Discovery of 9O-Substituted Palmatine Derivatives as a New Class of Anti-COL1A1 Agents Via Repressing TGF-β1/Smads and JAK1/STAT3 Pathways

Abstract

Twenty 9O-substituted palmatine derivatives were prepared and tested for their biological effect against collagen α1 (I) (COL1A1) promotor in human hepatic stellate LX-2 cells. The structure−activity relationship (SAR) indicated that the introduction of a benzyl motif on the 9O atom was favorable for activity. Among them, compound 6c provided the highest inhibitory effect against COL1A1 with an IC50 value of 3.98 μM, and it also dose-dependently inhibited the expression of fibrogenic COL1A1, α-soomth muscle actin (α-SMA), matrix metalloprotein 2 (MMP2) in both mRNA and protein levels, indicating extensive inhibitory activity against fibrogenesis. A further primary mechanism study indicated that it might repress the hepatic fibrogenesis via inhibiting both canonical transforming growth factor-beta 1 (TGF-β1)/Smads and non-canonical janus-activated kinase 1 (JAK1)/singal transducer and activator of transcription 3 (STAT3) signaling pathways. Additionally, 6c owned a high safety profile with the LD50 value of over 1000 mg·kg−1 in mice. These results identified palmatine derivatives as a novel class of anti-fibrogenic agents, and provided powerful information for further structure optimization.

Loss of signal transducer and activator of transcription 3 impaired the osteogenesis of mesenchymal progenitor cells in vivo and in vitro

“…The other down-regulated protein in Stat3 CKO BMSCs was COL1A1, which contributed importantly to bone matrix [32]. Fan and colleagues found that in the human hepatic stellate LX-2 cells, COL1A1 might act as a downstream gene in Jak1/Stat3 signaling pathway [33]. Our ChIP-seq analysis showed Stat3 could bind to the transcription start site of opn and col1a1, but the exact interaction between OPN, COL1A1, and Stat3 needs to be further explored.…”

Network Pharmacology-Based Strategy to Investigate the Pharmacologic Mechanisms of Coptidis Rhizoma for the Treatment of Alzheimer's Disease

“…3,050 enriched BP terms, 257 enriched MF terms, and 184 enriched CC terms. The BP terms mainly include a response to an inorganic substance, positive regulation of cell death, and cellular response to nitrogen compound; the CC terms mostly have membrane raft, neuronal cell body, and neuron spine; Seo et al, 2015;Zhang et al, 2018;Sun et al, 2019 Vanillic acid RELA,MMP2,STAT3 Bhavani et al, 2017;Zhu et al, 2019;Park et al, 2020 Palmatine IL1B, MMP2, TGFB1, STAT3,RELA Yan et al, 2017;Fan et al, 2020; the MF terms mainly involve antioxidant activity, superoxide dismutase activity, oxidoreductase activity. In the MCODE network topology analysis, nine analysis modules were obtained.…”

Loss of signal transducer and activator of transcription 3 impaired the osteogenesis of mesenchymal progenitor cells in vivo and in vitro

“…The other down-regulated protein in Stat3 CKO BMSCs was COL1A1, which contributed importantly to bone matrix [31]. Fan and colleagues found that in the human hepatic stellate LX-2 cells, COL1A1 might act as a downstream gene in Jak1/Stat3 signaling pathway [32]. The exact interaction between OPN, COL1a1, and Stat3 needs to be further explored.…”