ARMCX proteins regulate mitochondrial function in the Retinal Pigment Epithelium

Retinal Pigment Epithelium (RPE) functions, including energy absorption, photo-pigment recycling, and oxidative stress regulation, depend on a healthy mitochondrial network. Notably, RPE mitochondrial integrity declines during aging and even more so Age-related Macular Degeneration (AMD). Healthy mitochondria pervade the entirety of the cell as an organelle network undergoing constant dynamic renewal through fusion, fission and mitophagy. Armadillo repeat-containing genes located on the X chromosome (Armcx) form an Eutharian specific cluster of 6 genes which are implicated in mitochondrial motility in axons and, more generally, in mitophagy (as substrates of Parkin). Armcx6 is up-regulated in differentiated RPE whilst Armcx3 is down-regulated in AMD, collectively suggesting an important role in the homeostasis of RPE. This study specifically analysed the role of Armcx proteins in RPE cells. Armcx1, 2, 3 and 6 but not 4 or 5 are found as bona fide mitochondrial regulators and to be upregulated in RPE differentiation in vitro. Further analysis focused on Armcx1 and Armcx2 showed both proteins to affect mitochondrial network differently in RPE. Endogenous Armcx1 and Armcx2 were strongly associated with mitochondria in ARPE-19 cells and strongly expressed in the RPE layer of human retina. Armcx1 knockdown resulted in increased mitochondrial motility, whereas Armcx2 depletion led to decreased mitochondrial movements. Armcx overexpression resulted in aggregation and Page | 6 reduced mobility of mitochondria indicating disrupted dynamics. Armcx1 and Armcx2 knockdown resulted in fragmented mitochondria, however with different phenotypes, suggesting enhanced fission and/or mitophagy. Indeed, Armcx1 knockdown showed increased Parkin activation upon mitophagy induction, whereas Armcx2 resulted in no difference. In addition, Lamp2 expression was also affected differently, by Armcx1 depletion leading to upregulated Lamp2, in contrast to Armcx2 knockdown which decreased Lamp2 levels. Moreover, compensatory experiments using marsupial Armc10 revealed that Armcx1 and Armcx2 have acquired novel roles during their evolution in the Eutherian clade, probably to fulfil new functions essential to support the more complex Eutherian clade

Galectins in the Pathogenesis of Common Retinal Disease

Diseases of the retina are major causes of visual impairment and blindness in developed countries and, due to an ageing population, their prevalence is continually rising. The lack of effective therapies and the limitations of those currently in use highlight the importance of continued research into the pathogenesis of these diseases. Vascular endothelial growth factor (VEGF) plays a major role in driving vascular dysfunction in retinal disease and has therefore become a key therapeutic target. Recent evidence also points to a potentially similarly important role of galectins, a family of β-galactoside-binding proteins. Indeed, they have been implicated in regulating fundamental processes, including vascular hyperpermeability, angiogenesis, neuroinflammation, and oxidative stress, all of which also play a prominent role in retinopathies. Here, we review direct evidence for pathological roles of galectins in retinal disease. In addition, we extrapolate potential roles of galectins in the retina from evidence in cancer, immune and neuro-biology. We conclude that there is value in increasing understanding of galectin function in retinal biology, in particular in the context of the retinal vasculature and microglia. With greater insight, recent clinical developments of galectin-targeting drugs could potentially also be of benefit to the clinical management of many blinding diseases

GC-MS analysis and antibacterial activity of some fractions from Lagochilus ilicifolius Bge. grown in Mongolia

3-methyl-1,2,3,4-tetrahydroquinoline (1), 4-hydroxyisoquinoline (2), 4-(1E)-hydroxy-1-prophenyl)-2-methoxyphenol (3), 4-acetoxycinnamic acid (4), Songoramine (5), and Songorine (6) have been determined by GC-MS analysis from the crude alkaloid mixtures (G1) obtained from the aerial parts of Lagochilus ilicifolius Bge. grown in Mongolia and comparison of the measured data with those from the literature. The compounds 1-6 are described for the first time from L.ilicifolius. From these 3-methyl-1,2,3,4-tetrahydroquinoline (1) was determined for the first time from natural plants.In addition, the antibacterial activity of fractions and total alkaloids were evaluated against Staphylococcus aurous, Bacillus subtilis, Bacillus cereus and Escherichia coli strains, respectively. The growth inhibition zones against gram-positive S.aureus, B.subtilis, B.cereus and gram negative E.coli, strains were observed. Positive results were achieved on 500 μg/disc concentration, but lower results or no active on 100 μg/disc concentration were for the plant extracts, fractions and total alkaloids.Mongolian Journal of Chemistry 16 (42), 2015, 39-4

STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets

Proteins and their functional interactions form the backbone of the cellular machinery. Their connectivity network needs to be considered for the full understanding of biological phenomena, but the available information on protein-protein associations is incomplete and exhibits varying levels of annotation granularity and reliability. The STRING database aims to collect, score and integrate all publicly available sources of protein-protein interaction information, and to complement these with computational predictions. Its goal is to achieve a comprehensive and objective global network, including direct (physical) as well as indirect (functional) interactions. The latest version of STRING (11.0) more than doubles the number of organisms it covers, to 5090. The most important new feature is an option to upload entire, genome-wide datasets as input, allowing users to visualize subsets as interaction networks and to perform gene-set enrichment analysis on the entire input. For the enrichment analysis, STRING implements well-known classification systems such as Gene Ontology and KEGG, but also offers additional, new classification systems based on high-throughput text-mining as well as on a hierarchical clustering of the association network itself. The STRING resource is available online at https://string-db.org/

MODULATORY EFFECT OF CANNABINOID LIGANDS ON THE ANXIETY-LIKE BEHAVIOR OF BULBECTOMIZED RATS

Purpose: The endocannabinoid system is considered a key regulatory system in anxiety behavior. The aim of the present study was to examine the effects of intracerebroventricularly (i.c.v.) injected cannabinoid ligands on the anxiety-like behavior of rats with a model of depression. Material/Methods: The olfactory bulbectomized rat (OBX) is a well-established experimental model of depression. The OBX model exhibits neurochemical changes that are very similar to those seen in patients with depression. CB1 receptor agonist HU-210 and CB1 receptor antagonist SR 141716A were injected i.c.v. in OBX rats, and the anxiety-related behavior of the rats was measured in an elevated plus-maze (EPM) test. Results: OBX rats showed an increased anxiety-like behavior at the EPM test. HU-210 produced an anxiolytic-like effect and alleviated the OBX-induced anxiety, while SR 141716A failed to produce effects on the behavior of OBX rats. Conclusions: The results suggest that CB1 receptors may be involved in the modulation of anxiety-related behavior in OBX rats

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/

Proposed therapeutic range of treosulfan in reduced toxicity pediatric allogeneic hematopoietic stem cell transplant conditioning: results from a prospective trial

Treosulfan is given off‐label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan's pharmacokinetics (PKs), efficacy, and safety in a prospective trial. Pediatric patients (n = 87) receiving treosulfan‐fludarabine conditioning were followed for at least 1 year posttransplant. PKs were described with a two‐compartment model. During follow‐up, 11 of 87 patients died and 12 of 87 patients had low engraftment (≤ 20% myeloid chimerism). For each increase in treosulfan area under the curve from zero to infinity (AUC(0‐∞)) of 1,000 mg hour/L the hazard ratio (95% confidence interval) for mortality increase was 1.46 (1.23–1.74), and the hazard ratio for low engraftment was 0.61 (0.36–1.04). A cumulative AUC(0‐∞) of 4,800 mg hour/L maximized the probability of success (> 20% engraftment and no mortality) at 82%. Probability of success with AUC(0‐∞) between 80% and 125% of this target were 78% and 79%. Measuring PK at the first dose and individualizing the third dose may be required in nonmalignant disease

New insights into risk factors for transplant-associated thrombotic microangiopathy in pediatric HSCT

This study aimed to identify a risk profile for development of transplant-associated thrombotic microangiopathy (TA-TMA) in children undergoing hematopoietic stem cell transplantation (HSCT). Between 2013 and 2016, 439 children underwent 474 HSCTs at 2 supraregional United Kingdom centers. At a median of 153 days post-HSCT, TA-TMA occurred among 25 of 441 evaluable cases (5.6%) with no evidence of center variation. Sex, underlying disease, intensity of the conditioning, total body irradiation–based conditioning, the use of calcineurin inhibitors, venoocclusive disease, and viral reactivation did not influence the development of TA-TMA. Donor type: matched sibling donor/matched family donor vs matched unrelated donor vs mismatched unrelated donor/haplo-HSCT, showed a trend toward the development of TA-TMA in 1.8% vs 6.1% vs 8.3%, respectively. Presence of active comorbidity was associated with an increased risk for TA-TMA; 13% vs 3.7% in the absence of comorbidity. The risk of TA-TMA was threefold higher among patients who received >1 transplant. TA-TMA rates were significantly higher among patients with acute graft-versus-host disease (aGVHD) grades III to IV vs aGVHD grade 0 to II. On multivariate analysis, the presence of active comorbidity, >1 transplant, aGVHD grade III to IV were risk factors for TA-TMA (odds ratio [OR]: 5.1, 5.2, and 26.9; respectively), whereas the use of cyclosporine A/tacrolimus-based GVHD prophylaxis was not a risk factor for TA-TMA (OR: 0.3). Active comorbidity, subsequent transplant, and aGVHD grades III to IV were significant risk factors for TA-TMA. TA-TMA might represent a form of a vascular GVHD, and therefore, continuing control of aGVHD is important to prevent worsening of TA-TMA associated with GVHD

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

Perturbation Centrality and Turbine: A Novel Centrality Measure Obtained Using a Versatile Network Dynamics Tool

Analysis of network dynamics became a focal point to understand and predict changes of complex systems. Here we introduce Turbine, a generic framework enabling fast simulation of any algorithmically definable dynamics on very large networks. Using a perturbation transmission model inspired by communicating vessels, we define a novel centrality measure: perturbation centrality. Hubs and inter-modular nodes proved to be highly efficient in perturbation propagation. High perturbation centrality nodes of the Met-tRNA synthetase protein structure network were identified as amino acids involved in intra-protein communication by earlier studies. Changes in perturbation centralities of yeast interactome nodes upon various stresses well recapitulated the functional changes of stressed yeast cells. The novelty and usefulness of perturbation centrality was validated in several other model, biological and social networks. The Turbine software and the perturbation centrality measure may provide a large variety of novel options to assess signaling, drug action, environmental and social interventions. The Turbine algorithm is available at: http://www.turbine.linkgroup.huComment: 21 pages, 4 figues, 1 table, 58 references + a Supplement of 52 pages, 10 figures, 9 tables and 39 references; Turbine algorithm is available at: http://www.turbine.linkgroup.h