Norisoboldine induces apoptosis of fibroblast-like synoviocytes from adjuvant-induced arthritis rats.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by pronounced synovial inflammation and hyperplasia, in which there may be an imbalance between the growth and death of fibroblast-like synoviocytes (FLS). Norisoboldine (NOR), the main active constituent in the alkaloid fraction isolated from Radix Linderae, was previously demonstrated to alleviate arthritis severity in experimental RA. This study aimed to evaluate the effects of NOR on proliferation and apoptosis of FLS from adjuvant-induced arthritis (AIA) rats to elucidate the mechanism of its inhibitory effect on inflammatory synovial hyperplasia in RA. Our results indicated that NOR exhibited a pro-apoptotic effect on AIA FLS but only slightly affected cell proliferation and the cell cycle. Following treatment with NOR for 24h, the activation of caspase 3 and caspase 9 and the cleavage of poly (ADP-ribose) polymerase (PARP) in AIA FLS were observed; however, caspase 8 remained unaffected. Meanwhile, a flow cytometric assay revealed that NOR significantly increased the percentage of apoptotic cells, causing the loss of the depolarized mitochondrial membrane potential and the release of cytochrome C. The expression of Bax and Bcl-2 was also regulated by NOR treatment. Additionally, the expression of p53 protein was up-regulated by NOR, and pretreatment with PFT-α, a p53 specific inhibitor, reversed the increase in FLS apoptosis caused by NOR. These findings indicated that NOR-induced apoptosis in AIA FLS is achieved via a mitochondrial-dependent pathway, which may be mediated by promoting the release of cytochrome C and by regulating the expression of Bax and Bcl-2 proteins, and p53 might also be required for NOR-induced apoptosis in AIA FLS.

• Authors: Yubin Luo, Zhifeng Wei, Guixin Chou, Zhengtao Wang, Yufeng Xia, Yue Dai
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 20 Issue 1 Pg. 110-6 (May 2014) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 24613208 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• Alkaloids
• Bax protein, rat
• Proto-Oncogene Proteins c-bcl-2
• Tumor Suppressor Protein p53
• bcl-2-Associated X Protein
• norisoboldine
• Cytochromes c
• Poly(ADP-ribose) Polymerases
• Casp3 protein, rat
• Casp9 protein, rat
• Caspase 3
• Caspase 9

Topics

• Alkaloids (pharmacology)
• Animals
• Apoptosis (drug effects)
• Arthritis, Experimental (metabolism)
• Caspase 3 (metabolism)
• Caspase 9 (metabolism)
• Cell Cycle (drug effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cytochromes c (metabolism)
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Poly(ADP-ribose) Polymerases (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Rats, Sprague-Dawley
• Synovial Membrane (cytology)
• Tumor Suppressor Protein p53 (metabolism)
• bcl-2-Associated X Protein (metabolism)