Albumin downregulates Klotho in tubular cells

Background. Kidney tubular cells are the main sources of Klotho, a protein with phosphaturic action. Genetic Klotho deficiency causes premature cardiovascular aging in mice. Human chronic kidney disease (CKD) is characterized by acquired Klotho deficiency. Despite the lack of uremic toxin accumulation, Category G1 CKD [(normal glomerular filtration rate (GFR)] is already associated with decreased Klotho and with premature cardiovascular aging. Methods. We have explored whether albuminuria, a criterion to diagnose CKD when GFR is normal, may directly decrease Klotho expression in human CKD, preclinical models and cultured tubular cells. Results. In a CKD cohort, albuminuria correlated with serum phosphate after adjustment for GFR, age and sex. In this regard, urinary Klotho was decreased in patients with pathological albuminuria but preserved GFR. Proteinuria induced in rats by puromycin aminonucleoside and in mice by albumin overload was associated with interstitial inflammation and reduced total kidney Klotho messenger ribonucleic acid (mRNA) expression. Western blot disclosed reduced kidney Klotho protein in proteinuric rats and mice and immunohistochemistry localized the reduced kidney Klotho expression to tubular cells in proteinuric animals. In cultured murine and human tubular cells, albumin directly decreased Klotho mRNA and protein expression. This was inhibited by trichostatin A, an inhibitor of histone deacetylases, but unlike cytokine-induced Klotho downregulation, not by inhibitors of nuclear factor kappa-light-chain-enhancer of activated B cells. Conclusions. In conclusion, albumin directly decreases Klotho expression in cultured tubular cells. Thismay explain, or at least contribute to, the decrease in Klotho and promote fibroblast growth factor 23 resistance in early CKD categories, as observed in preclinical and clinical proteinuric kidney diseaseThis work was supported by FIS PI13/00047, CP14/00133, PI15/00298, PI16/02057, FEDER funds ISCIII-RETIC REDinREN RD12/0021, RD16/0009, Comunidad de Madrid (S2010/BMD-2378), Sociedad Espanola de Nefrología, EUTOX, FRIAT. Programa Intensificacion Actividad Investigadora (ISCIII/Agencia Lain-Entralgo/CM) to A.O., Miguel Servet MS14/00133, MS12/03262 to M.D.S.-N. and A.B.S., Joan Rodes to B.F.F. A.O. and M.D.S.-N. report grants from the Spanish government and grants from the Spanish Society of Nephrology during the conduct of the stud

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Global Consequences of Liver Ischemia/Reperfusion Injury

Liver ischemia/reperfusion injury has been extensively studied during the last decades and has been implicated in the pathophysiology of many clinical entities following hepatic surgery and transplantation. Apart from its pivotal role in the pathogenesis of the organ’s post reperfusion injury, it has also been proposed as an underlying mechanism responsible for the dysfunction and injury of other organs as well. It seems that liver ischemia and reperfusion represent an event with “global” consequences that influence the function of many remote organs including the lung, kidney, intestine, pancreas, adrenals, and myocardium among others. The molecular and clinical manifestation of these remote organs injury may lead to the multiple organ dysfunction syndrome, frequently encountered in these patients. Remote organ injury seems to be in part the result of the oxidative burst and the inflammatory response following reperfusion. The present paper aims to review the existing literature regarding the proposed mechanisms of remote organ injury after liver ischemia and reperfusion

The STRING database in 2021: customizable protein-protein networks, and functional characterization of user-uploaded gene/measurement sets

Cellular life depends on a complex web of functional associations between biomolecules. Among these associations, protein-protein interactions are particularly important due to their versatility, specificity and adaptability. The STRING database aims to integrate all known and predicted associations between proteins, including both physical interactions as well as functional associations. To achieve this, STRING collects and scores evidence from a number of sources: (i) automated text mining of the scientific literature, (ii) databases of interaction experiments and annotated complexes/pathways, (iii) computational interaction predictions from co-expression and from conserved genomic context and (iv) systematic transfers of interaction evidence from one organism to another. STRING aims for wide coverage; the upcoming version 11.5 of the resource will contain more than 14 000 organisms. In this update paper, we describe changes to the text-mining system, a new scoring-mode for physical interactions, as well as extensive user interface features for customizing, extending and sharing protein networks. In addition, we describe how to query STRING with genome-wide, experimental data, including the automated detection of enriched functionalities and potential biases in the user's query data. The STRING resource is available online, at https://string-db.org/

The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest

Much of the complexity within cells arises from functional and regulatory interactions among proteins. The core of these interactions is increasingly known, but novel interactions continue to be discovered, and the information remains scattered across different database resources, experimental modalities and levels of mechanistic detail. The STRING database (https://string-db.org/) systematically collects and integrates protein-protein interactions-both physical interactions as well as functional associations. The data originate from a number of sources: automated text mining of the scientific literature, computational interaction predictions from co-expression, conserved genomic context, databases of interaction experiments and known complexes/pathways from curated sources. All of these interactions are critically assessed, scored, and subsequently automatically transferred to less well-studied organisms using hierarchical orthology information. The data can be accessed via the website, but also programmatically and via bulk downloads. The most recent developments in STRING (version 12.0) are: (i) it is now possible to create, browse and analyze a full interaction network for any novel genome of interest, by submitting its complement of encoded proteins, (ii) the co-expression channel now uses variational auto-encoders to predict interactions, and it covers two new sources, single-cell RNA-seq and experimental proteomics data and (iii) the confidence in each experimentally derived interaction is now estimated based on the detection method used, and communicated to the user in the web-interface. Furthermore, STRING continues to enhance its facilities for functional enrichment analysis, which are now fully available also for user-submitted genomes

The STRING database in 2025: protein networks with directionality of regulation

Proteins cooperate, regulate and bind each other to achieve their functions. Understanding the complex network of their interactions is essential for a systems-level description of cellular processes. The STRING database compiles, scores and integrates protein-protein association information drawn from experimental assays, computational predictions and prior knowledge. Its goal is to create comprehensive and objective global networks that encompass both physical and functional interactions. Additionally, STRING provides supplementary tools such as network clustering and pathway enrichment analysis. The latest version, STRING 12.5, introduces a new 'regulatory network', for which it gathers evidence on the type and directionality of interactions using curated pathway databases and a fine-tuned language model parsing the literature. This update enables users to visualize and access three distinct network types-functional, physical and regulatory-separately, each applicable to distinct research needs. In addition, the pathway enrichment detection functionality has been updated, with better false discovery rate corrections, redundancy filtering and improved visual displays. The resource now also offers improved annotations of clustered networks and provides users with downloadable network embeddings, which facilitate the use of STRING networks in machine learning and allow cross-species transfer of protein information. The STRING database is available online at https://string-db.org/

Handedness in ADHD: Meta-Analyses

Meta-analyses have shown that several neurodevelopmental and psychiatric disorders, such as autism spectrum disorder and schizophrenia, are associated with a higher prevalence of atypical (left-, non-right-, or mixed-) handedness. One neurodevelopmental disorder for which this association is unclear is attention deficit hyperactivity disorder (ADHD). Here, some empirical studies have found evidence for a higher prevalence of atypical handedness in individuals with ADHD compared to neurotypical individuals. However, other studies failed to establish such an association. Therefore, meta-analytic integration is critical to estimate whether or not there is an association between handedness and ADHD. We report the results of three meta-analyses (left-, mixed-, and non-right-handedness) comparing handedness in individuals with ADHD to controls (typically developing individuals). The results show evidence of a trend towards elevated levels of atypical handedness when it comes to differences in left- and mixed-handedness (p = 0.09 and p = 0.07, respectively), but do show clear evidence of elevated levels of non-right-handedness between individuals with ADHD and controls (p = 0.02). These findings are discussed in the context of the hypothesis that ADHD is a disorder in which mostly right-hemispheric brain networks are affected. Since right-handedness represents a dominance of the left motor cortex for fine motor behavior, such as writing, as well as a left-hemispheric dominance for language functions, and about 90% of individuals are right-handers, this hypothesis might explain why there is not stronger evidence for an association of left-handedness with ADHD. We suggest that the mechanisms involved in the pathogenesis of ADHD might show an overlap with the mechanisms involved in handedness strength, but not handedness direction. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature