxidant markers with brain Al content, while brain Zn and Cu levels were closer to antioxidant enzyme expression., Conclusion: Administration of Al(NO3)3 induced metal imbalance, inflammation, and antioxidant status impairment in the brain. Those effects were blocked to a significant extent by silicic acid and beer administration.

Background: The effects of cinacalcet in persistent and/or hypercalcaemia-associated secondary hyperparathyroidism (SHPT) have been described in patients on dialysis., Objectives: To evaluate the efficacy and safety of cinacalcet in SHPT not on dialysis and its effects on bone turnover markers., Methods: Non-randomised, longitudinal, observational, analytical study of patients with chronic kidney disease (CKD) and SHPT (PTH> 80 pg/mL) as well as normo- or hypercalcaemia (≥8.5mg/dL), treated with cinacalcet., Results: Mean cinacalcet dose was 30mg/day in 66.7%. We studied 15 patients (10 women), aged 66.0±17.93years. The aetiology was unknown in 20% of cases. Sociodemographic variables and renal function parameters were recorded. We compared values at baseline as well as after 6 and 12 months. Calcium (10.3±0.55 vs. 9.4±1.04) and iPTH (392.4±317.65 vs. 141.8±59.26) levels decreased. Increased levels of phosphorus (3.7±1.06 vs. 3.9±0.85) and ß-CTX (884.2±797.22 vs. 1053.6±999.00) were detected, although there were no significant changes in GFR, urinary calcium or other bone markers. Two patients withdrew from the study (gastrointestinal intolerance and parathyroidectomy, respectively)., Conclusions: Cinacalcet at low doses is effective in the management of SHPT in CKD patients who are not on dialysis. Its use reduces iPTH and calcaemia, without causing serious side effects or significant changes in renal function., (Copyright © 2015 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.

Type 2 diabetes mellitus is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are highly susceptible to saturated FFAs but not to protective, monounsaturated FFAs. We report that patients with diabetic nephropathy develop alterations in glomerular gene expression of enzymes involved in fatty acid metabolism, including induction of stearoyl-CoA desaturase (SCD)-1, which converts saturated to monounsaturated FFAs. By IHC of human renal biopsy specimens, glomerular SCD-1 induction was observed in podocytes of patients with diabetic nephropathy. Functionally, the liver X receptor agonists TO901317 and GW3965, two known inducers of SCD, increased Scd-1 and Scd-2 expression in cultured podocytes and reduced palmitic acid-induced cell death. Similarly, overexpression of Scd-1 attenuated palmitic acid-induced cell death. The protective effect of TO901317 was associated with a reduction of endoplasmic reticulum stress. It was lost after gene silencing of Scd-1/-2, thereby confirming that the protective effect of TO901317 is mediated by Scd-1/-2. TO901317 also shifted palmitic acid-derived FFAs into biologically inactive triglycerides. In summary, SCD-1 up-regulation in diabetic nephropathy may be part of a protective mechanism against saturated FFA-derived toxic metabolites that drive endoplasmic reticulum stress and podocyte death., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

The technique of recording spinal cord withdrawal reflexes as single motor units (SMUs) does not require intense preparatory surgery and allows the study of the nociceptive system in physiological conditions. It has been used to show that the wind-up phenomenon depends on the level of excitability of spinal cord neurones, the integrity of the spinal cord and the parameters of the stimulation used. We have now used SMU recordings to assess whether wind-up is also an heterogeneous phenomenon depending on the muscle studied, and, if so, how the presence of hyperalgesia affects its generation. The experiments were performed in normal and carrageenan-induced inflammation in male Wistar rats anesthetized with alpha-chloralose. Wind-up was recorded in units from peroneus longus, tibialis anterior and extensor digitorum longus. The results showed that in normal animals, the curves of C-fibre mediated wind-up reached saturation at different times and the shape of the curves was different depending on the muscle studied and on the intensity of stimulation used. In inflammation, however, C-fibre mediated wind-up became very uniform in the muscles studied, with a similar shape and saturation point. A-fibre mediated wind-up was only observed in animals with inflammation and no differences were observed between muscles. We conclude that in the absence of preparatory surgery and inflammation, C-fibre wind-up is heterogeneous, and supports a modular organization of nociceptive spinal reflexes. In hyperalgesia, however, wind-up curves are similar in units from different muscles, confirming a loss of modular organization that also affects the generation of wind-up.

1 Puromycin aminonucleoside (PAN)-induced nephrosis is a model of human minimal change disease. In rats, PAN induces nephrotic-range proteinuria, renal epithelial cell (podocyte) damage, infiltration of mononuclear leukocytes, and apoptosis of several renal cell types. 2 Retinoic acid (RA) modulates a wide range of biological processes, such as inflammation and apoptosis. Since renal damage by PAN is characterized by inflammatory infiltration and epithelial cell death, the effect of treatment with all-trans RA (tRA) was examined in the PAN nephrosis model and in the cultured differentiated podocyte. 3 Treatment with tRA 4 days after PAN injection did not inhibit the proteinuria peak but reversed it significantly. However, treatment with tRA both before and 2 days after the injection of PAN protected the glomerular epithelial cells, diminishing the cellular edema and diffuseness of the foot process effacement. Preservation of the podocyte architecture correlated with the inhibition of proteinuria. The anti-inflammatory effect of tRA was evidenced by the inhibition of PAN-induced interstitial mononuclear cell infiltration and the decreased renal expression of two molecules involved in monocyte infiltration: fibronectin and monocyte chemoattractant protein-1. TUNEL assays showed that tRA inhibited the PAN-induced apoptosis of cultured differentiated mouse podocytes. 4 We conclude that tRA treatment may prevent proteinuria by protecting the podocytes from injury and diminishing the interstitial mononuclear infiltrate in the model of PAN nephrosis. Retinoids are a potential new treatment for kidney diseases characterized by proteinuria and mononuclear cell infiltration.