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Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has developed into a pandemic causing major disruptions and hundreds of thousands of deaths in wide parts of the world. As of July 3, 2020, neither vaccines nor approved drugs for effective treatment are available. In this article, we showcase how to individuate drug targets and potentially repurposable drugs in silico using CoVex a recently presented systems medicine platform for COVID-19 drug repurposing. Starting from initial hypotheses, CoVex leverages network algorithms to individuate host proteins involved in COVID-19 disease mechanisms, as well as existing drugs targeting these potential drug targets. Our analysis reveals GLA, PLAT, and GGCX as potential drug targets, and urokinase, argatroban, dabigatran etexilate, betrixaban, ximelagatran and anisindione as potentially repurposable drugs.This study investigated the impact of HFpEF on neuromuscular fatigue and peripheral hemodynamics during small muscle mass exercise not limited by cardiac output. Eight HFpEF patients (NYHA II-III, ejection-fraction 61 ± 2%) and eight healthy controls performed dynamic knee extension exercise (80% peak workload) to task failure and maximal intermittent quadriceps contractions (8 × 15 s). Controls repeated knee extension at the same absolute intensity as HFpEF. Leg blood flow (QL) was quantified using Doppler ultrasound. Pre/postexercise changes in quadriceps twitch torque (ΔQtw; peripheral fatigue), voluntary activation (ΔVA; central fatigue), and corticospinal excitability were quantified. At the same relative intensity, HFpEF (24 ± 5 W) and controls (42 ± 6 W) had a similar time-to-task failure (∼10 min), ΔQtw (∼50%), and ΔVA (∼6%). This resulted in a greater exercise-induced change in neuromuscular function per unit work in HFpEF, which was significantly correlated with a slower QL response time. Knee extenlopment is associated with the compromised peripheral hemodynamic response characterizing these patients during exercise. Given the role of neuromuscular fatigue as a factor limiting exercise, this impairment likely accounts for a significant portion of the exercise intolerance typical for this population.Interleukin-4 receptor α (IL4Rα) signaling plays an important role in cardiac remodeling during myocardial infarction (MI). However, the target cell type(s) of IL4Rα signaling during this remodeling remains unclear. Here, we investigated the contribution of endogenous myeloid-specific IL4Rα signaling in cardiac remodeling post-MI. We established a murine myeloid-specific IL4Rα knockout (MyIL4RαKO) model with LysM promoter-driven Cre recombination. Macrophages from MyIL4RαKO mice showed significant downregulation of alternatively activated macrophage markers but an upregulation of classical activated macrophage markers both in vitro and in vivo, indicating the successful inactivation of IL4Rα signaling in macrophages. To examine the role of myeloid IL4Rα during MI, we subjected MyIL4RαKO and littermate floxed control (FC) mice to MI. We found that cardiac function was significantly impaired as a result of myeloid-specific IL4Rα deficiency. This deficiency resulted in a dysregulated inflammatory response consis on the potential of activating myeloid-specific IL4Rα signaling to modify remodeling post-MI. This brings hope to patients with MI and diminishes side effects by cell type-specific instead of whole body treatment.Phenotypic screening is a neoclassical approach for drug discovery. We conducted phenotypic screening for insulin secretion enhancing agents using INS-1E insulinoma cells as a model system for pancreatic beta-cells. A principal regulator of insulin secretion in beta-cells is the metabolically regulated potassium channel Kir6.2/SUR1 complex. To characterize hit compounds, we developed an assay to quantify endogenous potassium channel activity in INS-1E cells. We quantified ligand-regulated potassium channel activity in INS-1E cells using fluorescence imaging and thallium flux. Potassium channel activity was metabolically regulated and coupled to insulin secretion. The pharmacology of channel opening agents (diazoxide) and closing agents (sulfonylureas) was used to validate the applicability of the assay. A precise high-throughput assay was enabled, and phenotypic screening hits were triaged to enable a higher likelihood of discovering chemical matter with novel and useful mechanisms of action.No abstract Keywords.

Podocytes dysfunction including the cell integrity, apoptosis and inflammation plays crucial role in diabetic nephropathy. Current exploration evaluated the protective role of eicosapentaenoic acid (EPA) in high glucose-treated podocytes and the underlying mechanisms.

MPC5 cell were stimulated by high glucose or treated by EPA of different concentrations. CCK8 assay was utilized to assess MPC5 cell viability, flow cytometry analyzed cell apoptosis.

Data showed that EPA prominently alleviated the high glucose-induced apoptosis and inflammation. TGF-beta inhibitor Besides, the disruption of the podocytes structure certifying by podocin and synaptopodin induced by hyperglycemia was hindered by EPA administration. In addition, overexpression of the sterol regulatory element-binding protein-1 (SREBP-1) reversed the protective effects of EPA in high glucose-treated podocytes. EPA inhibits the SREBP-1/TLR4/MYD88 signaling in high glucose treated cells.

This study suggests that EPA protects against podocytes dysfunction by regulating SREBP-1 and these findings provide a better understanding for diabetic nephropathy and a novel therapeutic strategy (Fig. 7, Ref. 24).

This study suggests that EPA protects against podocytes dysfunction by regulating SREBP-1 and these findings provide a better understanding for diabetic nephropathy and a novel therapeutic strategy (Fig. 7, Ref. 24).

Combination of hydroxychloroquine and azithromycin for the treatment of coronavirus disease 2019 (COVID-19) carries increased risk of corrected QT (QTc) prolongation and cardiac arrhythmias.

To characterize the ventricular repolarization indexes which are associated with malignant ventricular arrhythmias in patients treated with hydroxychloroquine and concomitant azithromycin for COVID-19.

A total of 81 patients who had hydroxychloroquine and azithromycin combination therapy because of possible or reverse-transcription polymertase chain reaction (RT-PCR) confirmed diagnosis of COVID-19 were included in the study. Baseline and control electrocardiograms (before and after treatment) were analyzed retrospectively. Tp-e interval, Tp-e/QT and Tp-e/QTc ratios, which are ventricular repolarization indexes, were calculated.

While there was no significant increase in QTc interval in patients receiving combination therapy, there was a significant increase in ventricular repolarization indexes.

The increase in ventricular replarization indexes is associated with the risk of arrhythmia.