Emodin Inhibits Proinflammatory Responses and Inactivates Histone Deacetylase 1 in Hypoxic Rheumatoid Synoviocytes

Ha, Mi-Kyoung; Song, Young Hoon; Jeong, Soo‐Jin; Lee, Hyo‐Jung; Jung, Ji Hoon; Kim, Bonglee; Song, Hae Jun; Huh, Jungwon

doi:10.1248/bpb.34.1432

Cited by 71 publications

(41 citation statements)

References 45 publications

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“…In fact, rhein, the active metabolite of acetylrhein, is the predominant form found in bloodstream that possesses potent bioactivities in mammals including rodents, rabbits and human [39]. The pharmacological actions of this anthraquinone derivative have been lately evidenced in various inflammatory diseases such as arthritis [31,40] and dermatological disorders [41]. A recent study by He et al demonstrated that rhein could effectively inhibit the activation of renal interstitial fibroblasts in mice [35] implicating its potential in targeting fibrogenesis.…”

Section: Discussionmentioning

confidence: 99%

Rhein, a Natural Anthraquinone Derivative, Attenuates the Activation of Pancreatic Stellate Cells and Ameliorates Pancreatic Fibrosis in Mice with Experimental Chronic Pancreatitis

et al. 2013

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Pancreatic fibrosis, a prominent histopathological feature of chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma, is essentially a dynamic process that leads to irreversible scarring of parenchymal tissues of the pancreas. Though the exact mechanisms of its initiation and development are poorly understood, recent studies suggested that the activation of pancreatic stellate cells (PSCs) plays a critical role in eliciting such active course of fibrogenesis. Anthraquinone compounds possess anti-inflammatory bioactivities whereas its natural derivative rhein has been shown to effectively reduce tissue edema and free-radical production in rat models of inflammatory conditions. Apart from its anti-inflammatory properties, rhein actually exerts strong anti-fibrotic effects in our current in-vivo and in-vitro experiments. In the mouse model of cerulein-induced CP, prolonged administration of rhein at 50 mg/kg/day significantly decreased immunoreactivities of the principal fibrotic activators alpha-smooth muscle actin (α-SMA) and transforming growth factor-beta (TGF-β) on pancreatic sections implicating the activation of PSCs, which is the central tread to fibrogenesis, was attenuated. Consequently, the overwhelmed deposition of extracellular matrix proteins fibronectin 1 (FN1) and type I collagen (COL I-α1) in exocrine parenchyma was found accordingly reduced. In addition, the expression levels of sonic hedgehog (SHH), which plays important roles in molecular modulation of various fibrotic processes, and its immediate effector GLI1 in pancreatic tissues were positively correlated to the degree of cerulein-induced fibrosis. Such up-regulation of SHH signaling was restrained in rhein-treated CP mice. In cultured PSCs, we demonstrated that the expression levels of TGF-β-stimulated fibrogenic markers including α-SMA, FN1 and COL I-α1 as well as SHH were all notably suppressed by the application of rhein at 10 μM. The present study firstly reported that rhein attenuates PSC activation and suppresses SHH/GLI1 signaling in pancreatic fibrosis. With strong anti-fibrotic effects provided, rhein can be a potential remedy for fibrotic and/or PSC-related pathologies in the pancreas.

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Section: Discussionmentioning

confidence: 99%

Rhein, a Natural Anthraquinone Derivative, Attenuates the Activation of Pancreatic Stellate Cells and Ameliorates Pancreatic Fibrosis in Mice with Experimental Chronic Pancreatitis

et al. 2013

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“…(21) Emodin isolated from the root of Rheum palmatum L. inhibited pro-inflammatory responses and inactivated histone deacetylase 1 (HDAC1) in hypoxic rheumatoid synoviocytes. (33) To the best of my knowledge, some groups reported anti-inflammatory activity of fisetin. Geraets et al reported that fisetin showed significant anti-inflammatory effect in a mouse model with LPS-induced acute pulmonary inflammation compared to tricetin, one of dietary flavonoids.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of c-Jun N-terminal kinase and nuclear factor κ B pathways mediates fisetin-exerted anti-inflammatory activity in lipopolysccharide-treated RAW264.7 cells

Kim

Kang

Jeong

et al. 2012

Immunopharmacology and Immunotoxicology

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Although fisetin, a natural flavonoid, was known to inhibit proliferation, carcinogenesis and inflammation, the underlying anti-inflammatory mechanism of fistein still remains unclear. Thus, in the present study, the anti-inflammatory mechanism of fisetin was investigated in association with mitogen-activated protein kinase (MAPK) and nuclear factor κ B (NF-κB) pathways in lipopolysaccharide (LPS)-stimulated RAW264.7 mouse macrophages. We found that fisetin significantly reduced the nitrate oxide (NO) production and also inhibited the expression of pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) at protein and mRNA levels in LPS-stimulated cells. Consistently, fisetin significantly reduced the LPS-stimulated secretion of proinflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor α (TNF-α). Furthermore, fisetin suppressed the activation of nuclear factor κ B (NF-κB) and the phosphorylation of c-Jun N-terminal kinase (JNK), but not extracellular signal regulated kinase (ERK) and p38 MAPK in LPS-treated RAW264.7 cells. Overall, our findings demonstrate that fisetin exerted anti-inflammatory activity via inactivation of JNK and NF-κB in LPS-stimulated macrophage cells.

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“…MMP-1, which is mainly synthesized by chondrocytes and fibroblasts in joint tissues afflicted with RA, is the most abundant member of the MMP-family, while MMP-13 efficiently cleaves the major component of the cartilage matrix type II collagen. MMP-1 and MMP-13 are both overexpressed in inflammatory arthritis cartilage and rate-limit the process of collagen degradation [39,40] . Cyclooxygenase (COX)-dependent prostaglandin E 2 (PGE 2 ), the major prostaglandin found in the synovial fluid of RA patients, is also closely associated with the remodeling of cartilage and bone.…”

Section: Discussionmentioning

confidence: 99%

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression

et al. 2013

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Aim: To explore the effects of norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms. Methods: AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR. Results: In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE 2 , and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE 2 , and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1 significantly decreased the secretion of RANKL, IL-6, PGE 2 , and MMP-13 proteins. Conclusion: NOR can alleviate joint destruction in AIA rats by reducing RANKL, IL-6, PGE 2 , and MMP-13 expression via the p38/ERK/ AKT/AP-1 pathway.

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Emodin Inhibits Proinflammatory Responses and Inactivates Histone Deacetylase 1 in Hypoxic Rheumatoid Synoviocytes

Cited by 71 publications

References 45 publications

Rhein, a Natural Anthraquinone Derivative, Attenuates the Activation of Pancreatic Stellate Cells and Ameliorates Pancreatic Fibrosis in Mice with Experimental Chronic Pancreatitis

Rhein, a Natural Anthraquinone Derivative, Attenuates the Activation of Pancreatic Stellate Cells and Ameliorates Pancreatic Fibrosis in Mice with Experimental Chronic Pancreatitis

Inhibition of c-Jun N-terminal kinase and nuclear factor κ B pathways mediates fisetin-exerted anti-inflammatory activity in lipopolysccharide-treated RAW264.7 cells

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression

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