Intracellular inflammatory and antioxidant pathways in postmortem frontal cortex of subjects with major depression: effect of antidepressants

Background: Studies show that Toll-like receptors (TLRs), members of the innate immune system, might participate in the pathogenesis of the major depressive disorder (MDD). However, evidence of this participation in the brain of patients with MDD has been elusive. Methods: This work explores whether the protein expression by immunodetection assays (Western blot) of elements of TLR-4 pathways controlling inflammation and the oxidative/nitrosative stress are altered in postmortem dorsolateral prefrontal cortex of subjects with MDD. The potential modulation induced by the antidepressant treatment on these parameters was also assessed. Thirty MDD subjects (15 antidepressant-free and 15 under antidepressant treatment) were matched for gender and age to 30 controls in a paired design. Results: No significant changes in TLR-4 expression were detected. An increased expression of the TLR-4 endogenous ligand Hsp70 (+ 33%), but not of Hsp60, and the activated forms of mitogen-activated protein kinases (MAPKs) p38 (+ 47%) and JNK (+ 56%) was observed in MDD. Concomitantly, MDD subjects present a 45% decreased expression of DUSP2 (a regulator of MAPKs) and reduced (- 21%) expression of the antioxidant nuclear factor Nrf2. Antidepressant treatment did not modify the changes detected in the group with MDD and actually increased (+ 25%) the expression of p11, a protein linked with the transport of neurotransmitters and depression. Conclusion: Data indicate an altered TLR-4 immune response in the brain of subjects with MDD. Additional research focused on the mechanisms contributing to the antidepressant-induced TLR-4 pathway modulation is warranted and could help to develop new treatment strategies for MDD.This work was supported by the Instituto de Salud Carlos III and Spanish Ministry of Economy, Industry and Competitiveness (MINECO) through the Plan Estatal de I+D+i 2013-2016 (FIS-PI13/01102 and SAF2016-75500-R to JCL), the Agencia Estatal de Investigacion (AEI) and Fondo Europeo de Desarrollo Regional (FEDER) (SAF2017-83053-R to JRC), the Basque Government (IT-616-13), CIBERSAM and the EDR Funds. JRC and BGB are Ramon y Cajal fellows (MINECO)

A major role of TWEAK/Fn14 axis as a therapeutic target for post-angioplasty restenosis

Background: Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12; TWEAK) and its receptor Fibroblast growth factor-inducible 14 (Tnfrsf12a; Fn14) participate in the inflammatory response associated with vascular remodeling.However, the functional effect ofTWEAK on vascular smoothmuscle cells (VSMCs) is not completely elucidated. Methods: Next generation sequencing-based methodswere performed to identify genes and pathways regulated by TWEAK in VSMCs. Flow-citometry, wound-healing scratch experiments and transwellmigration assays were used to analyze VSMCs proliferation and migration. Mouse wire injury model was done to evaluate the role of TWEAK/Fn14 during neointimal hyperplasia. Findings: TWEAK up-regulated 1611 and down-regulated 1091 genes in VSMCs. Using a gene-set enrichment method,we found a functionalmodule involved in cell proliferation defined as the minimal network connecting top TWEAK up-regulated genes. In vitro experiments in wild-type or Tnfrsf12a deficient VSMCs demonstrated that TWEAK increased cell proliferation, VSMCs motility and migration. Mechanistically, TWEAK increased cyclins (cyclinD1), cyclin-dependent kinases (CDK4, CDK6) and decreased cyclin-dependent kinase inhibitors (p15lNK4B) mRNA and protein expression. Downregulation of p15INK4B induced by TWEAK was mediated by mitogen-activated protein kinase ERK and Akt activation. Tnfrsf12a or Tnfsf12 genetic depletion and pharmacological intervention with TWEAK blocking antibody reduced neointimal formation, decreasing cell proliferation, cyclin D1 and CDK4/6 expression, and increasing p15INK4B expression compared with wild type or IgG-treated mice in wire-injured femoral arteries. Finally, immunohistochemistry in human coronary arteries with stenosis or in-stent restenosis revealed high levels of Fn14, TWEAK and PCNA in VSMCs enriched areas of the neointima as compared with healthy coronary arteries. Interpretation: Our data define a major role of TWEAK/Fn14 in the control of VSMCs proliferation and migration during neointimal hyperplasia after wire injury in mice, and identify TWEAK/Fn14 as a potential target for treating in-stent restenosis.This work was supported by Instituto de Salud Carlos III (Fondo de Investigaciones Sanitarias ISCiii/FEDER PI13/00395; PI16/01419; PI17/ 01495) and Spanish Biomedical Research Centre in Cardiovascular Disease (CIBERCV) and Metabolic Diseases and Diabetes (CIBERDEM). PM was supported by ISCIII Miguel Servet Program (CP16/00116). CGM was supported by Fundación Conchita Rábago. NMB and VE were supported by the Spanish Ministry of Economy and Competitiveness (Juan de la Cierva IJCI-2016-29630 and Ramón y Ramón Cajal Program RyC-2013-12880, respectively). JMM has been supported a postdoctoral fellowship fromthe American Diabetes Association (Grant 1-15-MI-03) and a postdoctoral fellowship fromthe American Heart Association

Noradrenaline in Alzheimer's Disease: A New Potential Therapeutic Target

A growing body of evidence demonstrates the important role of the noradrenergic system in the pathogenesis of many neurodegenerative processes, especially Alzheimer's disease, due to its ability to control glial activation and chemokine production resulting in anti-inflammatory and neuroprotective effects. Noradrenaline involvement in this disease was first proposed after finding deficits of noradrenergic neurons in the locus coeruleus from Alzheimer's disease patients. Based on this, it has been hypothesized that the early loss of noradrenergic projections and the subsequent reduction of noradrenaline brain levels contribute to cognitive dysfunctions and the progression of neurodegeneration. Several studies have focused on analyzing the role of noradrenaline in the development and progression of Alzheimer's disease. In this review we summarize some of the most relevant data describing the alterations of the noradrenergic system normally occurring in Alzheimer's disease as well as experimental studies in which noradrenaline concentration was modified in order to further analyze how these alterations affect the behavior and viability of different nervous cells. The combination of the different studies here presented suggests that the maintenance of adequate noradrenaline levels in the central nervous system constitutes a key factor of the endogenous defense systems that help prevent or delay the development of Alzheimer's disease. For this reason, the use of noradrenaline modulating drugs is proposed as an interesting alternative therapeutic option for Alzheimer's disease

CIBERER : Spanish national network for research on rare diseases: A highly productive collaborative initiative

Altres ajuts: Instituto de Salud Carlos III (ISCIII); Ministerio de Ciencia e Innovación.CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Chronic immobilisation stress ameliorates clinical score and neuroinflammation in a MOG-induced EAE in Dark Agouti rats:mechanisms implicated

BACKGROUND: Multiple sclerosis (MS) is the endpoint of a complex and still poorly understood process which results in inflammation, demyelination and axonal and neuronal degeneration. Since the first description of MS, psychological stress has been suggested to be one of the trigger factors in the onset and/or relapse of symptoms. However, data from animal models of MS, such as experimental autoimmune encephalomyelitis (EAE) are inconsistent and the effect of stress on EAE onset and severity depends on duration and time of application of the stress protocol and the underlying mechanisms. METHODS: Dark Agouti rats were inoculated with MOG/CFA to induce EAE, and an immobilisation stress protocol with two different durations (12 and 21 days, starting at the moment of MOG-inoculation) was applied in order to analyse the effect of stress on disease onset and neuroinflammation. RESULTS: Twelve days of stress exposure increased EAE clinical score in Dark Agouti rats. In addition, these animals presented higher levels of MMP-9 and proinflammatory PGE(2 )in spinal cord. In contrast, animals chronically exposed to stress (21 days) showed a significantly lower incidence of EAE clinical signs and reduced myelin loss, leukocyte infiltration and accumulation of inflammatory/oxidative mediators in spinal cord. Interestingly, chronically stressed animals showed a parallel increase in levels of the anti-inflammatory prostaglandin 15d-PGJ(2), the main endogenous agonist of PPARγ. CONCLUSIONS: Our results demonstrate that, depending on duration, stress exposure elicits opposite effects on PGE(2)/15d-PGJ(2 )ratios in spinal cord of EAE-induced Dark Agouti rats. Further studies are needed to elucidate if these changes in prostaglandin balance are sufficient to mediate the differences in clinical score and inflammation here reported, and to establish the potential utility of pharmacological intervention in MS directed toward anti-inflammatory pathways

Desarrollo de métodos rápidos y sencillos para la purificación de haptoglobina y ceruloplasmina porcina

Two fast and simple methods for porcine haptoglobin (Hp) and ceruloplasmin (Cp) purification are described in this paper. Hp was purified by ammonium sulphate fractionation and a FPLC Superdex-200 gel chromatography. The protein obtained showed two bands with a Mr (molecular mass) of about 44 kDa and 12.9 kDa corresponding to heavy (ß) and light (a) chains of Hp respectively, on sodium dodecyl sulphate-polyacrilamide gel electrophoresis, under reducing conditions. Ceruloplasmin (Cp) was isolated by one step of chromatography on amino-ethyl-derivatized Sepharose followed by gel filtration on a Superdex-200 column. The Mr of the protein, as estimated by SDS-PAGE was approximately 150 kDa. In conclusion, two new protocols have been developed for porcine Hp and Cp purification, being less time-consuming and technically demanding than those previously reported. This paper could represent an interesting guideline and be of help to obtain pure protein to use as specie-specific standard material and to produce specific antibodies