Abstract
Rheumatoid arthritis (RA) is a severely debilitating chronic autoimmune disease that leads to long-term joint damage. Signal transducer and activator of transcription 3 (STAT3)-targeted small molecules have shown promise as therapeutic drugs for treating RA. We previously identified (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), a tyrosine-fructose Maillard reaction product, as a small molecule with potent anti-inflammatory and anti-arthritic properties, mediated through the inhibition of STAT3 activation. The aim of this study was to develop a novel BHPH derivative with improved anti-arthritic properties and drug-likeness. We designed and synthesised (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), a novel synthetic BHPB analogue, and investigated its anti-inflammatory and anti-arthritic activities in experimentally-induced RA. We showed that MMPP strongly inhibited pro-inflammatory responses by inhibiting in vitro STAT3 activation and its downstream signalling in murine macrophages and human synoviocytes from patients with RA. Furthermore, we demonstrated that MMPP exhibited potent anti-arthritic activity in a collagen antibody-induced arthritis (CAIA) mouse model in vivo. Collectively, our results suggest that MMPP has great potential for use in the treatment of RA.
Highlights
Rheumatoid arthritis (RA) is a highly debilitating chronic autoimmune disease that leads to long-term joint damage, and often results in chronic pain, swelling, stiffness, loss of physical function, and reduced life expectancy
We initially evaluated the anti-inflammatory activity of newly synthesized BHPB analogues, and compared it with BHPB in RAW264.7 cells, which are a common murine macrophage-like cell line
We found that the LPS-induced production of pro-inflammatory mediators including tumour necrosis factor (TNF)-α, interleukin (IL)-1β,IL-6, prostaglandin E2 (PGE2), hydrogen peroxide (H2O2), and NO (Fig. 1b–g, respectively) in RAW264.7 cells was effectively suppressed by methoxy-4(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) treatment in a concentration-dependent manner, while the cell viability was not affected (Supplementary Fig. S1a)
Summary
Rheumatoid arthritis (RA) is a highly debilitating chronic autoimmune disease that leads to long-term joint damage, and often results in chronic pain, swelling, stiffness, loss of physical function, and reduced life expectancy. We showed that (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), a bioactive compound derived from a tyrosine-fructose Maillard reaction (MR) product[13], effectively inhibits the activation of STAT3 and its downstream signalling pathways by directly binding to its DNA-binding domain. This action mediates the potent therapeutic effects of BHPB against RA14 as well as Alzheimer’s disease[15,16,17], and tumour growth[18,19,20,21,22,23]. MMPP exhibited improved anti-arthritic efficacy in a collagen antibody-induced RA mouse model, with adequate drug-likeness properties
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