楊進木教授與鄒協成副教授研究團隊發表研究成果於International Journal of Molecular Sciences

連結網址：https://www.mdpi.com/1422-0067/23/23/14958

Abstract

Autoimmune hypophysitis (AH) is an autoimmune disease of the pituitary for which the pathogenesis is incompletely known. AH is often treated with corticosteroids; however, steroids may lead to considerable side effects. Using a mouse model of AH (experimental autoimmune hypophysitis, EAH), we show that interleukin-1 receptor-associated kinase 1 (IRAK1) is upregulated in the pituitaries of mice that developed EAH. We identified rosoxacin as a specific inhibitor for IRAK1 and found it could treat EAH. Rosoxacin treatment at an early stage (day 0–13) slightly reduced disease severity, whereas treatment at a later stage (day 14–27) significantly suppressed EAH. Further investigation indicated rosoxacin reduced production of autoantigen-specific antibodies. Rosoxacin downregulated production of cytokines and chemokines that may dampen T cell differentiation or recruitment to the pituitary. Finally, rosoxacin downregulated class II major histocompatibility complex expression on antigen-presenting cells that may lead to impaired activation of autoantigen-specific T cells. These data suggest that IRAK1 may play a pathogenic role in AH and that rosoxacin may be an effective drug for AH and other inflammatory diseases involving IRAK1 dysregulation.

楊進木教授研究團隊發表研究成果於Front. Immunol.

連結網址：https://www.frontiersin.org/articles/10.3389/fimmu.2022.1080897/full

Abstract

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 mM) 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 SARSCoV-

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.