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

Abstract

Rheumatoid arthritis (RA) is a known chronic autoimmune disease can cause joint deformity and even loss of joint function. Fibroblast-like synoviocytes (FLS), one of the main cell types in synovial tissues of RA patients, are key effector cells in the development of RA and are considered as promising therapeutic targets for treating RA. Herbal medicines are precious resources for finding novel agents for treating various diseases including RA. It is reported that induction of apoptosis in FLS is an important mechanism for the herbal medicines to treat RA. Consequently, this paper reviewed the current available references on pro-apoptotic effects of herbal medicines on FLS and summarized the related possible signal pathways. Taken together, the main related signal pathways are concluded as death receptors mediated apoptotic pathway, mitochondrial dependent apoptotic pathway, NF-κB mediated apoptotic pathways, mitogen-activated protein kinase (MAPK) mediated apoptotic pathway, endoplasmic reticulum stress (ERS) mediated apoptotic pathway, PI3K-Akt mediated apoptotic pathway, and other reported pathways such as janus kinase/signal transducers and activators of transcription (JAK-STAT) signal pathway. Understanding the apoptosis induction pathways in FLS of these herbal medicines will not only help clear molecular mechanisms of herbal medicines for treating RA but also be beneficial for finding novel candidate therapeutic drugs from natural herbal medicines. Thus, we expect the present review will highlight the importance of herbal medicines and its components for treating RA via induction of apoptosis in FLS, and provide some directions for the future development of these mentioned herbal medicines as anti-RA drugs in clinical.

Keywords: apoptosis; fibroblast-like synoviocytes; herbal medicine; rheumatoid arthritis; signal pathway.

Figure 1

Death receptors mediated apoptotic pathway in FLS induced by herbal medicines.

Figure 2

Mitochondrial dependent apoptotic pathway in fibroblast-like synoviocytes (FLS) induced by herbal medicines.

Figure 3

Mitochondrial dependent apoptotic pathway in FLS induced by herbal medicines.

Figure 4

Mitogen-activated protein kinase (MAPK) mediated apoptotic pathway in FLS induced by herbal medicines.

Figure 5

Endoplasmic reticulum (ER) mediated apoptotic pathway in FLS induced by herbal medicines.

Figure 6

PI3K-Akt mediated apoptotic pathway in FLS induced by herbal medicines.

Figure 7

The related monomers for inducing apoptosis in FLS. Resveratrol (1), Propyl gallate (2), Daphnetin (3), Scopoletin (4), 7, 3′-dimethoxy hesperetin (5), Berberine (6), 5,7,3′-triacetyl hesperetin (TAHP, 7), Andrographolide (8), Gallic acid (9), Celastrol (10), Quercetin (11), Bufalin (12), Tanshinone IIA (13), Oridonin (14), Pristimerin (15), Liquiritin (16), Cryptotanshinone (17), Sinomenine (18), Curcumin (19), 1,7-dihydroxy-3,4-dimethoxyxanthone (XAN, 20), Baicalin (21), Piperlongumine (22), Kaempferitrin (23), Hypericin (24), α-mangostin (25), Diosgenin (26), Hecogenin (27), Tigogenin (28), Apigenin (29), β-Elemene (30), Triptolide (31), Brucine (32), (E)-3-(3,5-dimethoxyphenyl)-1-(1-hydroxynaphthalen-2-yl)-prop-2-en-1-one (DK-59, 33), Genistein (34), Anacardic acid (35), Pectolinarin (36), Matrine (37), 10-Hydroxycamptothecine (10-HCPT, 38), Tamaractam (39), Cis-N-feruloyl-3-O-methylaids (40), Trans-N-feruloyl-3-O-methylaids (41), Wogonin (42), Cinnamic aldehyde (CINA, 43), and Paclitaxel (44).

Figure 8

The different apoptotic pathways of the natural monomers isolated from herbal medicines. 10-HCPT, 10-Hydroxycamptothecine; AGPD, Andrographolide; CFM, cis-n-feruloyl-3-o-methylaids; CINA, Cinnamic aldehyde; DK-59, (E)-3-(3,5-dimethoxyphenyl)-1-(1-hydroxynaphthalen-2-yl)prop-2-en-1-one; DMHP, 7,3′-Dimethoxy Hesperetin; PLM, Piperlongumine; TAHP, 5,7,3′-triacetyl-hesperetin; TFM, trans-n-feruloyl-3-O-methyla; XAN, 1,7-dihydroxy-,4-dimethoxyxanthone.