Pectolinarin inhibits proliferation, induces apoptosis, and suppresses inflammation in rheumatoid arthritis fibroblast‐like synoviocytes by inactivating the phosphatidylinositol 3 kinase/protein kinase B pathway

Abstract

Rheumatoid arthritis fibroblast‐like synoviocytes (RA‐FLSs), a pathological hallmark of rheumatoid arthritis (RA), exhibit the characteristics of tumor cells. The extracts of Cirsium japonicum var. ussuriense have been shown to possess antitumor and anti‐inflammatory activities. Our study aimed to investigate the effects of pectolinarin, a flavonoid compound isolated from C. japonicum var. ussuriense, on RA. Cell viability was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐tetrazolium bromide assay. Apoptosis was determined by flow cytometry analysis and Western blot analysis of Bax and Bcl‐2 levels. Inflammation was assessed by detecting the expressions and secretion of interleukin (IL)‐6 and IL‐8 using quantitative real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay, respectively. The production of nitric oxide (NO) and prostaglandin E2 (PGE2) was also measured. The effects of pectolinarin on the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway were examined by Western blot. We found that pectolinarin significantly inhibited cell viability at 24 and 48 hours in a dose‐dependently manner in RA‐FLSs. Pectolinarin reduced the apoptotic rate, increased Bax level, and decreased Bcl‐2 level in RA‐FLSs. Pectolinarin inhibited the messenger RNA expression and secretion of IL‐6 and IL‐8, as well as the production of PGE2 and NO in RA‐FLSs. Furthermore, pectolinarin inactivated the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) pathway in RA‐FLSs. Activation of the PI3K/Akt pathway by 740Y‐P impaired the effects of pectolinarin on cell viability, apoptosis, and inflammation in RA‐FLSs. In conclusion, pectolinarin suppressed cell proliferation and inflammatory response and induced apoptosis in RA‐FLSs via inactivation of the PI3K/Akt pathway.

Apoptosis Induction of Fibroblast-Like Synoviocytes Is an Important Molecular-Mechanism for Herbal Medicine along with its Active Components in Treating Rheumatoid Arthritis

“…Besides, from the results of Feng et al, Diosgenin (26) (10, 20, and 40 μg/mL) could also result in apoptosis in RA-FLS via regulation of the proteins related to PI3K-Akt signal [135]. In a recent study, Wang et al investigated the effect of Pectolinarin (36) (20 μM) on RA-FLS, and found that besides mitochondrial dependent apoptotic pathway, regulation of PI3K/Akt signaling might be also an important molecular mechanism responding to the apoptosis inducing effects of Pectolinarin [136]. The potential mechanisms of herbal medicine for inducing apoptosis in this part are summarized in Figure 6 and Table 1.…”

Gypenoside Inhibits Endothelial Cell Apoptosis in Atherosclerosis by Modulating Mitochondria through PI3K/Akt/Bad Pathway

“…Based on the close relationship between the PI3K/Akt/Bad pathway and apoptosis, we studied the effect of PI3K in our system. PI3K is a phosphatidylinositol kinase with activities as a serine/threonine-specific protein kinase and a phosphatidylinositol kinase [ 47 , 48 ]. After activation, phosphatidylinositol family members on the cell membrane can be phosphorylated and the downstream signal molecule Akt can be recruited and activated.…”

“…BioMed Research International and a phosphatidylinositol kinase [47,48]. After activation, phosphatidylinositol family members on the cell membrane can be phosphorylated and the downstream signal molecule Akt can be recruited and activated.…”

Isolation and Biological Properties of the Natural Flavonoids Pectolinarin and Pectolinarigenin—A Review

“…A further evaluation of pectolinarigenin as able to inhibit human non-small cell lung cancer cell proliferation, metastasis and epithelial–mesenchymal transition, as well as to promote apoptosis, has also been reported through the PTEN/PI3K/AKT signaling pathway [ 280 ]. The inactivation of the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) pathway was recently observed also for pectolinarin during its study on the capacity to suppress cell proliferation and inflammatory response, and induce apoptosis in rheumatoid arthritis fibroblast-like synoviocytes [ 281 ].…”