Mechanisms of action of autophagy modulators dissected by quantitative systems pharmacology analysis

Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles, or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1-antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here, we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g., artenimol and olanzapine acting as activators, fostamatinib as an inhibitor, or melatonin as a dual-modulator) as well as selected drugs that uniquely target specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulate the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression of ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker, bridging various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities

Effect of <i>Ligustrum lucidum</i> polysaccharide on immunity of immunosuppressed mice

The aim of this study was to observe the effects of Ligustrum lucidum polysaccharide on immune functions of hydrocortisone-induced immuno-suppressed mouse model. There were phagocytic function of mouse perito-neal macrophage, condition of formation of hemolysin and hemolytic plague as well as condition of mouse lymphocyte transformation. The results indicate that through comparison between high-dose, medium-dose, low-dose L. lucidum polysaccharide groups, lentinan group and model group, phagocytic rate and phagocytic index of peritoneal macrophage obviously improved, thus obviously enhancing formation of hemolysin and hemolytic plague, and obviously improving the transformation rate of peripheral blood lymphocyte. Therefore, L. lucidum polysaccharide could markedly improve the immune functions of hydrocortisone-induced immunosuppressed model mouse.

Design of Positioning Mechanism Fit Clearances Based on On-Orbit Re-Orientation Accuracy

The factors affecting the re-orientation accuracy of the on-orbit replaceable optical unit were studied, and the mathematical models of the relationships between fit clearances of positioning mechanisms and the limits of rotation angles were deduced. When the relative position relationship of positioning mechanisms was determined, fit clearances were designed according to the requirement of the rotation angle limits, and the rotation angle limits were determined to ensure that the angles were within the index range. Theodolites were used to measure the re-orientation angles of the optical unit, and the errors between the measurement angles and the real angles were deduced. Then, the numerical simulation proved that the errors were within limits. The microgravity test environment was established, and the weight of the optical unit was unloaded by a suspension method to simulate the state of the optical unit when it was replaced on orbit. The test results confirmed the correctness of the design method

Research and Experiment of Repairable Space Telescope Interface System

Space technology is the core competitiveness of a powerful country. Space maintenance technology has just started in our country. The biggest innovation of this article is to design a set of interface system, which is suitable for on-orbit maintenance of space science instruments. It represents that this technology from scratch in our country. A new measuring method is proposed. According to the homogeneous coordinate transformation, the mathematical models of the relationships between fit clearances of interface system and the six-degree of freedom change of the maintenance module are derived. According to the index requirements, the corresponding fit clearance and repeat positioning accuracy are determined. Set up an experimental platform, and use autocollimator and laser tracker to measure the repeated positioning accuracy of the module. Based on the theory of small displacement, the least square method is used to deduce the rotation angle and translation amount of the module through the change of the characteristic point coordinates. The experiment proves that the interface meets the requirement of on-orbit maintainable operation, and the experimental data proves that the theoretical equation is correct. Providing engineering reference for other space maintenance scientific instruments

Cyclophosphamide loaded thermo-responsive hydrogel system synergize with a hydrogel cancer vaccine to amplify cancer immunotherapy in a prime-boost manner

Although neoantigen-based cancer vaccines show great potential in cancer immunotherapy due to their ability to induce effective and long-lasting anti-tumor immunity, their development is hindered by the limitations of neoantigens identification, low immunogenicity, and weak immune response. Cyclophosphamide (CTX) not only directly kills tumors but also causes immunogenic cell death, providing a promising source of antigens for cancer vaccines. Herein, a combined immunotherapy strategy based on temperature-sensitive PLEL hydrogel is designed. First, CTX-loaded hydrogel is injected intratumorally into CT26 bearing mice to prime anti-tumor immunity, and then 3 days later, PLEL hydrogels loaded with CpG and tumor lysates are subcutaneously injected into both groins to further promote anti-tumor immune responses. The results confirm that this combined strategy reduces the toxicity of CTX, and produces the cytotoxic T lymphocyte response to effectively inhibit tumor growth, prolong survival, and significantly improve the tumor cure rate. Moreover, a long-lasting immune memory response is observed in the mice. About 90% of the cured mice survive for at least 60 days after being re-inoculated with tumors, and the distant tumor growth is also well inhibited. Hence, this PLEL-based combination therapy may provide a promising reference for the clinical promotion of chemotherapy combined with cancer vaccines

Characterization of Coke Formed during Thermal Reaction of Tar

Coking of volatiles generated from coal in pyrolysis has been a focal issue in coal pyrolysis and upgrading of coal tar, but limited work can be found in the literature on evolution of coke in composition and structure under the pyrolysis conditions. This work characterizes the coke formed in reaction of a subbituminous coal tar at 300, 400, and 500 °C in 40 min in a semibatch system which allows natural evaporation of light fractions. The coke is categorized into two types, the one suspended in tetrahydrofuran (THF), coke-S, and the one deposited on the wall of tube reactor, coke-D. It is found that coke-D accounts for 70–85% of total coke. With increasing tar reaction temperature and time the quantity of coke increases from 1.0% to 16.3 wt % and the particle size of coke-S increases from a most probable size of approximately 0.1 to 700–800 μm. This change is accompanied by reduction in alkyl side chains and heteroatoms (O, N, and S), as well as the enrichment in the aromatic C_ar–C_ar bond, which lead to a decrease in H/C ratio from 0.9 to 0.6 and increase in aromaticity <i>f</i>_a from 0.70 to 0.86. The carbon distribution in coke-S is similar to that in bituminous coals and is composed of 3–7 fused aromatic rings. The changes in coke-S also include increase in radical concentration and decreases in the radicals’ <i>g</i> value and line width, indicating continued pyrolysis and condensation of the coke due to the removal of oxygen atoms and side chains on the aromatic structure. When compared with coke-S, coke-D formed under the same conditions is more condensed as indicated by higher radical concentration and lower <i>g</i> value and line width. The morphological change in coke-D includes transformation of small irregular particles to spherical-like particles and to coke film that crack in 30 min at 300 °C or 10 min at 500 °C

A systems‐level study reveals host‐targeted repurposable drugs against SARS‐CoV‐2 infection

Abstract Understanding the mechanism of SARS‐CoV‐2 infection and identifying potential therapeutics are global imperatives. Using a quantitative systems pharmacology approach, we identified a set of repurposable and investigational drugs as potential therapeutics against COVID‐19. These were deduced from the gene expression signature of SARS‐CoV‐2‐infected A549 cells screened against Connectivity Map and prioritized by network proximity analysis with respect to disease modules in the viral–host interactome. We also identified immuno‐modulating compounds aiming at suppressing hyperinflammatory responses in severe COVID‐19 patients, based on the transcriptome of ACE2‐overexpressing A549 cells. Experiments with Vero‐E6 cells infected by SARS‐CoV‐2, as well as independent syncytia formation assays for probing ACE2/SARS‐CoV‐2 spike protein‐mediated cell fusion using HEK293T and Calu‐3 cells, showed that several predicted compounds had inhibitory activities. Among them, salmeterol, rottlerin, and mTOR inhibitors exhibited antiviral activities in Vero‐E6 cells; imipramine, linsitinib, hexylresorcinol, ezetimibe, and brompheniramine impaired viral entry. These novel findings provide new paths for broadening the repertoire of compounds pursued as therapeutics against COVID‐19