Computational drug repositioning of clopidogrel as a novel therapeutic option for focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is a glomerular lesion often associated with nephrotic syndrome. It is also associated with a high risk of progression to end-stage kidney disease. Current treatment of FSGS is limited to systemic corticosteroids or calcineurin inhibition, along with inhibitors of the renin-angiotensin-aldosterone system. FSGS is heterogeneous in etiology, and novel therapies targeting specific, dysregulated molecular pathways represent a major unmet medical need. We have generated a network-based molecular model of FSGS pathophysiology using previously established systems biology workflows to allow computational evaluation of compounds for their predicted interference with molecular processes contributing to FSGS. We identified the anti-platelet drug clopidogrel as a therapeutic option to counterbalance dysregulated FSGS pathways. This prediction of our computational screen was validated by testing clopidogrel in the adriamycin FSGS mouse model. Clopidogrel improved key FSGS outcome parameters and significantly reduced urinary albumin to creatinine ratio (P < 0.01) and weight loss (P < 0.01), and ameliorated histopathological damage (P < 0.05). Clopidogrel is used to treat several cardiovascular diseases linked to chronic kidney disease. Clopidogrel's favorable safety profile and its efficacy in the adriamycin mouse FSGS model thus recommend it as an attractive drug repositioning candidate for clinical trial in FSGS.

OntoloViz: a GUI for interactive visualization of ranked disease or drug lists using the MeSH and ATC ontologies.

Motivation: Structured vocabularies for drugs and diseases represent, besides their primary use for annotating scientific literature or scientific information in general, a valuable resource for visualizing aggregated information. The Medical Subject Headings (MeSH) and Anatomical Therapeutic Chemical (ATC) ontologies are widely used structured vocabularies for diseases and drugs, respectively. Their hierarchical tree-like structure can be used as a basis for creating intuitive visual displays for specific diseases and drugs within their higher-order classifications. Such displays are helpful means to contextualize diseases and drugs in various settings such as in drug repositioning. However, there are few tools that can harness the potential of these structured ontologies to create informative visual representations without extensive programming and data processing skills. Results: We have developed OntoloViz, a Graphical User Interface (GUI) for visualizing annotated lists of drugs or diseases in the context of their MeSH or ATC ontologies in an intuitively interpretable sunburst layout. Minimum input is a list of disease or drug names. Users in addition have the option to specify numerical parameters for the input lists to enhance the visualization, e.g. to visualize term frequencies. The GUI allows values to be propagated upwards in the respective ontology tree structure thus facilitating exploration of gene and drug lists. We present two use cases for OntoloViz, namely (i) a graphical representation of clinically tested drugs for coronavirus disease (COVID-19) based on ATC Classification and (ii) a graphical representation of literature annotation of human diseases on the MeSH ontology. Availability and implementation: The OntoloViz package can be retrieved from PyPi. The source code along with test data, template, and documentations are available at GitHub (https://github.com/Delta4AI/OntoloViz).

The effect of different fluoridation methods on the red wine staining potential on intensively bleached enamel in vitro.

PURPOSE: To study the effect in vitro of different fluoridation methods after intensive bleaching on the color of enamel slabs during a severe staining challenge with red wine. METHODS: 75 specimens were equally divided among five groups. Group 1 (no bleaching, no wine) served as control. Groups 2, 3 and 4 underwent bleaching with 35 % H2O2 for 10 minutes followed by home-bleaching for 8 hours/day with 10% carbamide peroxide on 14 consecutive days. Groups 2 and 3 were fluoridated for 1 hour with either Elmex gelée or Duraphat, respectively whereas Group 4 remained without fluoridation. Group 5 (no bleaching, no fluoride, wine) served as control for the influence of red wine on the color of untreated enamel. Color determination was accomplished using the CIE-Lab System. RESULTS: Nine successive cycles of wine saliva treatment (10 minutes wine, 23 hours 50 minutes saliva) for Groups 2-5 revealed the highest changes of a-values (deltaa= 4.17) (towards red) for the Duraphat-treated group (bleaching, Duraphat, wine) with significantly higher deltaa-values compared with Group 4 (bleaching, no fluoride, wine) (deltaa= 2.97). After final cleaning no differences were found between the three bleached groups (Groups 2, 3 and 4) for deltaL, deltaa, deltab and deltaE, respectively. Exposure to red wine led to an increase in a-values (deltaa= 0.44) of the intrinsic tooth color in Group 5 (no bleaching, no fluoride, wine) that was significantly different from baseline.

Thyroid hormone receptors TRalpha1 and TRbeta differentially regulate gene expression of Kcnq4 and prestin during final differentiation of outer hair cells.

Thyroid hormone (TH or T3) and TH-receptor beta (TRbeta) have been reported to be relevant for cochlear development and hearing function. Mutations in the TRbeta gene result in deafness associated with resistance to TH syndrome. The effect of TRalpha1 on neither hearing function nor cochlear T3 target genes has been described to date. It is also uncertain whether TRalpha1 and TRbeta can act simultaneously on different target genes within a single cell. We focused on two concomitantly expressed outer hair cell genes, the potassium channel Kcnq4 and the motor protein prestin Slc26a5. In outer hair cells, TH enhanced the expression of the prestin gene through TRbeta. Simultaneously Kcnq4 expression was activated in the same cells by derepression of TRalpha1 aporeceptors mediated by an identified THresponse element, which modulates KCNQ4 promoter activity. We show that T3 target genes can differ in their sensitivity to TH receptors having the ligand either bound (holoreceptors) or not bound (aporeceptors) within single cells, and suggest a role for TRalpha1 in final cell differentiation.