Inhibition of human rheumatoid arthritis synovial cell survival by hecogenin and tigogenin is associated with increased apoptosis, p38 mitogen-activated protein kinase activity and upregulation of cyclooxygenase-2

Abstract

Abstract. We conducted our study to assess the antiproliferative and proapoptotic potential of hecogenin and tigogenin, two saponins which are structurally similar to diosgenin. We particularly focused our attention on mitogenactivated protein kinase (MAPK) activation in relation to apoptosis but also with the COX-2 expression and activity. Rheumatoid arthritis (RA) synoviocytes were isolated from fresh synovial biopsies obtained from five RA patients undergoing hip arthroplasty. Measurement of cell proliferation was determined using the MTT assay. Apoptosis was evaluated by studying caspase-8, caspase-9 and caspase-3 activities but also by quantification of DNA fragmentation. Quantification of human phospho-MAPKs was realized by ELISA. COX-2 expression was demonstrated by Western blot analysis and COX-2 activity by assay of endogenous prostaglandin E 2 (PGE 2 ) production. Tigogenin was more effective than hecogenin in inducing apoptosis in human RA fibroblast-like synoviocytes (FLS) which was caspase dependent but poly(ADP-ribose) polymerase independent and characterized by DNA fragmentation. Our results demonstrated hecogenin-and tigogenin-induced apoptosis through activation of p38 without affecting the JNK and ERK pathways. Indeed, pretreatment with a p38 inhibitor decreased saponin-induced apoptosis with a significant decrease in DNA fragmentation. Furthermore, the rate of apoptosis induced by hecogenin or tigogenin was associated with overexpression of COX-2 correlated with overproduction of endogenous PGE 2 . These new results provide strong evidence that a family of structurally similar plant steroids is capable of inducing apoptosis in human RA FLS with different rates and different signalling pathways. This study also confirms the discussed appearance of the downregulation or upregulation of COX-2 in cell apoptosis as a function of cell type. IntroductionPlant steroids have been thoroughly described for their pharmacological properties, including hypocholesterolemic (1), antidiabetic (2) and antioxidant activities (3,4). Particular attention has been given to their potential for cancer chemoprevention, especially as apoptosis inducers (5-10).Apoptosis is considered to be one of the mechanisms regulating autoimmune diseases such as rheumatoid arthritis (RA) (11). In the pathogenesis of RA, it is thought that the normal balance between proliferation and apoptosis of synovial fibroblasts is lost, leading to hyperplasia of these fibroblasts (12). Activated synovial cells cause growth of synovium in the articular cavity along with angiogenesis, invade the adjacent bone, promote production of inflammatory mediators by inflammatory cells, and cause cartilage and bone destruction (13). Therefore, it has been shown that stimulation of apoptosis in synovial fibroblasts might be useful for the treatment of RA (14,15).We showed for the first time that a plant steroid, diosgenin, inhibited the growth of human RA fibroblast-like synoviocytes (FLS) with apoptosis induction characterized by a loss of mitochondrial me...

Effects of hecogenin and its possible mechanism of action on experimental models of gastric ulcer in mice

“…On the other hand, there are very few studies showing the anti-inflammatory activity of hecogenin (Peana et al, 1997) and none on its gastroprotection. Most of the literature data focus on diosgenin, also a steroidal sapogenin as hecogenin (Liagre et al, 2005(Liagre et al, , 2007a(Liagre et al, , 2007bMoalic et al, 2001;Shishodia and Aggarwal, 2006). Thus, the present study demonstrates, for the first time, the antiulcer property of hecogenin from A. sisalana, on experimental models of gastric ulceration in mice.…”

Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models

“…These results strongly suggest that MAPK pathways are closely involved in flavonol-rich RVHxR induced antiangiogenic process and likely upstream of VEGF expression. Considering that p38 MAPK is generally activated by genotoxic agents or apoptosis [36][37][38], activation of p38 MAPK by flavonolrich RVHxR may be associated with the apoptosis of RA FLS during antiangiogenic process.…”

β-Elemene induces apoptosis of human rheumatoid arthritis fibroblast-like synoviocytes via reactive oxygen species-dependent activation of p38 mitogen-activated protein kinase

“…Another study by the research 260 group showed that hecogenin-and tigogenin-induced apoptosis of 261 RA-FLS is mediated through activation of p38 without affecting the 262 JNK and ERK pathways [26]. Activation of the p38 MAPK pathway 263 has been found to stimulate the expression of Cyr61, which 264 protects RA-FLS from apoptosis [27].…”