Encyclopedia
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects:
Pathology
|
Biochemistry & Molecular Biology
Osteoarthritis (OA) is a most common type of arthritis occur in the aged population. It affects any joint in the body and degenerates the articular cartilage and subchondral bone. Despite the pathophysiology of OA is different, still cartilage resorption is a symbol of osteoarthritis. Matrix metalloproteinases (MMPs) are important proteolytic enzymes that degrade extra-cellular matrix proteins (ECM) in the body. MMPs contribute to the turnover of cartilage and its break down; their levels have increased in the joint tissues of OA patients. Application of chondroprotective drugs neutralize the activities of MMPs. Natural products derived from herbs and plants developed as traditional medicine have paid much attention due to their potential biological effects. Therapeutic value of natural products in OA has increased reputation by presenting clinical impact with insignificant side effects. Several MMPs inhibitor have been used as therapeutic drugs for long time. Recently, different types of compounds have been reviewed for their biological activities. In this review, we summarize numerous natural products for the development as MMPs inhibitors in arthritic diseases and describe the major signaling targets that involved for the treatments of these destructive joint diseases.
- arthritis
- MMPs
- natural products
- chondroprotection
- signaling pathways
1. Definition
Osteoarthritis (OA) is the most common type of joint disease that affect millions of people worldwide and it primarily cause disability in the aged population, affecting about 80% of individuals over the age of 75 [1]. Increased damage of cartilage degradation is the hallmark of this destructive joint disease. In the cartilage matrix, proteoglycan and collagen exist as major elements, and damage of proteoglycan could induce cartilage degeneration [2], followed by the catabolism of collagen fibrils, which increases the loss of cartilage structural integrity [3]. Matrix metalloproteinases (MMPs)-induced cartilage degeneration is controlled by endogenous tissue inhibitors of metalloproteinase (TIMPs) [4], and the disproportion in the ratio of TIMPs and MMPs could lead to a persistent matrix destruction in OA [5]. It was proposed that MMPs inhibition should be considered a therapeutic strategy in preventing cartilage degradation, which occurs in the arthritic process [6]. Although several inhibitors of the MMPs have been proposed as important therapeutic agents, there is a lack of evidence related to the inhibition of MMPs by natural compounds for chondroprotection in the destructive joint diseases.
2. MMPs and Osteoarthritis
Matrix metalloproteinases are proteolytic enzymes that restore and degrade extracellular matrix (ECM) proteins and their components. MMPs enzymes break down cartilages and their levels are elevated in joint tissues of patients with rheumatoid arthritis (RA) and OA [7]. Joint inflammation and joint degenerative diseases are associated with increased level of MMPs; so far, 23 MMP proteins have identified in humans [8]. Chondrocytes are vital cells that exist in the cartilage and are mostly accountable for affecting ECM in joint space. Chondrocytes synthesize collagen type II and aggrecan, which are similar to ECM and secrete proteolytic MMPs.
Collagenases, such as MMP-1 and 13 are highly degraded collagens in the cartilage and bone. In osteoarthritis, the components of cartilage matrix are hydrolyzed quickly and results in cartilage degradation. Collagenase-1 (MMP1) exists in various cells, including chondrocytes [9]. MMP13 (collagenase-3) majorly induce collagen degrading activity, especially of type II collagen [10], and this enzyme plays a major role in the degradation of cartilage. Various MMP inhibitors were established and verified for potential clinical use [11]. Moreover, MMP-13 expression co-express with CII degradation in OA lesions, indicating that this enzyme exerts a pivotal role in cartilage degradation in OA [12]. Moreover, immunohistochemistry has revealed the presence of MMP13-specific type II collagen degradation products and MMP13 enzymes in OA cartilage [13,14]. Though MMPs1, 8, and 13 have reported the only mammalian enzymes that degrade native fibrillary collagen types I, II, and III, other MMPs, including MMP2 and MMP14 also possess this activity [15,16]. The collagenases enzyme MMP2 and MMP9 degrade type IV collagen, gelatin, and elastin, which are complicated in joint diseases [17].
3. Inflammatory Cytokines in Osteoarthritic Chondrocytes
Inflammatory cytokines are the most important class of compounds contributing to the pathogenesis of OA. In the cartilages, interleukin-1β (IL-1) and tumor necrosis factor-α (TNF) were shown to induce of MMPs 1, 3, 9, and 13 expression [18], and these cytokines are found to be a suitable model in the human SW1353 chondrosarcoma cell line that is compatible with primary chondrocytes in OA [19]. Interleukin-1β stimulates the release of degenerative MMPs enzymes from chondrocytes and synoviocytes, and extracellular matrix proteins in chondrocytes [20]. IL-1β is also involved in the osteoclastogenesis and bone resorption, which is augmented in rheumatoid arthritis (RA) joints [21]. Apoptotic chondrocyte death in articular cartilage was observed in clinical specimens from RA and OA cartilages [22]. A previous study reported that anti-TNF-α treatment with a TNF antibody, gives a continued reduction of pain symptoms in OA [23], therefore, antagonists to TNF-α might serve as a potential beneficial strategy to decrease OA pain in patients [24].
Interleukin (IL)-1 is one of the most essential degrading cytokines secreted by chondrocytes in arthritic joint disease [25]. Augmented levels of IL-1 were noticed in synovial fluids from RA and OA patients [26], and its over expression in osteoarthritic cartilage tissue was also reported by Teslow et al. [13]. A high level of IL-1 receptor type 16 was observed in osteoarthritic chondrocytes, compared to normal chondrocytes, and inhibitors of IL-1 converting enzyme, a protease crucial for IL-1β processing, was found to reduce collagen-induced arthritis [27]. Moreover, opposing data were noted in a potential up- and down-regulation of IL-1β, in osteoarthritic cartilage [28]. IL-1 was reported to produce excessive effects in chondrocytes, including (i) a major reduction in the expression of collagen type II [29]; (ii) over expression of MMP-1, 3, and 13 [30]; and (iii) solid stimulation of intercellular mediators like leukemia inhibitory factor and IL-6. Interleukin-6, another well-recognized cytokine involved in cartilage degradation, was reported to connect with hyperalgesia and hypersensitivity in joint tissues [31]. This cytokine played a vital role in the progression of RA, as its level was found to increase in the serum and synovial fluid of arthritic patients [32]. Interleukin-6 reacted remarkably to primary afferent neurons [33], and hence it could play a role in pain transmission in arthritic states. In the skeleton system, IL-6 triggers osteoclasts and stimulates the synovium to produce MMPs that are responsible for degrading cartilage in OA [34]. Therefore, inhibiting IL-6 over-expression in synovial fibroblasts (SF) is believed to be an auspicious method to prevent OA progression, in which the clarification of molecular mechanisms underlying IL-6 over-expression in SF is essential.
4. Conclusions and Future Direction on Therapy for Osteoarthritis
A conservative controlling of osteoarthritis cannot discourse the major cause of the disease, when the application of agents is used alone. Additionally, these agents are not acceptable for long-term control of osteoarthritis, as they display major side effects. In contrast, varieties of natural products show protective effects against proinflammatory cytokine-induced expression and the catabolic activity of MMPs in articular cartilage, via the regulation of the NF-κB signaling pathway. Natural products exhibited inhibitive effects on the apoptosis in chondrocytes, and decline in the production of the ECM in articular cartilage. Nevertheless, although several preclinical and clinical studies are directed so far in natural product chemistry, still there are no perfect natural products recommended as an antagonist to the progression of the symptoms of osteoarthritis. This review might provide absolute readings about how natural compounds are beneficial for the treatments of joint diseases. Additionally, the information of the chondroprotective mechanism of natural substances would afford new opportunities to promote therapeutic strategies projected at encouraging destructive joint disorders.
References
1. Brosseau, L.; Wells, G.A.; Kenny, G.P.; Reid, R.; Maetzel, A.; Tugwell, P.; Huijbregts, M.; McCullough, C.;
De Angelis, G.; Chen, L. The implementation of a community‐based aerobic walking program for mild to
moderate knee osteoarthritis (OA): A knowledge translation (KT) randomized controlled trial (RCT): Part
II: Clinical outcomes. BMC Public Health 2012, 12, 1073–1088.
2. Mankin, H.J.; Lippiello, L. Biochemical and Metabolic Abnormalities in Articular Cartilage from Osteo‐
Arthritic Human Hips. J. Bone Joint Surg. Am. 1970, 52, 424–434.
3. Jubb, R.W.; Fell, H.B. The breakdown of collagen by chondrocytes. J. Pathol. 1980, 130, 59–167.
4. Burger, D.; Rezzonico, R.; Li, J.M.; Modoux, C.; Pierce, R.A.; Welgus, H.G.; Dayer, J.M. Imbalance between
interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon
direct contact with stimulated T lymphocytes: Involvement of membrane‐associated cytokines. Arthritis
Rheum. 2004, 41, 1748–1759.
5. Lin, N.; Liu, C.; Xiao, C.; Jia, H.; Imada, K.; Wu, H.; Ito, A. Triptolide, a diterpenoid triepoxide, suppresses
inflammation and cartilage destruction in collagen‐induced arthritis mice. Biochem. Pharmacol. 2007, 73,
136–146.
6. Brinckerhoff, C.E. Joint destruction in arthritis: Metalloproteinases in the spotlight. Arthritis. Rheum. 1991,
34, 1073–1075.
7. Abeles, A.M.; Pillinger, M.H. The role of the synovial fibroblast in rheumatoid arthritis‐cartilage
destruction and the regulation of matrix metalloproteinases. Bull. NYU Hosp. Joint Dis. 2006, 64, 20–24.
8. Hadler‐Olsen, E.; Fadnes, B.; Sylte, I.; Uhlin‐Hansen, L.; Winberg, J.O. Regulation of matrix
metalloproteinase activity in health and disease. FEBS J. 2011, 278, 28–45.
9. Shlopov, B.V.; Lie, W.R.; Mainardi, C.L.; Cole, A.A.; Chubinskaya, S.; Hasty, K.A. Osteoarthritic lesions:
Involvement of three different collagenases. Arthritis Rheum. 1997, 40, 2065–2074.
10. Knauper, V.; Cowell, S.; Smith, B.; Lopez‐Otin, C.; O’Shea, M.; Morris, H.; Zardi, L.; Murphy, G. The role
of the C‐terminal domain of human collagenase‐ 3 (MMP‐13) in the activation of procollagenase‐3,
substrate specificity, and tissue inhibitor of metalloproteinase interaction. J. Biol. Chem. 1997, 272, 7608–
7616.
11. Cawston, T.E.; Wilson, A.J. Understanding the role of tissue degrading enzymes and their inhibitors in
development and disease. Best Pract. Res. Clin. Rheumatol. 2006, 20, 983–1002.
12. Mitchell, P.G.; Magna, H.A.; Reeves, L.M.; Lopresti‐Morrow, L.L.; Yocum, S.A.; Rosner, P.J.; Geoghegan,
K.F.; Hambor, J.E. Cloning, expression and type II collagenolytic activity of matrix metalloproteinase‐13
from human osteoarthritic cartilage. J. Clin. Invest. 1996, 97, 761–768.
13. Teslow, L.C.; Adlam, D.J.; Woolley, D.E. Matrix metalloproteinase and proinflammatory cytokine
production by chondrocytes of human osteoarthritic cartilage. Arthritis Rheum. 2001, 44, 585–594.
14. Wu, W.; Billinghurst, R.C.; Pidour, I.; Antoniou, J.; Zukor, D.; Tanzer, M.; Poole, A.R. Sites of collagenase
cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their
relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis
Rheum. 2002, 46, 2087–2094.
15. Konttinen, Y.T.; Ceponis, A.; Takagi, M.; Ainola, M.; Sorsa, T.; Sutinen, M.E.; Salo, T.; Ma, J.; Santavirta, S.;
Seiki, M. New collagenolytic enzymes cascade identified at the pannus–hard tissue junction in rheumatoid
arthritis: Destruction from above. Matrix Biol. 1998, 17, 585–601.
16. Ohuchi, E.; Imai, K.; Fujii, Y.; Sato, H.; Seiki, M.; Okada, Y. Membrane type 1 matrix metalloproteinase
digests interstitial collagens and other extracellular matrix macromolecules. J. Biol. Chem. 1997, 272, 2446–
2451.
17. Konttinen, Y.T.; Ainola, M.; Valleala, H.; Ma, J.; Ida, H.; Mandelin, J.; Kinne, R.W.; Santavirta, S.; Sorsa, T.;
López‐Otín, C.; et al. Analysis of 16 different matrix metalloproteinases (MMP‐1 to MMP‐20) in the synovial
membrane: Different profiles in trauma and rheumatoid arthritis. Ann. Rheum. Dis. 1999, 58, 691–697.
18. Mengshol, J.A.; Vincenti, M.P.; Coon, C.I.; Barchowsky, A.; Brinckerhoff, C.E. Interleukin‐1 induction of
collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c‐Jun N‐terminal
kinase, and nuclear factor kappaB: Differential regulation of collagenase 1 and collagenase 3. Arthritis
Rheum. 2000, 43, 801–811.
19. Shi, J.; Schmitt‐Talbot, E.; Dimattia, D.A.; Dullea, R.G. The differential effects of IL‐1 and TNF‐alpha on
proinflammatory cytokine and matrix metalloproteinase expression in human chondrosarcoma cells.
Inflamm. Res. 2004, 53, 377–389.
20. Malemud, C.J.; Islam, N.; Haqqi, T.M. Pathophysiological mechanisms in osteoarthritis lead to novel
therapeutic strategies. Cells Tissues Organs 2003, 174, 34–48.
21. Jimi, E.; Aoki, K.; Saito, H.; D’Acquisto, F.; May, M.J.; Nakamura, I.; Suda, T.; Kojima, T.; Okamoto, F.;
Fukushima, H.; et al. Selective inhibition of NF‐κB blocks osteoclastogenesis and prevents inflammatory
bone destruction in vivo. Nat. Med. 2004, 10, 617–624.
22. Héraud, F.; Héraud, A.; Harmand, M.F. Apoptosis in normal and osteoarthritic articular cartilage. Ann.
Rheum. Dis. 2000, 59, 959–965.
23. Grunke, M.; Schulze‐Koops, H. Successful treatment of inflammatory knee osteoarthritis with tumour
necrosis factor blockade. Ann. Rheum. Dis. 2006, 65, 555–556.
24. Dray, A.; Read, S.J. Arthritis and Pain. Future Targets to Control Osteoarthritis Pain. Arthritis Res. Ther.
2007, 9, 212.
25. Goldring, M.B. Osteoarthritis and cartilage: The role of cytokines. Curr. Rheumatol. Rep. 2000, 2, 459–465.
26. Westacott, C.I.; Sharif, M. Cytokines in osteoarthritis: mediators or markers of joint destruction? Semin.
Arthritis Rheum. 1996, 25, 254–272.
27. Ku, G.; Faust, T.; Lauffer, L.L.; Livingston, D.J.; Harding, M.W. Interleukin‐1_ converting enzyme inhibition
blocks progression of type II collageninduced arthritis in mice. Cytokine 1996, 8, 377–386.
28. Murata, M.; Trahan, C.; Hirahashi, J.; Mankin, H.J.; Towle, C.A. Intracellular interleukin‐1 receptor
antagonist in osteoarthritis chondrocytes. Clin. Orthop. Relat. Res. 2003, 409, 285–295.
29. Richardson, D.W.; Dodge, G.R. Effects of interleukin‐1β and tumor necrosis factor‐α on expression of
matrix‐related genes by cultured equine articular chondrocytes. Am. J. Vet. Res. 2000, 61, 624–630.
30. Bau, B.; Gebhard, P.M.; Haag, J.; Knorr, T.; Bartnik, E.; Aigner, T. Relative messenger RNA expression
profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis
Rheum. 2002, 46, 2648–2657.
31. Brenn, D.; Richter, F.; Schaible, H. Sensitization of unmyelinated sensory fibers of the joint nerve to
mechanical stimuli by interleukin‐6 in the rat: An inflammatory mechanism of joint pain. Arthritis Rheum.
2007, 56, 351–359.
32. Silacci , P.; Dayer, J.M.; Desgeorges, A.; Peter, R.; Manueddu, C.; Guerne, P.A. Interleukin (IL)‐6 and its
soluble receptor induce TIMP‐1 expression in synoviocytes and chondrocytes, and block IL‐1‐induced
collagenolytic activity. J. Biol. Chem. 1998, 273, 13625–13629.
33. Obreja, O.; Biasio, W.; Andratsch, M.; Lips, K.S.; Rathee, P.K.; Ludwig, A.; Rose‐John, S.; Kress, M. Fast
modulation of heat‐activated ionic current by proinflammatory interleukin 6 in rat sensory neurons. Brain
2005, 128, 1634–1641.
34. Sakao, K.; Takahashi, K.A.; Arai, Y.; Saito, M.; Honjo, K.; Hiraoka, N.; Asada, H.; Shin‐Ya, M.; Imanishi, J.;
Mazda, O.; et al. Osteoblasts derived from osteophytes produce interleukin‐6, interleukin‐8, and matrix
metalloproteinase‐13 in osteoarthritis. J. Bone Miner. Metab. 2009, 27, 412–423.
35. Goel, G.; Makkar, H.P.S.; Francis, G.; Becker, K. Phorbol esters: Structure, biological activity, and toxicity
in animals. Int. J. Toxicol. 2007, 26, 279–288.
36. Moore, A.R.; Iwamura, H.; Larbre, J.P.; Scott, D.L.; Willoughby, D.A. Cartilage degradation by
polymorphonuclear leucocytes: In vitro assessment of the pathogenic mechanisms. Ann. Rheum. Dis. 1993,
52, 27–31.
37. Lu, Y.C.; Jayakumar, T.; Duann, Y.F.; Chou, Y.C.; Hsieh, C.Y.; Yu, S.Y.; Sheu, J.R.; Hsiao, G.
Chondroprotective role of sesamol by inhibiting MMPs expression via retaining NF‐KB signaling in
activated SW1353 cells. J. Agric. Food Chem. 2011, 59, 4969–4978.
38. Aigner, T.; Cook, J.L.; Gerwin, N.; Glasson, S.S.; Laverty, S.; Little, C.B.; McIlwraith, W.; Kraus, V.B.
Histopathology atlas of animal model systems—overview of guiding principles. Osteoarthr. Car. 2010, 18,
S2–S6.
39. Takahashi, I.; Matsuzaki, T.; Hoso, M. Long‐term histopathological developments in knee‐joint
components in a rat model of osteoarthritis induced by monosodium iodoacetate. J. Phys. Ther. Sci. 2017,
27, 590–597.
40. Bove, S.E.; Calcaterra, S.L.; Brooker, R.M.; Huber, C.M.; Guzman, R.E.; Juneau, P.L.; Schrier, D.J.; Kilgore,
K.S. Weight bearing as a measure of disease progression and efficacy of anti‐inflammatory compounds in
a model of monosodium iodoacetate‐induced osteoarthritis. Osteoarth. Cart. 2003, 11, 821–830.
41. Kobayashi, K.; Imaizumi, R.; Sumichika, H.; Tanaka, H.; Goda, M.; Fukunari, A.; Komatsu, H. Sodium
iodoacetate‐induced experimental osteoarthritis and associated pain model in rats. J. Veter. Med. Sci. 2003,
65, 1195–1199.
42. Guzman, R.E.; Evans, M.G.; Bove, S.; Morenko, B.; Kilgore. K. Mono‐iodoacetate‐induced histologic
changes in subchondral bone and articular cartilage of rat femorotibial joints: An animal model of
osteoarthritis. Toxicol. Pathol. 2003, 31, 619–624.
43. Janusz, M.J.; Hookfin, E.B.; Heitmeyer, S.A.; Woessner, J.F.; Freemont, A.J.; Hoyland, J.A.; Brown, K.K.;
Hsieh, L.C.; Almstead, N.G.; De, B.; et al. Moderation of iodoacetate‐induced experimental osteoarthritis
in rats by matrix metalloproteinase inhibitors. Osteoarth. Cartil. 2001, 9,751–760.
44. Udo, M.; Muneta, T.; Tsuji, K.; Ozeki, N.; Nakagawa, Y.; Ohara, T.; Saito, R.; Yanagisawa, K.; Koga, H.;
Sekiya, I. Monoiodoacetic acid induces arthritis and synovitis in rats in a dose‐ and time‐dependent
manner: Proposed model‐specific scoring systems. Osteoarth. Cartil. 2016, 24, 1284–1291.
45. Lampropoulou‐Adamidou, K.; Lelovas, P.; Karadimas, E.V.; Liakou, C.; Triantafillopoulos, I.K.; Dontas, I.;
Papaioannou, N.A. Useful animal models for the research of osteoarthritis. Eur. J. Orthop. Surg. Traumatol.
2014, 24, 263–271.
46. Nolan, G.P.; Baltimore, D. The inhibitory ankyrin and activator Rel proteins. Curr. Opin. Genet. Dev. 1992,
2, 211–220.
47. Baeuerle, P.A.; Henkel, T. Function and activation of NF‐kappa B in the immune system. Annu. Rev.
Immunol. 1994, 12, 141–179.
48. Siebenlist, U.; Franzo, G.; Brown, K. Structure, regulation and function of NF‐kappa B. Annu. Rev. Cell Biol.
1994, 10, 405–455.
49. Grilli, M.; Chiu, J.J.S.; Lenardo, M.J. NF‐kappa B and Rel: Participants in a multiform transcriptional
regulatory system. Int. Rev. Cytol. 1993, 143, 1–62.
50. Goldring, M.B.; Goldring, S.R. Osteoarthritis. J. Cell. Physiol. 2007, 213, 626–634.
51. Roman‐Blas, J.A.; Jimenez, S.A. NF‐κB as a potential therapeutic target in osteoarthritis and rheumatoid
arthritis. Osteoarth. Cartil. 2006, 14, 839–848.
52. Yeung, F.; Hoberg, J.E.; Ramsey, C.S.; Keller, M.D.; Jones, D.R.; Frye, R.A.; Mayo, M.W. Modulation of NFkappaB‐
dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004, 23, 2369–2380.
53. Calao, M.; Burny, A.; Quivy, V.; Dekoninck, A.; Van Lint, C. A pervasive role of histone acetyltransferases
and deacetylases in an NF‐kappaB‐signaling code. Trends Biochem. Sci. 2008, 33, 339–349.
54. Spange, S.; Wagner, T.; Heinzel, T.; Kramer, O.H. Acetylation of non‐histone proteins modulates cellular
signalling at multiple levels. Int. J. Biochem. Cell. Biol. 2009, 41, 185–198.
55. Shakibaei, M.; John, T.; Schulze‐Tanzil, G.; Lehmann, I.; Mobasheri, A. Suppression of NF‐kappa B
activation by curcumin leads to inhibition of expression of cyclo‐oxygenase‐2 and matrix
metalloproteinase‐9 in human articular chondrocytes: Implications for the treatment of osteoarthritis.
Biochem. Pharmacol. 2007, 73,1434–1445.
56. Saeki, Y.; Matsui, T.; Saisho, K.; Tohma, S. Current treatments of rheumatoid arthritis: from the “NinJa”
registry. Exp. Rev. Clin. Immunol. 2012, 8, 455–465.
57. Lichtenstein, D.R.; Syngal, S.; Wolfe, M.M. Nonsteroidal antiinflammatory drugs and the gastrointestinal
tract. The double‐edged sword. Arthritis Rheum. 1995, 38, 5–18.
58. Boileau, C.; Martel‐Pelletier, J.; Caron, J.; Msika, P.; Guillou, G.B. Protective effects of total fraction of
avocado/soybean unsaponifiables on the structural changes in experimental dog osteoarthritis: Inhibition
of nitric oxide synthase and matrix metalloproteinase‐13. Arthritis Res. Ther. 2009, 11, R41.
59. Jacobs, J.W.G.; Kraaimaat, F.W.; Bijlsma, J.W. Why do patients with rheumatoid arthritis use alternative
treatments? Clin. Rheumatol. 2001, 20, 192–196.
60. Whittaker, M.; Floyd, C.D.; Brown, P.; Gearing, A.J. Design and therapeutic application of matrix
metalloproteinase inhibitors. Chem. Rev. 1999, 99, 2735–2776.
61. Sankar, D.; Sambandam, G.; Ramakrishna, R.; Pugalendi, K.V. Modulation of blood pressure, lipid profiles
and redox status in hypertensive patients taking different edible oils. Clin. Chim. Acta 2005, 355, 97–104.
62. Fukuda, Y.; Osawa, T.; Namiki, M. Chemistry of lignan antioxidants in sesame seed and oil. In Food
Phytochemicals for Cancer Prevention II: Teas, Spices and Herbs; Ho, C.T., Osawa, T., Huang, M.T., Rosen, R.T.,
Eds.; ACS Symposium Series: Washington, DC, USA, 1994; Volume 547, pp. 264–274.
63. White, J.P. Fatty acids in oil seeds. In Fatty Acids in Foods and Their Health Applications; Dekker M.
Incorporated: New York, NY, USA, 1992; pp. 237–262.
64. Parihar, V.K.; Prabhakar, K.R.; Veerapur, V.P.; Kumar, M.S.; Reddy, Y.R.; Joshi, R.; Unnikrishnan, M.K.;
Rao, C.M. Effect of sesamol on radiation‐induced cytotoxicity in Swiss albino mice. Mutat. Res. 2006, 611,
9–16.
65. Periasamy, S.; Mo, F.E.; Chen, S.Y.; Chang, C.C.; Liu, M.Y. Sesamol attenuates isoproterenol‐induced acute
myocardial infarction via inhibition of matrix metalloproteinase‐2 and ‐9 expression in rats. Cell. Physiol.
Biochem. 2011, 27, 273–280.
66. Chu, P.Y.; Hsu, D.Z.; Hsu, P.; Liu, M.Y. Sesamol down‐regulates the lipopolysaccharide‐induced
inflammatory response by inhibiting nuclear factor‐kappa B activation. Innate Immun. 2010, 16, 333–339.
67. Geetha, T.; Rohit, B.; Pal, K.I. Sesamol: An efficient antioxidant with potential therapeutic benefits. Med.
Chem. 2009, 5, 367–371.
68. Shenoy, R.R.; Sudheendra, A.T.; Nayak, P.G.; Paul, P.; Kutty, N.G.; Rao, C.M. Normal and delayed wound
healing is improved by sesamol, an active constituent of Sesamum indicum (L.) in albino rats. J.
Ethnopharmacol. 2011, 133, 608–612.
69. Campo, G.; Avenoso, M.; Campo, A.; D’Ascola, S.; Traina, A.; Calatroni, P.; Differential effect of molecular
size HA in mouse chondrocytes stimulated with PMA. Biochim. Biophys. Acta 2009, 1790, 1353–1367.
70. Chockalingam, P.S.; Varadarajan, U.; Sheldon, R.; Fortier, E.; LaVallie, E.R.; Morris, E.A.; Yaworsky, P.J.;
Majumdar, M.K. Involvement of protein kinase Czeta in interleukin‐1β induction of ADAMTS‐4 and type
2 nitric oxide synthase via NF‐κB signaling in primary human osteoarthritic chondrocytes. Arthritis Rheum.
2007, 56, 4074–4083.
71. Hemshekhar, M.; Thushara, R.M.; Jnaneshwari, S.; Devaraja, S.; Kemparaju, K.; Girish, K.S. Attenuation of
adjuvant‐induced arthritis by dietary sesamol via modulation of inflammatory mediators, extracellular
matrix degrading enzymes and antioxidant status. Eur. J. Nutr. 2013, 52, 1787–1799.
72. Hsiao, G.; Teng, C.M.; Sheu, J.R.; Cheng, Y.W.; Lam, K.K.; Lee, Y.M.; Wu, T.S.; Yen, M.H. Cinnamophilin
as a novel antiperoxidative cytoprotectant and free radical scavenger. Biochim. Biophys. Acta 2001, 1525, 77–
88.
73. Yu, S.M.; Ko, F.N.; Wu, T.S.; Lee, J.Y.; Teng, C.M. Cinnamophilin, a novel thromboxane A2 receptor
antagonist, isolated from Cinnamomum philippinense. Eur. J. Pharmacol. 1994, 256, 85–91.
Int. J. Mol. Sci. 2020, 21, 4931 18 of 21
74. Su, M.J.; Chen, W.P.; Lo, T.Y.; Wu, T.S. Ionic mechanisms for the antiarrhythmic action of cinnamophilin
in rat heart. J. Biomed. Sci. 1999, 6, 376–386.
75. Cheng, H.T.; Chang, H. Reduction of reperfusion injury in rat skeletal muscle following administration of
cinnamophilin, a novel dual inhibitor of thromboxane synthase and thromboxane A2 receptor. Thorac.
Cardiovasc. Surg. 1995, 43, 73–76.
76. Lee, E.J.; Chen, H.Y.; Lee, M.Y.; Chen, T.Y.; Hsu, Y.S.; Hu, Y.L.; Chang, G.L.; Wu, T.S. Cinnamophilin
reduces oxidative damage and protects against transient focal cerebral ischemia in mice. Free Radic. Biol.
Med. 2005, 39, 495–510.
77. Lee, E.J.; Chen, H.; Hung, Y.C.; Chen, T.Y.; Lee, M.Y.; Yu, S.C.; Chen, Y.H.; Chuang, I.C.; Wu, T.S.
Therapeutic window for cinnamophilin following oxygen‐glucose deprivation and transient focal cerebral
ischemia. Exp. Neurol. 2009, 217, 74–83.
78. Lu, Y.C.; Hsiao, G.; Lin, K.H.; Hsieh, M.S.; Jayakumar, T.; Wu, T.S.; Sheu, J.R. Cinnamophilin isolated from
Cinnamomum Philippinense protects against collagen degradation in human chondrocytes. Phytother. Res.
2013, 27, 892–899.
79. Shukla, S.; Gupta, S. Apigenin: A promising molecule for cancer prevention. Pharm. Res. 2010, 27, 962–978.
80. Park, J.S.; Kim, D.K.; Shin, H.D.; Lee, H.J.; Jo, H.S.; Jeong, J.H.; Choi, Y.L.; Lee, C.J.; Hwang, S.C. Apigenin
regulates interleukin‐1β‐induced production of matrix metalloproteinase both in the knee joint of rat and
in primary cultured articular chondrocytes. Biomol. Ther. (Seoul) 2016, 24,163–170.
81. Chang, X.; He, H.; Zhu, L.; Gao, J.; Wei, T.; Ma, Z.; Ya, T. Protective effect of apigenin on Freund’s complete
adjuvant‐induced arthritis in rats via inhibiting P2X7/NF‐κB pathway. Chem. Biol. Interact. 2015, 236, 41–46.
82. Li, Y.; Sato, T.; Metori, K.; Koike, K.; Che, Q.M.; Takahashi, S. The promoting effects of geniposidic acid and
aucubin in Eucommia ulmoides oliver leaves on collagen synthesis. Biol. Pharm. Bull. 1998, 21, 1306–1310.
83. Jin, L.; Xue, H.Y.; Jin, L.J.; Li, S.Y.; Xu, Y.P. Antioxidant and pancreas‐protective effect of aucubin on rats
with streptozotocin‐induced diabetes. Eur. J. Pharmacol. 2008, 582, 162–167.
84. Wang, S.N.; Xie, G.P.; Qin, C.H.; Chen, Y.R.; Zhang, K.R.; Li, X.; Wu, Q.; Dong, W.Q.; Yang, J.; Yu, B.
Aucubin prevents interleukin‐1 beta induced inflammation and cartilage matri degradation via inhibition
of NF‐κB signaling pathway in rat articular chondrocytes. Int. Immunopharmacol. 2015, 24, 408–415.
85. Chi, Y.I.; Chuang, S.T.; Hsu, C.H.; Sun, Y.J.; Liu, H.C.; Chen, Y.S.; Lin, F.H. Protective effects of aucubin on
osteoarthritic chondrocyte model induced by hydrogen peroxide and mechanical stimulus. BMC Comp.
Alternat. Med. 2017, 17, 1–11.
86. Wei, Z.F.; Wang, X.Q.; Peng, X.; Wang, W.; Zhao, C.J.; Zu, Y.G.; Fu, Y.J. Fast and green extraction and
separation of main bioactive flavonoids from Radix Scutellariae. Ind. Crops Prod. 2015, 63, 175–181.
87. Zhang, X.; Zhu, Y.; Chen, X.; Zhang, Y.; Zhang, Y.; Jia, Y.; Wang, H.; Liu, Y.; Xiao, L. Baicalein ameliorates
inflammatory‐related apoptotic and catabolic phenotypes in human chondrocytes. Int. Immunopharmacol.
2014, 21, 301–308.
88. Li, Y.; Wang, J.; Song, X.; Bai, H.; Ma, T.; Zhang, Z.; Li, X.; Jiang, R.; Wang, G.; Fan, X.; Liu, X.; Gao, L. Effects
of baicalein on IL‐1β‐induced inflammation and apoptosis in rat articular chondrocytes. Oncotarget 2017, 8,
90781–90795.
89. Xu, J.; Liu, J.; Yue, G.; Sun, M.; Li, J.; Xiu, X.; Gao, Z. Therapeutic effect of the natural compounds baicalein
and baicalin on autoimmune diseases. Mol. Med. Rep. 2018, 18, 1149–1154.
90. Wu, C.M.; Li, T.M.; Tan, T.W.; Fong, Y.C.; Tang, C.H. Berberine reduces the metastasis of chondrosarcoma
by modulating the α v β 3 integrin and the PKC δ, c‐Src, and AP‐1 signaling pathways. Evid. Based
Complement. Alternat. Med. 2013, 2013, doi:10.1155/2013/423164.
91. Zhao, H.; Zhang, T.; Xia, C.; Shi, L.; Wang, S.; Zheng, X.; Hu, T.; Zhang, B. Berberine ameliorates cartilage
degeneration in interleukin‐1β‐stimulated rat chondrocytes and in a rat model of osteoarthritis via Akt
signaling. J. Cell Mol. Med. 2014, 18, 283–292.
92. Liu, S.C.; Lee, H.P.; Hung, C.Y.; Tsai, C.H.; Li, T.M.; Tang, C.H. Berberine attenuates CCN2‐induced IL‐1β
expression and prevents cartilage degradation in a rat model of osteoarthritis. Toxicol. Appl. Pharmacol. 2015,
289, 20–29.
93. Zhou, Y.; Liu, S.Q.; Yu, L.; He, B.; Wu, S.H.; Zhao, Q.; Xia, S.Q.; Mei, H.J. Berberine prevents nitric oxideinduced
rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and
p38 MAPK signaling. Apoptosis 2015, 20, 1187–1199.
94. Wang, X.H.; Jiang, S.M.; Sun, Q.W. Effects of berberine on human rheumatoid arthritis fibroblast‐like
synoviocytes. Exp. Biol. Med. (Maywood) 2011, 236, 859–866.
95. Ra, H.J.; Lee, H.J.; Jo, H.S.; Nam, D.C.; Lee, Y.B.; Kang, B.H.; Moon, D.K.; Kim, D.H.; Lee, C.J.; Hwang, S.C.
Betulin suppressed interleukin‐1β‐induced gene expression, secretion and proteolytic activity of matrix
metalloproteinase in cultured articular chondrocytes and production of matrix metalloproteinase in the
knee joint of rat. K. J. Physiol. Pharmacol. 2017, 21, 19–26.
96. Ko, W.C.; Lin, L.H.; Shen, H.Y.; Lai, C.Y.; Chen, C.M.; Shih, C.H. Biochanin a, a phytoestrogenic isoflavone
with selective inhibition of phosphodiesterase 4, suppresses ovalbumin‐induced airway
hyperresponsiveness. Evid. Based Complement. Alternat. Med. 2011, 2011, 635058.
97. Kole, L.; Giri, B.; Manna, S.K.; Pal, B.; Ghosh, S. Biochanin‐A, an isoflavon, showed anti‐proliferative and
anti‐inflammatory activities through the inhibition of iNOS expression, p38‐MAPK and ATF‐2
phosphorylation and blocking NFκB nuclear translocation. Eur. J. Pharmacol. 2011, 653, 8–15.
98. Wu, D.Q.; Zhong, H.M.; Ding, Q.H.; Ba, L. Protective effects of biochanin A on articular cartilage: In vitro
and in vivo studies. BMC Complement. Altern. Med. 2014, 14, 444.
99. Gao, H.Y.; Wu, B.; Li, W.; Chen, D.H.; Wu, L.J. Chemical constituents of Chaenomeles sinensis (Thouin)
Koehne. Chin. J. Nat. Med. 2004, 2, 351–353.
100. Feng, W.Y. Metabolism of green tea catechins: An overview. Curr. Drug Metab. 2006, 7, 755–809.
101. Jin, Y.; Zhao, Y.Q.; Ni, C.L. Chemical constituents of Acacia catechu (L.f) wild. Chin. Tradit. Herb Drugs 2005,
36, 790–792.
102. Liu, X.Q.; Li, W.W.; Sheng, K.X.; Liu, J.; Chen, F.K. Studies on the chemical constituents of the n‐Buoh
extract of Polygonum bistorta. J. Shenyang Pharmaceut. Univ. 2006, 23, 15–17.
103. Haqqi, T.M.; Anthony, D.D.; Gupta, S.; Ahmed, N.; Lee, M.S.; Kumar, G.K.; Mukhtar, H. Prevention of
collagen‐induced arthritis in mice by a polyphenolic fraction from green tea. Proc. Natl. Acad. Sci. USA 1999,
96, 4524–4529.
104. Adcocks, C.; Collin, P.; Buttle, D.J. Catechins from green tea (Camellia sinensis) inhibit bovine and human
cartilage proteoglycan and type‐II collagen degradation in vitro. J. Nutr. 2002, 132, 341–346.
105. Ahmed, S.; Wang, N.; Lalonde, M.; Goldberg, V.M.; Haqqi, T.M. Green tea polyphenol epigallocatechin‐3‐
gallate (EGCG) differentially inhibits interleukin‐1β–induced expression of matrix metalloproteinase‐1 and
‐13 in human chondrocytes. J. Pharmacol. Exp. Ther. 2004, 308, 767–773.
106. Singh, R.; Ahmed, S.; Islam, N.; Goldberg, V.M.; Haqqi, T.M. Epigallocatechin3‐gallate inhibits interleukin‐
1β‐induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes:
Suppression of nuclear factor‐B (NF‐B/p65) activation by inhibiting IB‐α degradation. Arthritis Rheum. 2002,
46, 2079–2086.
107. Singh, R.; Ahmed, S.; Malemud, C.J.; Goldberg, V.M.; Haqqi, T.M. Epigallocatechin‐3‐gallate selectively
inhibits interleukin‐1‐induced activation of mitogen activated protein kinase subgroup c‐Jun‐N‐terminal
kinase in human osteoarthritis chondrocytes. J. Orthop. Res. 2002, 21, 102–109.
108. Ahmed, S.; Rahman, A.; Hasnain, A.; Goldberg, V.M.; Haqqi, T.M. Phenyl‐Ntert‐butylnitrone downregulates
interleukin‐1‐stimulated matrix metalloproteinase‐13 gene expression in human chondrocytes:
Suppression of c‐Jun NH2‐ terminal kinase, p38‐mitogen‐activated protein kinase and activating protein‐
1. J. Pharmacol. Exp. Ther. 2003, 305, 981–988.
109. Huang, G.S.; Tseng, C.Y.; Lee, C.H.; Su, S.L.; Lee, H.S. Effects of (‐)‐epigallocatechin‐3‐gallate on
cyclooxygenase 2, PGE, and IL‐8 expression induced by IL‐1beta in human synovial fibroblasts. Rheumatol.
Int. 2010, 30, 1197–203.
110. Leong, D.J.; Choudhury, M.; Hanstein, R.; Hirsh, D.M.; Kim, S.J.; Majeska, R.J.; Schaffler, M.B.; Hardin, J.A.;
Spray, D.C.; Goldring, M.B.; et al. Green tea polyphenol treatment is chondroprotective, anti‐inflammatory
and palliative in a mouse posttraumatic osteoarthritis model. Arthritis Res. Ther. 2014, 16, 508.
111. Ding, Q.H.; Cheng, Y.; Chen, W.P.; Zhong, H.M.; Wang, X.H. Celastrol, an inhibitor of heat shock protein
90β potently suppresses the expression of matrix metalloproteinases, inducible nitric oxide synthase and
cyclooxygenase‐2 in primary human osteoarthritic chondrocytes. Eur. J. Pharmacol. 2013, 708, 1–7.
112. Liu, W.; Sun, Y.; Cheng, Z.; Guo, Y.; Liu, P.; Wen, Y. Crocin exerts anti‐inflammatory and anti‐arthritic
effects on type II collagen‐induced arthritis in rats. Pharm. Biol. 2018, 56, 209–216.
113. Ding, Q.; Zhong, H.; Qi, Y.; Cheng, Y.; Li, W.; Yan, S.; Wang, X. Anti‐arthritic effects of crocin in interleukin‐
1β‐treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflamm. Res. 2010, 62, 17–
25.
114. Chen, M.P.; Yang, S.H.; Chou, C.H.; Yang, K.C.; Wu, C.C.; Cheng, Y.H.; Lin, F.H. The chondroprotective
effects of ferulic acid on hydrogen peroxide‐stimulated chondrocytes: Inhibition of hydrogen peroxideInt.
J. Mol. Sci. 2020, 21, 4931 20 of 21
induced proinflammatory cytokines and metalloproteinase gene expression at the mRNA level. Inflamm.
Res. 2010, 59, 587–595.
115. Kim, S.; Na, J.Y.; Song, K.B.; Choi, D.S.; Kim, J.H.; Kwon, Y.B.; Kwon, J. Protective effect of ginsenoside Rb1
on hydrogen peroxide‐induced oxidative stress in rat articular chondrocytes. J. Ginseng Res. 2012, 36, 161–
168.
116. Cheng, W.; Wu, D.; Zuo, Q.; Wang, Z.; Fan, W. Ginsenoside Rb1 prevents interleukin‐1 beta induced
inflammation and apoptosis in human articular chondrocytes. Int. Orthop. 2013, 37, 2065–2070.
117. Huang, Y.; Wu, D.; Fan, W. Protection of ginsenoside Rg1 on chondrocyte from IL‐1β‐induced
mitochondria‐activated apoptosis through PI3K/Akt signaling. Mol. Cell. Biochem. 2014, 392, 249–257.
118. Lee, J.H.; Lim, H.; Shehzad, O.; Kim, Y.S.; Kim, H.P. Ginsenosides from Korean red ginseng inhibit matrix
metalloproteinase‐ 13 expression in articular chondrocytes and prevent cartilage degradation. Eur. J.
Pharmacol. 2014, 724, 145–151.
119. Chen, Y.J.; Tsai, K.S.; Chan, D.C.; Lan, K.C.; Chen, C.F.; Yang, R.S.; Liu, S.H. Honokiol, a low molecular
weight natural product, prevents inflammatory response and cartilage matrix degradation in human
osteoarthritis chondrocytes. J. Orthop. Res. 2014, 32, 573–580.
120. Kim, K.R.; Park, K.K.; Chun, K.S.; Chung, W.Y. Honokiol inhibits the progression of collagen‐induced
arthritis by reducing levels of pro‐inflammatory cytokines and matrix metalloproteinases and blocking
oxidative tissue damage. J. Pharmacol. Sci. 2010, 114, 69–78.
121. Wu, H.; Yin, Z.; Wang, L.; Li, F.; Qiu, Y. Honokiol improved chondrogenesis and suppressed inflammation
in human umbilical cord derived mesenchymal stem cells via blocking nuclear factor‐κB pathway. BMC
Cell Biol. 2017, 18, 1–13.
122. Li, D.; Yuan, T.; Zhang, X.; Xiao, Y.; Wang, R.; Fan, Y.; Zhang, X. Icariin: A potential promoting compound
for cartilage tissue engineering. Osteoarthr. Cartil. 2012, 20, 1647–1656.
123. Kang, B.J.; Ryu, J.; Lee, C.J.; Hwang, S.C. Luteolin inhibits the activity, secretion and gene expression of
MMP‐3 in cultured articular chondrocytes and production of MMP‐3 in the rat knee. Biomol. Ther. (Seoul)
2014, 22, 239–245.
124. Wang, F.; Wu, L.; Li, L.; Chen, S. Monotropein exerts protective effects against IL‐1β‐induced apoptosis
and catabolic responses on osteoarthritis chondrocytes. Int. Immunopharmacol. 2014, 23, 575–580.
125. Ou, L.; Gao, F.; Li, M.; Wei, P. Monotropein accelerates chondrocyte progression in osteoarthritis by
alleviating TNF‐α induced inflammation through regulation of MAPK/NF‐κB signaling pathway. Int. J.
Clin. Exp. Med. 2020, 13, 417–428.
126. Xie, M.X.; Long, M.; Liu, Y.; Qin, C.; Wang.Y.D. Characterization of the interaction between human serum
albumin and morin. Biochim. Biophys. Acta 2006, 1760, 1184–1191.
127. Bartosikova, L.; Necas, I.; Suchy, V. Monitoring of antioxidative effect of morin in alloxan‐induced diabetic
mellitus in the laboratory rat. Acta Vet. Brno 2003, 72, 191–200.
128. Galvez, J.; Coelho, G.; Crespo, M.E.; Cruz, T.; Rodriguez‐Cabezas, M.E.; Concha, A. Intestinal antiinflammatory
activity of morin on chronic experimental colitis in the rat. Aliment. Pharmacol. Ther. 2001, 15,
2027–2039.
129. Kim, J.W.; Lee, J.H.; Hwang, B.Y.; Mun, S.H.; Ko, N.Y.; Kim, K. Morin inhibits Fyn kinase in mast cells and
IgE‐mediated type I hypersensitivity response in vivo. Biochem. Pharmacol. 2009, 77, 1506–1512.
130. Chen, W.P.; Wang, Y.L.; Tang, J.L.; Hu, P.F.; Bao, J.P.; Wu, L.D. Morin inhibits interleukin 1β induced nitric
oxide and prostaglandin E2 production in human chondrocytes. Int. Immunopharmacol. 2012, 12, 447–452.
131. Sultana, F.; Rasool, M. A Novel therapeutic approach targeting rheumatoid arthritis by combined
administration of morin, a dietary flavanol and non‐Steroidal anti‐inflammatory drug indomethacin with
reference to pro‐inflammatory cytokines, inflammatory enzymes, RANKL and transcription factors. Chem.
Biol. Interact. 2015, 230, 58–70.
132. Chen, W.P.; Hu, P.F.; Bao, J.P.; Wu, L.D. Morin exerts antiosteoarthritic properties: an in vitro and in vivo
study. Exp. Biol. Med. 2012, 237, 380–386.
133. Long, C.; Yang, J.; Yang, H.; Li, X.; Wang, G. Attenuation of renal ischemia/reperfusion injury by oleanolic
acid preconditioning via its antioxidant, anti‐inflammatory, and anti‐apoptotic activities. Mol. Med. Rep.
2016, 13, 4697–4704.
134. Choi, J.K.; Kim, S.W.; Kim, D.S.; Lee, J.Y.; Lee, S.; Oh, H.M.; Ha, Y.S.; Yoo, J.; Park, P.H.; Shin, T.Y.; et al.
Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrixdegrading
enzymes. Toxicol. Appl. Pharmacol. 2016, 290, 1–9.
135. Kang, D.G.; Lee, H.J.; Kim, K.T.; Hwang, S.C.; Lee, C.J.; Park, J.S. Effect of oleanolic acid on the activity,
secretion and gene expression of matrix metalloproteinase‐3 in articular chondrocytes in vitro and the
production of matrix metalloproteinase‐3 in vivo. Korean J. Physiol. Pharmacol. 2017, 21, 197–204.
136. Zhang, Z.; Leong, D.J.; Xu, L.; He, Z.; Wang, A.; Navati, M.; Kim, S.J.; Hirsh, D.M.; Hardin, J.A.; Cobelli,
N.J.; et al. Curcumin slows osteoarthritis progression and relieves osteoarthritis‐associated pain symptoms
in a post‐traumatic osteoarthritis mouse model. Arthritis Res. Ther. 2016, 18, 1–12.
137. Onodera, S.; Kaneda, K.; Mizue, Y.; Koyama Y.; Fujinaga, M.; Nishihira J. Macrophage migration inhibitory
factor up‐regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis
J. Biol. Chem. 2000, 275, 444–450.
138. Henrotin, Y.; Clutterbuck, A.L.; Allaway, D.; Lodwig, E.M.; Harris, P.; Mathy‐Hartert, M.; Shakibaei, M.;
Mobasheri, A. Biological actions of curcumin on articular chondrocytes. Osteoarthr. Cartil. 2010, 18, 141–
149.
139. Lin, S.K.; Kok, S.H.; Yeh, F.T.; Kuo, M.Y.; Lin, C.C.; Wang, C.C. MEK/ERK and signal transducer and
activator of transcription signaling pathways modulate oncostatin M‐stimulated CCL2 expression in
human osteoblasts through a common transcription factor. Arthritis Rheum. 2004, 50, 785–793.
140. Therkleson, T. Ginger compress therapy for adults with osteoarthritis. J. Adv. Nurs. 2010, 66, 2225–2233.
141. Srivastava, K.C.; Mustafa, T. Ginger (Z ingiber officinale ) in rheumatism and musculoskeletal disorders.
Med. Hypotheses 1992, 39, 342–348.
142. Kundu, J.K.; Na, H.K.; Surh, Y.J. Ginger‐derived phenolic substances with cancer preventive and
therapeutic potential. Forum Nutr. 2009, 61, 182–192.
143. Ahn, S.I.; Lee, J.K.; Youn, H.S. Inhibition of homodimerization of toll‐like receptor 4 by 6‐shogaol. Mol. Cells
2009, 27, 211–215.
144. Levy, A.S.; Simon, O.; Shelly, J.; Gardener, M. 6‐Shogaol reduced chronic inflammatory response in the
knees of rats treated with complete Freund’s adjuvant. BMC Pharmacol. 2006, 1, 1–18.
145. Villalvilla, A.; da Silva, J.A.; Largo, R.; Gualillo, O.; Vieira, P.C.; Herrero‐Beaumont, G.; Gómez, R. 6‐
Shogaol inhibits chondrocytes’ innate immune responses and cathepsin‐K activity. Mol. Nutr. Food Res.
2014, 58, 256–266.
De Angelis, G.; Chen, L. The implementation of a community‐based aerobic walking program for mild to
moderate knee osteoarthritis (OA): A knowledge translation (KT) randomized controlled trial (RCT): Part
II: Clinical outcomes. BMC Public Health 2012, 12, 1073–1088.
2. Mankin, H.J.; Lippiello, L. Biochemical and Metabolic Abnormalities in Articular Cartilage from Osteo‐
Arthritic Human Hips. J. Bone Joint Surg. Am. 1970, 52, 424–434.
3. Jubb, R.W.; Fell, H.B. The breakdown of collagen by chondrocytes. J. Pathol. 1980, 130, 59–167.
4. Burger, D.; Rezzonico, R.; Li, J.M.; Modoux, C.; Pierce, R.A.; Welgus, H.G.; Dayer, J.M. Imbalance between
interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon
direct contact with stimulated T lymphocytes: Involvement of membrane‐associated cytokines. Arthritis
Rheum. 2004, 41, 1748–1759.
5. Lin, N.; Liu, C.; Xiao, C.; Jia, H.; Imada, K.; Wu, H.; Ito, A. Triptolide, a diterpenoid triepoxide, suppresses
inflammation and cartilage destruction in collagen‐induced arthritis mice. Biochem. Pharmacol. 2007, 73,
136–146.
6. Brinckerhoff, C.E. Joint destruction in arthritis: Metalloproteinases in the spotlight. Arthritis. Rheum. 1991,
34, 1073–1075.
7. Abeles, A.M.; Pillinger, M.H. The role of the synovial fibroblast in rheumatoid arthritis‐cartilage
destruction and the regulation of matrix metalloproteinases. Bull. NYU Hosp. Joint Dis. 2006, 64, 20–24.
8. Hadler‐Olsen, E.; Fadnes, B.; Sylte, I.; Uhlin‐Hansen, L.; Winberg, J.O. Regulation of matrix
metalloproteinase activity in health and disease. FEBS J. 2011, 278, 28–45.
9. Shlopov, B.V.; Lie, W.R.; Mainardi, C.L.; Cole, A.A.; Chubinskaya, S.; Hasty, K.A. Osteoarthritic lesions:
Involvement of three different collagenases. Arthritis Rheum. 1997, 40, 2065–2074.
10. Knauper, V.; Cowell, S.; Smith, B.; Lopez‐Otin, C.; O’Shea, M.; Morris, H.; Zardi, L.; Murphy, G. The role
of the C‐terminal domain of human collagenase‐ 3 (MMP‐13) in the activation of procollagenase‐3,
substrate specificity, and tissue inhibitor of metalloproteinase interaction. J. Biol. Chem. 1997, 272, 7608–
7616.
11. Cawston, T.E.; Wilson, A.J. Understanding the role of tissue degrading enzymes and their inhibitors in
development and disease. Best Pract. Res. Clin. Rheumatol. 2006, 20, 983–1002.
12. Mitchell, P.G.; Magna, H.A.; Reeves, L.M.; Lopresti‐Morrow, L.L.; Yocum, S.A.; Rosner, P.J.; Geoghegan,
K.F.; Hambor, J.E. Cloning, expression and type II collagenolytic activity of matrix metalloproteinase‐13
from human osteoarthritic cartilage. J. Clin. Invest. 1996, 97, 761–768.
13. Teslow, L.C.; Adlam, D.J.; Woolley, D.E. Matrix metalloproteinase and proinflammatory cytokine
production by chondrocytes of human osteoarthritic cartilage. Arthritis Rheum. 2001, 44, 585–594.
14. Wu, W.; Billinghurst, R.C.; Pidour, I.; Antoniou, J.; Zukor, D.; Tanzer, M.; Poole, A.R. Sites of collagenase
cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their
relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis
Rheum. 2002, 46, 2087–2094.
15. Konttinen, Y.T.; Ceponis, A.; Takagi, M.; Ainola, M.; Sorsa, T.; Sutinen, M.E.; Salo, T.; Ma, J.; Santavirta, S.;
Seiki, M. New collagenolytic enzymes cascade identified at the pannus–hard tissue junction in rheumatoid
arthritis: Destruction from above. Matrix Biol. 1998, 17, 585–601.
16. Ohuchi, E.; Imai, K.; Fujii, Y.; Sato, H.; Seiki, M.; Okada, Y. Membrane type 1 matrix metalloproteinase
digests interstitial collagens and other extracellular matrix macromolecules. J. Biol. Chem. 1997, 272, 2446–
2451.
17. Konttinen, Y.T.; Ainola, M.; Valleala, H.; Ma, J.; Ida, H.; Mandelin, J.; Kinne, R.W.; Santavirta, S.; Sorsa, T.;
López‐Otín, C.; et al. Analysis of 16 different matrix metalloproteinases (MMP‐1 to MMP‐20) in the synovial
membrane: Different profiles in trauma and rheumatoid arthritis. Ann. Rheum. Dis. 1999, 58, 691–697.
18. Mengshol, J.A.; Vincenti, M.P.; Coon, C.I.; Barchowsky, A.; Brinckerhoff, C.E. Interleukin‐1 induction of
collagenase 3 (matrix metalloproteinase 13) gene expression in chondrocytes requires p38, c‐Jun N‐terminal
kinase, and nuclear factor kappaB: Differential regulation of collagenase 1 and collagenase 3. Arthritis
Rheum. 2000, 43, 801–811.
19. Shi, J.; Schmitt‐Talbot, E.; Dimattia, D.A.; Dullea, R.G. The differential effects of IL‐1 and TNF‐alpha on
proinflammatory cytokine and matrix metalloproteinase expression in human chondrosarcoma cells.
Inflamm. Res. 2004, 53, 377–389.
20. Malemud, C.J.; Islam, N.; Haqqi, T.M. Pathophysiological mechanisms in osteoarthritis lead to novel
therapeutic strategies. Cells Tissues Organs 2003, 174, 34–48.
21. Jimi, E.; Aoki, K.; Saito, H.; D’Acquisto, F.; May, M.J.; Nakamura, I.; Suda, T.; Kojima, T.; Okamoto, F.;
Fukushima, H.; et al. Selective inhibition of NF‐κB blocks osteoclastogenesis and prevents inflammatory
bone destruction in vivo. Nat. Med. 2004, 10, 617–624.
22. Héraud, F.; Héraud, A.; Harmand, M.F. Apoptosis in normal and osteoarthritic articular cartilage. Ann.
Rheum. Dis. 2000, 59, 959–965.
23. Grunke, M.; Schulze‐Koops, H. Successful treatment of inflammatory knee osteoarthritis with tumour
necrosis factor blockade. Ann. Rheum. Dis. 2006, 65, 555–556.
24. Dray, A.; Read, S.J. Arthritis and Pain. Future Targets to Control Osteoarthritis Pain. Arthritis Res. Ther.
2007, 9, 212.
25. Goldring, M.B. Osteoarthritis and cartilage: The role of cytokines. Curr. Rheumatol. Rep. 2000, 2, 459–465.
26. Westacott, C.I.; Sharif, M. Cytokines in osteoarthritis: mediators or markers of joint destruction? Semin.
Arthritis Rheum. 1996, 25, 254–272.
27. Ku, G.; Faust, T.; Lauffer, L.L.; Livingston, D.J.; Harding, M.W. Interleukin‐1_ converting enzyme inhibition
blocks progression of type II collageninduced arthritis in mice. Cytokine 1996, 8, 377–386.
28. Murata, M.; Trahan, C.; Hirahashi, J.; Mankin, H.J.; Towle, C.A. Intracellular interleukin‐1 receptor
antagonist in osteoarthritis chondrocytes. Clin. Orthop. Relat. Res. 2003, 409, 285–295.
29. Richardson, D.W.; Dodge, G.R. Effects of interleukin‐1β and tumor necrosis factor‐α on expression of
matrix‐related genes by cultured equine articular chondrocytes. Am. J. Vet. Res. 2000, 61, 624–630.
30. Bau, B.; Gebhard, P.M.; Haag, J.; Knorr, T.; Bartnik, E.; Aigner, T. Relative messenger RNA expression
profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis
Rheum. 2002, 46, 2648–2657.
31. Brenn, D.; Richter, F.; Schaible, H. Sensitization of unmyelinated sensory fibers of the joint nerve to
mechanical stimuli by interleukin‐6 in the rat: An inflammatory mechanism of joint pain. Arthritis Rheum.
2007, 56, 351–359.
32. Silacci , P.; Dayer, J.M.; Desgeorges, A.; Peter, R.; Manueddu, C.; Guerne, P.A. Interleukin (IL)‐6 and its
soluble receptor induce TIMP‐1 expression in synoviocytes and chondrocytes, and block IL‐1‐induced
collagenolytic activity. J. Biol. Chem. 1998, 273, 13625–13629.
33. Obreja, O.; Biasio, W.; Andratsch, M.; Lips, K.S.; Rathee, P.K.; Ludwig, A.; Rose‐John, S.; Kress, M. Fast
modulation of heat‐activated ionic current by proinflammatory interleukin 6 in rat sensory neurons. Brain
2005, 128, 1634–1641.
34. Sakao, K.; Takahashi, K.A.; Arai, Y.; Saito, M.; Honjo, K.; Hiraoka, N.; Asada, H.; Shin‐Ya, M.; Imanishi, J.;
Mazda, O.; et al. Osteoblasts derived from osteophytes produce interleukin‐6, interleukin‐8, and matrix
metalloproteinase‐13 in osteoarthritis. J. Bone Miner. Metab. 2009, 27, 412–423.
35. Goel, G.; Makkar, H.P.S.; Francis, G.; Becker, K. Phorbol esters: Structure, biological activity, and toxicity
in animals. Int. J. Toxicol. 2007, 26, 279–288.
36. Moore, A.R.; Iwamura, H.; Larbre, J.P.; Scott, D.L.; Willoughby, D.A. Cartilage degradation by
polymorphonuclear leucocytes: In vitro assessment of the pathogenic mechanisms. Ann. Rheum. Dis. 1993,
52, 27–31.
37. Lu, Y.C.; Jayakumar, T.; Duann, Y.F.; Chou, Y.C.; Hsieh, C.Y.; Yu, S.Y.; Sheu, J.R.; Hsiao, G.
Chondroprotective role of sesamol by inhibiting MMPs expression via retaining NF‐KB signaling in
activated SW1353 cells. J. Agric. Food Chem. 2011, 59, 4969–4978.
38. Aigner, T.; Cook, J.L.; Gerwin, N.; Glasson, S.S.; Laverty, S.; Little, C.B.; McIlwraith, W.; Kraus, V.B.
Histopathology atlas of animal model systems—overview of guiding principles. Osteoarthr. Car. 2010, 18,
S2–S6.
39. Takahashi, I.; Matsuzaki, T.; Hoso, M. Long‐term histopathological developments in knee‐joint
components in a rat model of osteoarthritis induced by monosodium iodoacetate. J. Phys. Ther. Sci. 2017,
27, 590–597.
40. Bove, S.E.; Calcaterra, S.L.; Brooker, R.M.; Huber, C.M.; Guzman, R.E.; Juneau, P.L.; Schrier, D.J.; Kilgore,
K.S. Weight bearing as a measure of disease progression and efficacy of anti‐inflammatory compounds in
a model of monosodium iodoacetate‐induced osteoarthritis. Osteoarth. Cart. 2003, 11, 821–830.
41. Kobayashi, K.; Imaizumi, R.; Sumichika, H.; Tanaka, H.; Goda, M.; Fukunari, A.; Komatsu, H. Sodium
iodoacetate‐induced experimental osteoarthritis and associated pain model in rats. J. Veter. Med. Sci. 2003,
65, 1195–1199.
42. Guzman, R.E.; Evans, M.G.; Bove, S.; Morenko, B.; Kilgore. K. Mono‐iodoacetate‐induced histologic
changes in subchondral bone and articular cartilage of rat femorotibial joints: An animal model of
osteoarthritis. Toxicol. Pathol. 2003, 31, 619–624.
43. Janusz, M.J.; Hookfin, E.B.; Heitmeyer, S.A.; Woessner, J.F.; Freemont, A.J.; Hoyland, J.A.; Brown, K.K.;
Hsieh, L.C.; Almstead, N.G.; De, B.; et al. Moderation of iodoacetate‐induced experimental osteoarthritis
in rats by matrix metalloproteinase inhibitors. Osteoarth. Cartil. 2001, 9,751–760.
44. Udo, M.; Muneta, T.; Tsuji, K.; Ozeki, N.; Nakagawa, Y.; Ohara, T.; Saito, R.; Yanagisawa, K.; Koga, H.;
Sekiya, I. Monoiodoacetic acid induces arthritis and synovitis in rats in a dose‐ and time‐dependent
manner: Proposed model‐specific scoring systems. Osteoarth. Cartil. 2016, 24, 1284–1291.
45. Lampropoulou‐Adamidou, K.; Lelovas, P.; Karadimas, E.V.; Liakou, C.; Triantafillopoulos, I.K.; Dontas, I.;
Papaioannou, N.A. Useful animal models for the research of osteoarthritis. Eur. J. Orthop. Surg. Traumatol.
2014, 24, 263–271.
46. Nolan, G.P.; Baltimore, D. The inhibitory ankyrin and activator Rel proteins. Curr. Opin. Genet. Dev. 1992,
2, 211–220.
47. Baeuerle, P.A.; Henkel, T. Function and activation of NF‐kappa B in the immune system. Annu. Rev.
Immunol. 1994, 12, 141–179.
48. Siebenlist, U.; Franzo, G.; Brown, K. Structure, regulation and function of NF‐kappa B. Annu. Rev. Cell Biol.
1994, 10, 405–455.
49. Grilli, M.; Chiu, J.J.S.; Lenardo, M.J. NF‐kappa B and Rel: Participants in a multiform transcriptional
regulatory system. Int. Rev. Cytol. 1993, 143, 1–62.
50. Goldring, M.B.; Goldring, S.R. Osteoarthritis. J. Cell. Physiol. 2007, 213, 626–634.
51. Roman‐Blas, J.A.; Jimenez, S.A. NF‐κB as a potential therapeutic target in osteoarthritis and rheumatoid
arthritis. Osteoarth. Cartil. 2006, 14, 839–848.
52. Yeung, F.; Hoberg, J.E.; Ramsey, C.S.; Keller, M.D.; Jones, D.R.; Frye, R.A.; Mayo, M.W. Modulation of NFkappaB‐
dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004, 23, 2369–2380.
53. Calao, M.; Burny, A.; Quivy, V.; Dekoninck, A.; Van Lint, C. A pervasive role of histone acetyltransferases
and deacetylases in an NF‐kappaB‐signaling code. Trends Biochem. Sci. 2008, 33, 339–349.
54. Spange, S.; Wagner, T.; Heinzel, T.; Kramer, O.H. Acetylation of non‐histone proteins modulates cellular
signalling at multiple levels. Int. J. Biochem. Cell. Biol. 2009, 41, 185–198.
55. Shakibaei, M.; John, T.; Schulze‐Tanzil, G.; Lehmann, I.; Mobasheri, A. Suppression of NF‐kappa B
activation by curcumin leads to inhibition of expression of cyclo‐oxygenase‐2 and matrix
metalloproteinase‐9 in human articular chondrocytes: Implications for the treatment of osteoarthritis.
Biochem. Pharmacol. 2007, 73,1434–1445.
56. Saeki, Y.; Matsui, T.; Saisho, K.; Tohma, S. Current treatments of rheumatoid arthritis: from the “NinJa”
registry. Exp. Rev. Clin. Immunol. 2012, 8, 455–465.
57. Lichtenstein, D.R.; Syngal, S.; Wolfe, M.M. Nonsteroidal antiinflammatory drugs and the gastrointestinal
tract. The double‐edged sword. Arthritis Rheum. 1995, 38, 5–18.
58. Boileau, C.; Martel‐Pelletier, J.; Caron, J.; Msika, P.; Guillou, G.B. Protective effects of total fraction of
avocado/soybean unsaponifiables on the structural changes in experimental dog osteoarthritis: Inhibition
of nitric oxide synthase and matrix metalloproteinase‐13. Arthritis Res. Ther. 2009, 11, R41.
59. Jacobs, J.W.G.; Kraaimaat, F.W.; Bijlsma, J.W. Why do patients with rheumatoid arthritis use alternative
treatments? Clin. Rheumatol. 2001, 20, 192–196.
60. Whittaker, M.; Floyd, C.D.; Brown, P.; Gearing, A.J. Design and therapeutic application of matrix
metalloproteinase inhibitors. Chem. Rev. 1999, 99, 2735–2776.
61. Sankar, D.; Sambandam, G.; Ramakrishna, R.; Pugalendi, K.V. Modulation of blood pressure, lipid profiles
and redox status in hypertensive patients taking different edible oils. Clin. Chim. Acta 2005, 355, 97–104.
62. Fukuda, Y.; Osawa, T.; Namiki, M. Chemistry of lignan antioxidants in sesame seed and oil. In Food
Phytochemicals for Cancer Prevention II: Teas, Spices and Herbs; Ho, C.T., Osawa, T., Huang, M.T., Rosen, R.T.,
Eds.; ACS Symposium Series: Washington, DC, USA, 1994; Volume 547, pp. 264–274.
63. White, J.P. Fatty acids in oil seeds. In Fatty Acids in Foods and Their Health Applications; Dekker M.
Incorporated: New York, NY, USA, 1992; pp. 237–262.
64. Parihar, V.K.; Prabhakar, K.R.; Veerapur, V.P.; Kumar, M.S.; Reddy, Y.R.; Joshi, R.; Unnikrishnan, M.K.;
Rao, C.M. Effect of sesamol on radiation‐induced cytotoxicity in Swiss albino mice. Mutat. Res. 2006, 611,
9–16.
65. Periasamy, S.; Mo, F.E.; Chen, S.Y.; Chang, C.C.; Liu, M.Y. Sesamol attenuates isoproterenol‐induced acute
myocardial infarction via inhibition of matrix metalloproteinase‐2 and ‐9 expression in rats. Cell. Physiol.
Biochem. 2011, 27, 273–280.
66. Chu, P.Y.; Hsu, D.Z.; Hsu, P.; Liu, M.Y. Sesamol down‐regulates the lipopolysaccharide‐induced
inflammatory response by inhibiting nuclear factor‐kappa B activation. Innate Immun. 2010, 16, 333–339.
67. Geetha, T.; Rohit, B.; Pal, K.I. Sesamol: An efficient antioxidant with potential therapeutic benefits. Med.
Chem. 2009, 5, 367–371.
68. Shenoy, R.R.; Sudheendra, A.T.; Nayak, P.G.; Paul, P.; Kutty, N.G.; Rao, C.M. Normal and delayed wound
healing is improved by sesamol, an active constituent of Sesamum indicum (L.) in albino rats. J.
Ethnopharmacol. 2011, 133, 608–612.
69. Campo, G.; Avenoso, M.; Campo, A.; D’Ascola, S.; Traina, A.; Calatroni, P.; Differential effect of molecular
size HA in mouse chondrocytes stimulated with PMA. Biochim. Biophys. Acta 2009, 1790, 1353–1367.
70. Chockalingam, P.S.; Varadarajan, U.; Sheldon, R.; Fortier, E.; LaVallie, E.R.; Morris, E.A.; Yaworsky, P.J.;
Majumdar, M.K. Involvement of protein kinase Czeta in interleukin‐1β induction of ADAMTS‐4 and type
2 nitric oxide synthase via NF‐κB signaling in primary human osteoarthritic chondrocytes. Arthritis Rheum.
2007, 56, 4074–4083.
71. Hemshekhar, M.; Thushara, R.M.; Jnaneshwari, S.; Devaraja, S.; Kemparaju, K.; Girish, K.S. Attenuation of
adjuvant‐induced arthritis by dietary sesamol via modulation of inflammatory mediators, extracellular
matrix degrading enzymes and antioxidant status. Eur. J. Nutr. 2013, 52, 1787–1799.
72. Hsiao, G.; Teng, C.M.; Sheu, J.R.; Cheng, Y.W.; Lam, K.K.; Lee, Y.M.; Wu, T.S.; Yen, M.H. Cinnamophilin
as a novel antiperoxidative cytoprotectant and free radical scavenger. Biochim. Biophys. Acta 2001, 1525, 77–
88.
73. Yu, S.M.; Ko, F.N.; Wu, T.S.; Lee, J.Y.; Teng, C.M. Cinnamophilin, a novel thromboxane A2 receptor
antagonist, isolated from Cinnamomum philippinense. Eur. J. Pharmacol. 1994, 256, 85–91.
Int. J. Mol. Sci. 2020, 21, 4931 18 of 21
74. Su, M.J.; Chen, W.P.; Lo, T.Y.; Wu, T.S. Ionic mechanisms for the antiarrhythmic action of cinnamophilin
in rat heart. J. Biomed. Sci. 1999, 6, 376–386.
75. Cheng, H.T.; Chang, H. Reduction of reperfusion injury in rat skeletal muscle following administration of
cinnamophilin, a novel dual inhibitor of thromboxane synthase and thromboxane A2 receptor. Thorac.
Cardiovasc. Surg. 1995, 43, 73–76.
76. Lee, E.J.; Chen, H.Y.; Lee, M.Y.; Chen, T.Y.; Hsu, Y.S.; Hu, Y.L.; Chang, G.L.; Wu, T.S. Cinnamophilin
reduces oxidative damage and protects against transient focal cerebral ischemia in mice. Free Radic. Biol.
Med. 2005, 39, 495–510.
77. Lee, E.J.; Chen, H.; Hung, Y.C.; Chen, T.Y.; Lee, M.Y.; Yu, S.C.; Chen, Y.H.; Chuang, I.C.; Wu, T.S.
Therapeutic window for cinnamophilin following oxygen‐glucose deprivation and transient focal cerebral
ischemia. Exp. Neurol. 2009, 217, 74–83.
78. Lu, Y.C.; Hsiao, G.; Lin, K.H.; Hsieh, M.S.; Jayakumar, T.; Wu, T.S.; Sheu, J.R. Cinnamophilin isolated from
Cinnamomum Philippinense protects against collagen degradation in human chondrocytes. Phytother. Res.
2013, 27, 892–899.
79. Shukla, S.; Gupta, S. Apigenin: A promising molecule for cancer prevention. Pharm. Res. 2010, 27, 962–978.
80. Park, J.S.; Kim, D.K.; Shin, H.D.; Lee, H.J.; Jo, H.S.; Jeong, J.H.; Choi, Y.L.; Lee, C.J.; Hwang, S.C. Apigenin
regulates interleukin‐1β‐induced production of matrix metalloproteinase both in the knee joint of rat and
in primary cultured articular chondrocytes. Biomol. Ther. (Seoul) 2016, 24,163–170.
81. Chang, X.; He, H.; Zhu, L.; Gao, J.; Wei, T.; Ma, Z.; Ya, T. Protective effect of apigenin on Freund’s complete
adjuvant‐induced arthritis in rats via inhibiting P2X7/NF‐κB pathway. Chem. Biol. Interact. 2015, 236, 41–46.
82. Li, Y.; Sato, T.; Metori, K.; Koike, K.; Che, Q.M.; Takahashi, S. The promoting effects of geniposidic acid and
aucubin in Eucommia ulmoides oliver leaves on collagen synthesis. Biol. Pharm. Bull. 1998, 21, 1306–1310.
83. Jin, L.; Xue, H.Y.; Jin, L.J.; Li, S.Y.; Xu, Y.P. Antioxidant and pancreas‐protective effect of aucubin on rats
with streptozotocin‐induced diabetes. Eur. J. Pharmacol. 2008, 582, 162–167.
84. Wang, S.N.; Xie, G.P.; Qin, C.H.; Chen, Y.R.; Zhang, K.R.; Li, X.; Wu, Q.; Dong, W.Q.; Yang, J.; Yu, B.
Aucubin prevents interleukin‐1 beta induced inflammation and cartilage matri degradation via inhibition
of NF‐κB signaling pathway in rat articular chondrocytes. Int. Immunopharmacol. 2015, 24, 408–415.
85. Chi, Y.I.; Chuang, S.T.; Hsu, C.H.; Sun, Y.J.; Liu, H.C.; Chen, Y.S.; Lin, F.H. Protective effects of aucubin on
osteoarthritic chondrocyte model induced by hydrogen peroxide and mechanical stimulus. BMC Comp.
Alternat. Med. 2017, 17, 1–11.
86. Wei, Z.F.; Wang, X.Q.; Peng, X.; Wang, W.; Zhao, C.J.; Zu, Y.G.; Fu, Y.J. Fast and green extraction and
separation of main bioactive flavonoids from Radix Scutellariae. Ind. Crops Prod. 2015, 63, 175–181.
87. Zhang, X.; Zhu, Y.; Chen, X.; Zhang, Y.; Zhang, Y.; Jia, Y.; Wang, H.; Liu, Y.; Xiao, L. Baicalein ameliorates
inflammatory‐related apoptotic and catabolic phenotypes in human chondrocytes. Int. Immunopharmacol.
2014, 21, 301–308.
88. Li, Y.; Wang, J.; Song, X.; Bai, H.; Ma, T.; Zhang, Z.; Li, X.; Jiang, R.; Wang, G.; Fan, X.; Liu, X.; Gao, L. Effects
of baicalein on IL‐1β‐induced inflammation and apoptosis in rat articular chondrocytes. Oncotarget 2017, 8,
90781–90795.
89. Xu, J.; Liu, J.; Yue, G.; Sun, M.; Li, J.; Xiu, X.; Gao, Z. Therapeutic effect of the natural compounds baicalein
and baicalin on autoimmune diseases. Mol. Med. Rep. 2018, 18, 1149–1154.
90. Wu, C.M.; Li, T.M.; Tan, T.W.; Fong, Y.C.; Tang, C.H. Berberine reduces the metastasis of chondrosarcoma
by modulating the α v β 3 integrin and the PKC δ, c‐Src, and AP‐1 signaling pathways. Evid. Based
Complement. Alternat. Med. 2013, 2013, doi:10.1155/2013/423164.
91. Zhao, H.; Zhang, T.; Xia, C.; Shi, L.; Wang, S.; Zheng, X.; Hu, T.; Zhang, B. Berberine ameliorates cartilage
degeneration in interleukin‐1β‐stimulated rat chondrocytes and in a rat model of osteoarthritis via Akt
signaling. J. Cell Mol. Med. 2014, 18, 283–292.
92. Liu, S.C.; Lee, H.P.; Hung, C.Y.; Tsai, C.H.; Li, T.M.; Tang, C.H. Berberine attenuates CCN2‐induced IL‐1β
expression and prevents cartilage degradation in a rat model of osteoarthritis. Toxicol. Appl. Pharmacol. 2015,
289, 20–29.
93. Zhou, Y.; Liu, S.Q.; Yu, L.; He, B.; Wu, S.H.; Zhao, Q.; Xia, S.Q.; Mei, H.J. Berberine prevents nitric oxideinduced
rat chondrocyte apoptosis and cartilage degeneration in a rat osteoarthritis model via AMPK and
p38 MAPK signaling. Apoptosis 2015, 20, 1187–1199.
94. Wang, X.H.; Jiang, S.M.; Sun, Q.W. Effects of berberine on human rheumatoid arthritis fibroblast‐like
synoviocytes. Exp. Biol. Med. (Maywood) 2011, 236, 859–866.
95. Ra, H.J.; Lee, H.J.; Jo, H.S.; Nam, D.C.; Lee, Y.B.; Kang, B.H.; Moon, D.K.; Kim, D.H.; Lee, C.J.; Hwang, S.C.
Betulin suppressed interleukin‐1β‐induced gene expression, secretion and proteolytic activity of matrix
metalloproteinase in cultured articular chondrocytes and production of matrix metalloproteinase in the
knee joint of rat. K. J. Physiol. Pharmacol. 2017, 21, 19–26.
96. Ko, W.C.; Lin, L.H.; Shen, H.Y.; Lai, C.Y.; Chen, C.M.; Shih, C.H. Biochanin a, a phytoestrogenic isoflavone
with selective inhibition of phosphodiesterase 4, suppresses ovalbumin‐induced airway
hyperresponsiveness. Evid. Based Complement. Alternat. Med. 2011, 2011, 635058.
97. Kole, L.; Giri, B.; Manna, S.K.; Pal, B.; Ghosh, S. Biochanin‐A, an isoflavon, showed anti‐proliferative and
anti‐inflammatory activities through the inhibition of iNOS expression, p38‐MAPK and ATF‐2
phosphorylation and blocking NFκB nuclear translocation. Eur. J. Pharmacol. 2011, 653, 8–15.
98. Wu, D.Q.; Zhong, H.M.; Ding, Q.H.; Ba, L. Protective effects of biochanin A on articular cartilage: In vitro
and in vivo studies. BMC Complement. Altern. Med. 2014, 14, 444.
99. Gao, H.Y.; Wu, B.; Li, W.; Chen, D.H.; Wu, L.J. Chemical constituents of Chaenomeles sinensis (Thouin)
Koehne. Chin. J. Nat. Med. 2004, 2, 351–353.
100. Feng, W.Y. Metabolism of green tea catechins: An overview. Curr. Drug Metab. 2006, 7, 755–809.
101. Jin, Y.; Zhao, Y.Q.; Ni, C.L. Chemical constituents of Acacia catechu (L.f) wild. Chin. Tradit. Herb Drugs 2005,
36, 790–792.
102. Liu, X.Q.; Li, W.W.; Sheng, K.X.; Liu, J.; Chen, F.K. Studies on the chemical constituents of the n‐Buoh
extract of Polygonum bistorta. J. Shenyang Pharmaceut. Univ. 2006, 23, 15–17.
103. Haqqi, T.M.; Anthony, D.D.; Gupta, S.; Ahmed, N.; Lee, M.S.; Kumar, G.K.; Mukhtar, H. Prevention of
collagen‐induced arthritis in mice by a polyphenolic fraction from green tea. Proc. Natl. Acad. Sci. USA 1999,
96, 4524–4529.
104. Adcocks, C.; Collin, P.; Buttle, D.J. Catechins from green tea (Camellia sinensis) inhibit bovine and human
cartilage proteoglycan and type‐II collagen degradation in vitro. J. Nutr. 2002, 132, 341–346.
105. Ahmed, S.; Wang, N.; Lalonde, M.; Goldberg, V.M.; Haqqi, T.M. Green tea polyphenol epigallocatechin‐3‐
gallate (EGCG) differentially inhibits interleukin‐1β–induced expression of matrix metalloproteinase‐1 and
‐13 in human chondrocytes. J. Pharmacol. Exp. Ther. 2004, 308, 767–773.
106. Singh, R.; Ahmed, S.; Islam, N.; Goldberg, V.M.; Haqqi, T.M. Epigallocatechin3‐gallate inhibits interleukin‐
1β‐induced expression of nitric oxide synthase and production of nitric oxide in human chondrocytes:
Suppression of nuclear factor‐B (NF‐B/p65) activation by inhibiting IB‐α degradation. Arthritis Rheum. 2002,
46, 2079–2086.
107. Singh, R.; Ahmed, S.; Malemud, C.J.; Goldberg, V.M.; Haqqi, T.M. Epigallocatechin‐3‐gallate selectively
inhibits interleukin‐1‐induced activation of mitogen activated protein kinase subgroup c‐Jun‐N‐terminal
kinase in human osteoarthritis chondrocytes. J. Orthop. Res. 2002, 21, 102–109.
108. Ahmed, S.; Rahman, A.; Hasnain, A.; Goldberg, V.M.; Haqqi, T.M. Phenyl‐Ntert‐butylnitrone downregulates
interleukin‐1‐stimulated matrix metalloproteinase‐13 gene expression in human chondrocytes:
Suppression of c‐Jun NH2‐ terminal kinase, p38‐mitogen‐activated protein kinase and activating protein‐
1. J. Pharmacol. Exp. Ther. 2003, 305, 981–988.
109. Huang, G.S.; Tseng, C.Y.; Lee, C.H.; Su, S.L.; Lee, H.S. Effects of (‐)‐epigallocatechin‐3‐gallate on
cyclooxygenase 2, PGE, and IL‐8 expression induced by IL‐1beta in human synovial fibroblasts. Rheumatol.
Int. 2010, 30, 1197–203.
110. Leong, D.J.; Choudhury, M.; Hanstein, R.; Hirsh, D.M.; Kim, S.J.; Majeska, R.J.; Schaffler, M.B.; Hardin, J.A.;
Spray, D.C.; Goldring, M.B.; et al. Green tea polyphenol treatment is chondroprotective, anti‐inflammatory
and palliative in a mouse posttraumatic osteoarthritis model. Arthritis Res. Ther. 2014, 16, 508.
111. Ding, Q.H.; Cheng, Y.; Chen, W.P.; Zhong, H.M.; Wang, X.H. Celastrol, an inhibitor of heat shock protein
90β potently suppresses the expression of matrix metalloproteinases, inducible nitric oxide synthase and
cyclooxygenase‐2 in primary human osteoarthritic chondrocytes. Eur. J. Pharmacol. 2013, 708, 1–7.
112. Liu, W.; Sun, Y.; Cheng, Z.; Guo, Y.; Liu, P.; Wen, Y. Crocin exerts anti‐inflammatory and anti‐arthritic
effects on type II collagen‐induced arthritis in rats. Pharm. Biol. 2018, 56, 209–216.
113. Ding, Q.; Zhong, H.; Qi, Y.; Cheng, Y.; Li, W.; Yan, S.; Wang, X. Anti‐arthritic effects of crocin in interleukin‐
1β‐treated articular chondrocytes and cartilage in a rabbit osteoarthritic model. Inflamm. Res. 2010, 62, 17–
25.
114. Chen, M.P.; Yang, S.H.; Chou, C.H.; Yang, K.C.; Wu, C.C.; Cheng, Y.H.; Lin, F.H. The chondroprotective
effects of ferulic acid on hydrogen peroxide‐stimulated chondrocytes: Inhibition of hydrogen peroxideInt.
J. Mol. Sci. 2020, 21, 4931 20 of 21
induced proinflammatory cytokines and metalloproteinase gene expression at the mRNA level. Inflamm.
Res. 2010, 59, 587–595.
115. Kim, S.; Na, J.Y.; Song, K.B.; Choi, D.S.; Kim, J.H.; Kwon, Y.B.; Kwon, J. Protective effect of ginsenoside Rb1
on hydrogen peroxide‐induced oxidative stress in rat articular chondrocytes. J. Ginseng Res. 2012, 36, 161–
168.
116. Cheng, W.; Wu, D.; Zuo, Q.; Wang, Z.; Fan, W. Ginsenoside Rb1 prevents interleukin‐1 beta induced
inflammation and apoptosis in human articular chondrocytes. Int. Orthop. 2013, 37, 2065–2070.
117. Huang, Y.; Wu, D.; Fan, W. Protection of ginsenoside Rg1 on chondrocyte from IL‐1β‐induced
mitochondria‐activated apoptosis through PI3K/Akt signaling. Mol. Cell. Biochem. 2014, 392, 249–257.
118. Lee, J.H.; Lim, H.; Shehzad, O.; Kim, Y.S.; Kim, H.P. Ginsenosides from Korean red ginseng inhibit matrix
metalloproteinase‐ 13 expression in articular chondrocytes and prevent cartilage degradation. Eur. J.
Pharmacol. 2014, 724, 145–151.
119. Chen, Y.J.; Tsai, K.S.; Chan, D.C.; Lan, K.C.; Chen, C.F.; Yang, R.S.; Liu, S.H. Honokiol, a low molecular
weight natural product, prevents inflammatory response and cartilage matrix degradation in human
osteoarthritis chondrocytes. J. Orthop. Res. 2014, 32, 573–580.
120. Kim, K.R.; Park, K.K.; Chun, K.S.; Chung, W.Y. Honokiol inhibits the progression of collagen‐induced
arthritis by reducing levels of pro‐inflammatory cytokines and matrix metalloproteinases and blocking
oxidative tissue damage. J. Pharmacol. Sci. 2010, 114, 69–78.
121. Wu, H.; Yin, Z.; Wang, L.; Li, F.; Qiu, Y. Honokiol improved chondrogenesis and suppressed inflammation
in human umbilical cord derived mesenchymal stem cells via blocking nuclear factor‐κB pathway. BMC
Cell Biol. 2017, 18, 1–13.
122. Li, D.; Yuan, T.; Zhang, X.; Xiao, Y.; Wang, R.; Fan, Y.; Zhang, X. Icariin: A potential promoting compound
for cartilage tissue engineering. Osteoarthr. Cartil. 2012, 20, 1647–1656.
123. Kang, B.J.; Ryu, J.; Lee, C.J.; Hwang, S.C. Luteolin inhibits the activity, secretion and gene expression of
MMP‐3 in cultured articular chondrocytes and production of MMP‐3 in the rat knee. Biomol. Ther. (Seoul)
2014, 22, 239–245.
124. Wang, F.; Wu, L.; Li, L.; Chen, S. Monotropein exerts protective effects against IL‐1β‐induced apoptosis
and catabolic responses on osteoarthritis chondrocytes. Int. Immunopharmacol. 2014, 23, 575–580.
125. Ou, L.; Gao, F.; Li, M.; Wei, P. Monotropein accelerates chondrocyte progression in osteoarthritis by
alleviating TNF‐α induced inflammation through regulation of MAPK/NF‐κB signaling pathway. Int. J.
Clin. Exp. Med. 2020, 13, 417–428.
126. Xie, M.X.; Long, M.; Liu, Y.; Qin, C.; Wang.Y.D. Characterization of the interaction between human serum
albumin and morin. Biochim. Biophys. Acta 2006, 1760, 1184–1191.
127. Bartosikova, L.; Necas, I.; Suchy, V. Monitoring of antioxidative effect of morin in alloxan‐induced diabetic
mellitus in the laboratory rat. Acta Vet. Brno 2003, 72, 191–200.
128. Galvez, J.; Coelho, G.; Crespo, M.E.; Cruz, T.; Rodriguez‐Cabezas, M.E.; Concha, A. Intestinal antiinflammatory
activity of morin on chronic experimental colitis in the rat. Aliment. Pharmacol. Ther. 2001, 15,
2027–2039.
129. Kim, J.W.; Lee, J.H.; Hwang, B.Y.; Mun, S.H.; Ko, N.Y.; Kim, K. Morin inhibits Fyn kinase in mast cells and
IgE‐mediated type I hypersensitivity response in vivo. Biochem. Pharmacol. 2009, 77, 1506–1512.
130. Chen, W.P.; Wang, Y.L.; Tang, J.L.; Hu, P.F.; Bao, J.P.; Wu, L.D. Morin inhibits interleukin 1β induced nitric
oxide and prostaglandin E2 production in human chondrocytes. Int. Immunopharmacol. 2012, 12, 447–452.
131. Sultana, F.; Rasool, M. A Novel therapeutic approach targeting rheumatoid arthritis by combined
administration of morin, a dietary flavanol and non‐Steroidal anti‐inflammatory drug indomethacin with
reference to pro‐inflammatory cytokines, inflammatory enzymes, RANKL and transcription factors. Chem.
Biol. Interact. 2015, 230, 58–70.
132. Chen, W.P.; Hu, P.F.; Bao, J.P.; Wu, L.D. Morin exerts antiosteoarthritic properties: an in vitro and in vivo
study. Exp. Biol. Med. 2012, 237, 380–386.
133. Long, C.; Yang, J.; Yang, H.; Li, X.; Wang, G. Attenuation of renal ischemia/reperfusion injury by oleanolic
acid preconditioning via its antioxidant, anti‐inflammatory, and anti‐apoptotic activities. Mol. Med. Rep.
2016, 13, 4697–4704.
134. Choi, J.K.; Kim, S.W.; Kim, D.S.; Lee, J.Y.; Lee, S.; Oh, H.M.; Ha, Y.S.; Yoo, J.; Park, P.H.; Shin, T.Y.; et al.
Oleanolic acid acetate inhibits rheumatoid arthritis by modulating T cell immune responses and matrixdegrading
enzymes. Toxicol. Appl. Pharmacol. 2016, 290, 1–9.
135. Kang, D.G.; Lee, H.J.; Kim, K.T.; Hwang, S.C.; Lee, C.J.; Park, J.S. Effect of oleanolic acid on the activity,
secretion and gene expression of matrix metalloproteinase‐3 in articular chondrocytes in vitro and the
production of matrix metalloproteinase‐3 in vivo. Korean J. Physiol. Pharmacol. 2017, 21, 197–204.
136. Zhang, Z.; Leong, D.J.; Xu, L.; He, Z.; Wang, A.; Navati, M.; Kim, S.J.; Hirsh, D.M.; Hardin, J.A.; Cobelli,
N.J.; et al. Curcumin slows osteoarthritis progression and relieves osteoarthritis‐associated pain symptoms
in a post‐traumatic osteoarthritis mouse model. Arthritis Res. Ther. 2016, 18, 1–12.
137. Onodera, S.; Kaneda, K.; Mizue, Y.; Koyama Y.; Fujinaga, M.; Nishihira J. Macrophage migration inhibitory
factor up‐regulates expression of matrix metalloproteinases in synovial fibroblasts of rheumatoid arthritis
J. Biol. Chem. 2000, 275, 444–450.
138. Henrotin, Y.; Clutterbuck, A.L.; Allaway, D.; Lodwig, E.M.; Harris, P.; Mathy‐Hartert, M.; Shakibaei, M.;
Mobasheri, A. Biological actions of curcumin on articular chondrocytes. Osteoarthr. Cartil. 2010, 18, 141–
149.
139. Lin, S.K.; Kok, S.H.; Yeh, F.T.; Kuo, M.Y.; Lin, C.C.; Wang, C.C. MEK/ERK and signal transducer and
activator of transcription signaling pathways modulate oncostatin M‐stimulated CCL2 expression in
human osteoblasts through a common transcription factor. Arthritis Rheum. 2004, 50, 785–793.
140. Therkleson, T. Ginger compress therapy for adults with osteoarthritis. J. Adv. Nurs. 2010, 66, 2225–2233.
141. Srivastava, K.C.; Mustafa, T. Ginger (Z ingiber officinale ) in rheumatism and musculoskeletal disorders.
Med. Hypotheses 1992, 39, 342–348.
142. Kundu, J.K.; Na, H.K.; Surh, Y.J. Ginger‐derived phenolic substances with cancer preventive and
therapeutic potential. Forum Nutr. 2009, 61, 182–192.
143. Ahn, S.I.; Lee, J.K.; Youn, H.S. Inhibition of homodimerization of toll‐like receptor 4 by 6‐shogaol. Mol. Cells
2009, 27, 211–215.
144. Levy, A.S.; Simon, O.; Shelly, J.; Gardener, M. 6‐Shogaol reduced chronic inflammatory response in the
knees of rats treated with complete Freund’s adjuvant. BMC Pharmacol. 2006, 1, 1–18.
145. Villalvilla, A.; da Silva, J.A.; Largo, R.; Gualillo, O.; Vieira, P.C.; Herrero‐Beaumont, G.; Gómez, R. 6‐
Shogaol inhibits chondrocytes’ innate immune responses and cathepsin‐K activity. Mol. Nutr. Food Res.
2014, 58, 256–266.
This entry is adapted from the peer-reviewed paper 10.3390/ijms21144931
This entry is offline, you can click here to edit this entry!
