Methotrexate inhibition of SARS-CoV-2 entry, infection and inflammation revealed by bioinformatics approach and a hamster model.

Background: Drug repurposing is a fast and effective way to develop drugs for an emerging disease such as COVID-19. The main challenges of effective drug repurposing are the discoveries of the right therapeutic targets and the right drugs for combating the disease. Methods: Here, we present a systematic repurposing approach, combining Homopharma and hierarchal systems biology networks (HiSBiN), to predict 327 therapeutic targets and 21,233 drug-target interactions of 1,592 FDA drugs for COVID-19. Among these multi-target drugs, eight candidates (along with pimozide and valsartan) were tested and methotrexate was identified to affect 14 therapeutic targets suppressing SARS-CoV-2 entry, viral replication, and COVID-19 pathologies. Through the use of in vitro (EC50 = 0.4 µM) and in vivo models, we show that methotrexate is able to inhibit COVID-19 via multiple mechanisms. Results: Our in vitro studies illustrate that methotrexate can suppress SARS-CoV-2 entry and replication by targeting furin and DHFR of the host, respectively. Additionally, methotrexate inhibits all four SARS-CoV-2 variants of concern. In a Syrian hamster model for COVID-19, methotrexate reduced virus replication, inflammation in the infected lungs. By analysis of transcriptomic analysis of collected samples from hamster lung, we uncovered that neutrophil infiltration and the pathways of innate immune response, adaptive immune response and thrombosis are modulated in the treated animals. Conclusions: We demonstrate that this systematic repurposing approach is potentially useful to identify pharmaceutical targets, multi-target drugs and regulated pathways for a complex disease. Our findings indicate that methotrexate is established as a promising drug against SARS-CoV-2 variants and can be used to treat lung damage and inflammation in COVID-19, warranting future evaluation in clinical trials.

Photocatalytic Hydrogen Evolution from Water Splitting Using Core-Shell Structured Cu/ZnS/COF Composites.

Hydrogen is considered to be a very efficient and clean fuel since it is a renewable and non-polluting gas with a high energy density; thus, it has drawn much attention as an alternative fuel, in order to alleviate the issue of global warming caused by the excess use of fossil fuels. In this work, a novel Cu/ZnS/COF composite photocatalyst with a core-shell structure was synthesized for photocatalytic hydrogen production via water splitting. The Cu/ZnS/COF microspheres formed by Cu/ZnS crystal aggregation were covered by a microporous thin-film COF with a porous network structure, where COF was also modified by the dual-effective redox sites of C=O and N=N. The photocatalytic hydrogen production results showed that the hydrogen production rate reached 278.4 µmol g-1 h-1, which may be attributed to its special structure, which has a large number of active sites, a more negative conduction band than the reduction of H+ to H2, and the ability to inhibit the recombination of electron-hole pairs. Finally, a possible mechanism was proposed to effectively explain the improved photocatalytic performance of the photocatalytic system. The present work provides a new concept, in order to construct a highly efficient hydrogen production catalyst and broaden the applications of ZnS-based materials.

An electroactive alginate hydrogel nanocomposite reinforced by functionalized graphite nanofilaments for neural tissue engineering.

To address the need to biodegradable, electroactive conduits accelerating nerve regeneration, here we develop a nanocomposite hydrogel made of alginate reinforced by citric acid functionalized graphite nanofilaments. The green, simple functionalization enhances the nanofillers distribution and their biocompatibility, as verified using mesenchymal stem cells in vitro. The uniformly distributed nanofilaments raise mechanical stability of the nanocomposite hydrogel versus the neat one up to three times. Also, the nanofilaments enable electrical contact and intercellular signaling thereby stimulating their biological activity. In vitro studies proved the biocompatibility of the nanocomposite hydrogel whereon PC12 cells proliferate and spread evidently. In vivo tests also supported applicability of the nanocomposite hydrogel for implantation within body, and the samples showed no adverse reaction and no inflammatory responses after 14 days. Conclusively, the results certify that the developed electroactive nanocomposite hydrogel is able to stimulate nerve generation and could be confidently used as a nerve conduit material.

Is abnormal non-high-density lipoprotein cholesterol a gender-specific predictor for metabolic syndrome in patients with schizophrenia taking second-generation antipsychotics?

Evidence supports an association between metabolic syndrome (MetS) and schizophrenia. However, specific risk factors for MetS and gender differences in patients with schizophrenia taking second-generation antipsychotics (SGAs) have not been well explored. A cross-sectional cohort of 329 Han Chinese patients was recruited in a psychiatric hospital in central Taiwan. Using the definitions of the International Diabetes Federation for Chinese, the prevalence of MetS was 23.7% (men: 25.7%; women: 21.2%). Logistic regression analyses showed that patients with a BMI ≥ 24 and an abnormal non-high-density lipoprotein cholesterol (non-HDL-C) were significantly (p < 0.001) more likely to develop MetS. A BMI ≥ 24 was a significant risk factor in men (OR: 6.092, p < 0.001) and women (OR: 5.886, p < 0.001). An abnormal non-HDL-C was a significant specific risk factor for men with MetS (OR: 4.127, p < 0.001), but not for women. This study supports a greater prevalence of MetS in patients with schizophrenia taking SGAs than in the general population. Abnormal BMI and non-HDL-C were significantly associated with developing MetS, and an abnormal non-HDL-C was a specific risk factor for men. Future development of specific interventions and regular monitoring for MetS is imperative for early identification and prevention.