Novel synthetic (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol inhibits arthritis by targeting signal transducer and activator of transcription 3

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.

(E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) Phenol Ameliorates MPTP-Induced Dopaminergic Neurodegeneration by Inhibiting the STAT3 Pathway

“…In our study, MMPP inhibited STAT3 DNA binding and transcriptional activity, suggesting that MMPP can inhibit neuroinflammation through inactivation of astrocytes via blocking STAT3-mediated p38 and JNK MAPK pathways. Previously, we reported that MMPP has anti-inflammatory effects in inflammatory disease models such as AD, rheumatoid arthritis, and cancer [29,49,50]. We did not detect any side effects of MMPP with the effective dose of MMPP (5 mg/kg) during treatment for 30 days [29].…”

Periploca forrestii saponin ameliorates CIA via suppressing proinflammatory cytokines and nuclear factor kappa-B pathways

“…Previous studies have reported that STAT3 involved in numerous inflammatory diseases including RA. STAT3 could interact with NF-κB, and concomitant activation of the STAT3 and NF-κB pathways could exacerbate the inflammatory responses such as those for TNF-α and IL-6, which recruit immune cells to the inflamed synovium and pannus [ 37 ]. STAT3 also plays a pivotal role in RANKL-induced osteoclast formation, a delicately controlled balance by a bioavailable molecule can attenuate RANKL-induced osteoclastogenesis by blocking both NF-κB and STAT3 activity [ 38 ].…”

Targeting IgG in Arthritis: Disease Pathways and Therapeutic Avenues

“…At the effector level of arthritis, apart from targeting effector molecules, like C5 [ 67 , 153 ] and its break down product C5a [ 65 , 154 , 155 ], receptors (FcRs [ 156 ], TLRs [ 157 ]), transcription factors [ 158 , 159 ]), and cytokines, using different strategies and drugs [ 160 , 161 , 162 ], methods for direct targeting of pathogenic IgG antibodies could be attractive and optimal for therapeutic applications.…”