Review Article | Open Access
Zingiber officinale: A Potential Plant against Rheumatoid Arthritis
Rheumatoid arthritis (RA) is an autoimmune disease particularly affecting elderly people which leads to massive bone destruction with consequent inflammation, pain, and debility. Allopathic medicine can provide only symptomatic relief. However, Zingiber officinale is a plant belonging to the Zingiberaceae family, which has traditionally been used for treatment of RA in alternative medicines of many countries. Many of the phytochemical constituents of the rhizomes of this plant have therapeutic benefits including amelioration of RA. This review attempts to list those phytochemical constituents with their reported mechanisms of action. It is concluded that these phytochemicals can form the basis of discovery of new drugs, which not only can provide symptomatic relief but also may provide total relief from RA by stopping RA-induced bone destruction. As the development of RA is a complex process, further research should be continued towards elucidating the molecular details leading to RA and drugs that can stop or reverse these processes by phytoconstituents of ginger.
Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation due to synovial hyperplasia which further progresses with massive irreversible bone destruction [1–4]. Other symptoms include stiffness and loss of physical movement and systemic features including cardiovascular, pulmonary, physiological, and skeletal disorders [5–7]. Recent epidemiological study shows that about 1% of people all over the world are now affected with rheumatoid arthritis, which exerts significant impact on the quality of life [8, 9]. In all populations, it is more prevalent among women rather than men. Generally, RA is developed (almost in 80% of cases) from the mid of the fourth decade in life to the last of the fifth [10–12]. Medications and lifestyle changes are considered as treatment for RA. Current treatment provides nonsteroidal anti-inflammatory drugs (NSAIDs), for example, salicylic acid and steroids (typically cortisone injection) [13–15]. Though these drugs ease the pain, they are incapable of repairing damaged tissues. Although a broad range of drugs are prescribed for managing the pain and slowing the progression of RA, no drug is known to cure the disease completely [16, 17]. Moreover stomach ulcer is an adverse effect observed in RA patients, regularly taking NSAIDS, and adrenal suppression by steroids [18–20]. These undesirable side effects frequently force the patients to look for complementary and alternative medicine (CAM) . A recent survey indicates that people suffering from chronic pain in RA and those dissatisfied with allopathic treatment are more prone to seek alternative medicine, where 60–90% of arthritic patients use CAM [22, 23]. Therefore, it is highly desirable to find out a potential alternative to eradicate the drawbacks of present allopathic treatment.
Natural products from plants have played a remarkable role to cure and avert different diseases from ancient times [24–26]. A study conducted by World Health Organization (WHO) has reported that about 80% of world’s population relies on traditional medicine . In USA, nearly 121 drugs are prescribed today, where 90 of them come from the natural sources particularly from plants in a direct or indirect manner .
Herbal remedies can form an alternative source to relieve symptoms in patients having RA as well as to address the drawbacks associated with present treatment methods with allopathic drugs. Among all investigated plants (list of plants is presented in Table 1), it is scientifically palpable that Zingiber officinale Roscoe (Zingiberaceae) has a pivotal role to lessen the unbearable pain and inflammation associated with RA [29, 30].
The objective of this present review is to evaluate the therapeutic potential of Zingiber officinale in rheumatoid arthritis. We have also aimed to present a summary of mechanism of action of specific phytochemicals of Zingiber officinale to reduce the pain claimed by RA-affected patients.
2. Zingiber officinale in Rheumatoid Arthritis
2.1. Pathophysiology of Rheumatoid Arthritis (RA)
Though a great deal of research has been carried out to determine the exact mechanism of inflammation raised in arthritis and consequent tissue destruction, the precise mechanism(s) are yet to be elucidated. On the basis of extensive research on the pathophysiology behind RA, it appears that development of RA follows a series of complex chain of events. Activated T cells express α4β1-integrin, which binds to vascular cellular adhesion molecule (VCAM) on the surface of venules in inflamed tissues . As a result activated T cells are allowed to penetrate into extracellular fluid by passing through the endothelial wall . Upon encounter with antigen regarding class II major histocompatibility complex (MHC) on an antigen presenting cell, T cells are activated following receiving the second signal via CD28 molecule on the T cell surface. T cells are generated due to influence of cytokines IL-1, IL-6, IL-12, IL-15, IL-23, T cell receptor (TCR), tumor necrosis factor (TNF), and transforming growth factor (TGF) which further differentiate the T cells to T helper 1 (TH1) and T helper 17 (TH17) . The cytokine IL-17 secreted from the TH17 cells then activates macrophage and IL-21, and IL-23 released from macrophage also activates itself. Potency of IL-17 is accelerated via synergy with the effects of tumor necrosis factor [32–34]. In addition, extension of macrophage infiltration into the synovium enhances the severity and progression of RA by secreting IL-1, IL-6, TNF, and matrix metalloproteinase (MMPs) . Recent evidences suggest that the novel cytokines IL-18 and receptor activator of nuclear factor κB (RANKL) are also behind the etiology of the progression of RA [32, 35, 36]. RANKL is a member of TNF superfamily. It is released from activated T cells and highly present in synovial fibroblasts. These cytokines stimulate synovial fibroblasts and chondrocytes in the adjacent articular cartilage to secrete the enzymes. Furthermore, these enzymes degrade peptidoglycan and the cartilage, which subsequently leads to bone destruction [8, 37]. On the other hand after activation by IL-17, osteoclasts induce intrinsic nitric oxide synthase (iNOS) which further participates in bone destruction. Inflammation is developed following activation of fibroblasts. Notably, IL-17 from TH17 cell and TNF-α and IL-18 secreted from macrophage activate fibroblasts. These fibroblasts then develop inflammation by releasing IL-6, IL-8, LIF, and GM-CSF which produce prostaglandin E2. Besides this, cytokines IL-1, IL-6, and TNF released from macrophage directly can participate in inflammation. The overall mechanisms behind the pathogenic pathways of rheumatoid arthritis (RA) are presented in Figure 1.
Another important mediator to develop inflammation in RA is leukotriene B4 (LTB4) having strong attraction to neutrophils . LTB4 is derived from arachidonic acid by sequential biochemical reactions of 5-lipoxygenase (5-LO) and LTA4 hydrolase. Inhibition of LTB4 receptor activity may be a potential target to protect AR .
2.2. Zingiber officinale
Ginger is obtained from rhizomes of Zingiber officinale. The plant belongs to Zingiberaceae family. Since ancient times, it has been widely used as a medicinal herb and spice . Because of containing phytochemical ingredients and as a beneficial therapeutic agent, Zingiber officinale has been contributing pivotal roles against a broad range of diseases like asthma, diabetes, stroke, constipation, and others [29, 40]. It is reported that 100,000 tons of gingers are annually produced, and 80% of this is produced in China .
2.3. Phytochemical Constituents of Zingiber officinale
Ginger contains a large number of phytochemical constituents. The presented table summarizes some major active compounds of ginger. Chemical structures of reported phytochemicals having beneficial effect in RA are presented in Figures 2, 3, and 4.
2.4. Beneficial Effects of Zingiber officinale on Arthritis Associated Symptoms
Ginger has been cultivated since ancient period as a source of medicinal plant in China as well as other countries all over the world for use as a spice and for therapeutic benefits . Evidences reported that consumption of ginger aids in relieving pain of joints associated with rheumatoid arthritis .
Anti-inflammatory effect of ginger was scientifically proved first by Kiuchi et al. in 1982 . They isolated four new different compounds from ginger and all showed potential inhibitory effect to reduce prostaglandin synthesis, which is the key to inflammation. In another study carried out in 1992, they found that ginger showed anti-inflammatory activity by inhibiting not only prostaglandin but also leukotriene biosynthesis . A diarylheptanoid having catechol group showed activity against 5-lipoxygenase which further inhibited leukotriene biosynthesis which can produce an anti-inflammatory effect. Another constituent, namely, yakuchinone A, inhibited prostaglandin production, which can again result in an anti-inflammatory effect.
The activity of Zingiber officinale as an anti-inflammatory agent was investigated by Thomson and his group in rats . Experimental rats were treated with aqueous extract of Zingiber officinale either orally or intraperitoneally daily for 4 weeks. Though at low dose ginger did not reduce prostaglandin E2 concentrations, at high doses it significantly lowered PGE2 levels. Therefore, ginger could reduce inflammation associated with RA.
Recently, in vitro anti-inflammatory effect of ginger was carried out by Ribel-Madsen et al. where they isolated synovial cells from synovial membrane or synovial fluid . Cells were stimulated by TNF-α. Ginger treated cells showed similar inhibitory effect to betamethasone by inhibiting production of cytokines IL-1 and IL-6 indicating anti-inflammatory effect.
It is known that 5-lipoxygenase is one of the major key elements of inflammation, and reduction of this factor aids in reducing inflammation. Flynn et al. reported that gingerol and gingerdione significantly showed analgesic and anti-inflammatory activities by inhibiting PGE2 synthesis .
Acetic acid induced writhing and foot pad edema tests were evaluated as acute and chronic inflammatory model by Shimoda et al. in experiments with ginger . Considerable suppression in the frequency of writhing and footpad edema primarily indicated anti-inflammatory effect of Zingiber officinale. They also determined the effect of prostaglandin and nitric oxide production in mouse leukemic monocytes (RAW 264 cells) stimulated by lipopolysaccharide to find out the mechanism. They demonstrated that both nitric oxide (NO) and prostaglandin production were considerably reduced by the extract of ginger. To find out the responsible active constituents, bioassay guided separation was performed and they concluded that 6-shogaol, gingerdiols, and proanthocyanidins were responsible for these novel effects.
Young et al. observed both analgesic and anti-inflammatory effect of 6-gingerol, one of the major phytochemical constituents of Zingiber officinale . Acetic acid writhing and formalin induced licking tests were carried out to evaluate anti-inflammatory effect whereas carrageenan induced paw edema experiment was run to observe analgesic effect in male ICR mice. Both analgesic and anti-inflammatory effects of ethanol extract of dried Zingiber officinale were observed by Ojewole . Hot plate and acetic acid tests were carried out in mice to evaluate analgesic effect while egg albumin-induced pedal edema in rat was developed to observe anti-inflammatory effects. Findings from these experimental animal studies indicated potential analgesic and anti-inflammatory activity by ginger which can be applied to reduce pain and inflammation arising from arthritis .
Antiarthritic activity of crude extract ginger from Zingiber officinale was evaluated in animal model of rheumatoid arthritis and streptococcal cell wall induced arthritis by Funk’s group . Therapeutic potency of crude extract was compared with the phytochemical constituent gingerol and its derivatives. They found that the individual phytochemicals showed considerable effect. Interestingly, the crude extract containing essential oils and more polar compounds exhibited better activities by preventing joint inflammation and bone destruction. They concluded that not only gingerol but also non-gingerol compounds of Zingiber officinale had considerable antiarthritic activity. Another study by Sharma’s group showed both antiarthritic and anti-inflammatory strong effects of ginger oil . In the study, ginger oil was administered orally at a dose of 33 mg/kg for 26 days in arthritic rats. The ginger oil significantly suppressed both paw and joint swelling. Antiarthritic activity by ginger was also observed by Srivastava et al. in patients experiencing rheumatoid arthritis, osteoarthritis, and muscular discomfort independently . More than three-quarters of RA patients of the study experienced relief in pain and swelling remarkably. Surprisingly all the patients of muscular discomfort claimed reduction of pain after receiving ginger powder. This study showed that the beneficial effects of ginger to reduce pain associated with RA were due to inhibition of prostaglandin and leukotriene biosynthesis.
van Breemen et al. reported the mechanism of anti-inflammatory effect of ginger constituents. They found that 10-gingerol, 8-shogaol, and 10-shogaol strongly inhibited COX 2 and thereby significantly reduced inflammation . Though most papers show that ginger exhibits its anti-inflammatory effect by blocking COX-2 enzymes, Grzanna has reported blocking the activities of both COX-1 and COX-2 . Along with these, this study also showed that ginger could suppress leukotriene biosynthesis by inhibiting 5-lipoxygenase . Inhibition of COX-1 activity by ginger was also demonstrated by Nurtjahja-Tjendraputra et al. Their study revealed that 8-paradol of ginger was a potent COX-1 inhibitor .
Earlier we mentioned that macrophage plays the pivotal role in the development of arthritis by manufacturing different cytokines and chemokines. If it is possible to inactivate the macrophage, then inflammation can be reduced. Tripathi and her group studied the effectiveness of ginger regarding this condition . Interestingly a positive result was observed where they found that proinflammatory cytokines (IL-12, TNF-α, and IL-1β) and proinflammatory chemokines release was significantly inhibited in LPS-induced macrophages by the constituents of Zingiber officinale .
Suppression of inflammation associated with RA by ginger extract was also investigated by Phan et al. in human synoviocytes . The study demonstrated significant inhibition of cytokine expression by Zingiber officinale.
Lantz et al. reported that gingerols and shogaols of ginger showed significant anti-inflammatory activity . In their study they found gingerols could inhibit LPS-induced COX-2 expression but shogaol could not do so.
Anti-inflammatory activity of ginger was experimentally compared with ibuprofen (a market available anti-inflammatory drug prescribed for arthritic patient) by Haghighi and his group . Ginger and ibuprofen both showed similar anti-inflammatory activities indicating ginger as a potential anti-inflammatory agent.
Analgesic effect of ginger extract was evaluated in 261 patients affected with osteoarthritis of the knee by Yoshikawa’s group . Among all patients, 247 (94.6%) patients claimed to have reduction in pain indicating potential analgesic effect due to administration of extract of Zingiber officinale.
Mechanism of inhibition of COX-2 by ginger extract was investigated in-depth by Tjendraputra and coworkers . 8-Paradol and 8-shogaol, the major phytoconstituents of ginger, significantly reduced activities of COX-2 enzyme. The structure activity relationship conducted by them in the same study concluded three possible ways through which 8-paradol and 8-shogaol exhibited their effect to COX-2: (I) lipophilicity of the alkyl side chain, (II) substitution pattern of hydroxy and carbonyl groups on the side chain, and (III) substitution pattern of hydroxy and methoxy groups on the aromatic moiety.
Dual activity of 6-shogaol showed itself by suppressing LPS-induced upexpression of iNOS and COX-2 activities in murine macrophages . 6-Shogaol significantly blocked protein and mRNA expression of iNOS and COX-2 which were determined by Western blotting and reverse transcription-PCR analyses.
Eun et al. (2009) evaluated pharmacological effects of 14 phytochemicals isolated from Zingiber officinale, using the RAW 264.7 cell line . They observed that 6-shogaol, 1-dehydro-10-gingerdione, and 10-gingerdione significantly decreased LPS-induced nitric oxide production while the first two remarkably reduced iNOS expression. During development of RA high level of nitric oxide and iNOS play pivotal role in cartilage damage and inflammation. So, these compounds may have beneficial effect to reduce the inflammation in RA.
Both in vivo and in vitro experiments were conducted to evaluate the effect of 6-gingerol as an inflammatory agent by Pragasam et al. Monosodium urate crystal-induced inflammation was developed in mice as a model of gouty arthritis . They found that 6-gingerol significantly reduced the lysosomal enzymes level as well as inhibiting lactate dehydrogenase and acid phosphate. They concluded that these results were clear indication of anti-inflammatory activity of this ginger phytochemical.
During development of rheumatoid arthritis, toll-like receptors (TLRS) play the vital role in inflammation . Cellular activity of nuclear factor κβ (NF-κβ) was stimulated by TLR ligands through adaptor molecules, like the myeloid differentiation primary-response gene 88 (MyD88) at an early time point, and the toll/IL-1 receptor domain-containing adaptor-inducing IFN-β (TRIF) in delayed kinetics . Under normal conditions, NF-κB was sequestered in the cytoplasm as an inactive complex bound to inhibitory κβ (IκB) proteins . Cytoplasmic IκBs were phosphorylated by TLR2/6, TLR4, or TLR5 agonist which stimulated macrophages or other target cells. This phosphorylation was induced by the catalytic activity of IκB kinase b (IKKβ) . After degradation of phospho (p)-IκBs by proteasome, NF-κβ was translocated into the nucleus . For transcriptional activation of nuclear NF-κβ, the promoter regions of inflammatory genes including inducible iNOS, COX-2, and IL-6 bind to the κB motifs . Therefore, NF-κβ is an attractive therapeutic target for inflammatory and autoimmune disorders. Zingiber officinale can be a potential one which can inhibit the function of NF-κβ. For example, Lee et al. demonstrated that 6-gingerol isolated from Zingiber officinale exhibited anti-inflammatory effect by blocking NF-κβ and protein kinase C (PKC) signaling pathways . 6-Gingerol significantly suppressed Ikβα phosphorylation, NF-κβ nuclear activation, and PKC-α translocation which in turn inhibited Ca2+ mobilization and disrupted mitochondrial membrane potential in LPS-stimulated macrophages. Therefore inducible nitric oxide synthase and TNF-α expression were significantly inhibited and reduced inflammation. Recently it has been reported that 1-dehydro-10-gingerdione is one of the significant compounds having anti-inflammatory activity by suppressing the NF-κB regulated expression of inflammatory genes linked to TLR mediated innate immunity . They carried this study in RAW 264.7 macrophages or primary macrophages derived from bone marrows of C57BL/6 or C3H/HeJ mice, which were stimulated with the TLR4 agonist LPS in the presence of 1-dehydro-10-gingerdione. The expression of inflammatory genes was assayed by RT-PCR analysis and a promoter-dependent reporter assay and catalytic activity of inhibitory κB (IκB) kinase b (IKKβ) was determined through kinase assay and immunoblot analysis. It was observed that cytoplasmic IKKβ-catalyzed IκBα phosphorylation in macrophages activated by TLR agonists or TNF-α was irreversibly inhibited by 1-dehydro-10-gingerdione. These effects of 1-dehydro--gingerdione were abolished by substitution of the Cys179 with Ala in the activation loop of IKKβ, indicating a direct interacting site of 1-dehydro-10-gingerdione. Conclusively, this entire study demonstrated that NF-κB activation in LPS-stimulated macrophages was disrupted and the suppression of NF-κB-regulated gene expression of inducible NOS, COX-2, and IL-6 was evident by 1-dehydro-10-gingerdione.
In conclusion, various phytochemical constituents of ginger have potential therapeutic roles in amelioration of RA symptoms and even possibly RA itself. It is expected that further elucidation of the molecular mechanisms behind the action of these phytochemicals not only can lead to discovery of new drugs for symptomatic relief of RA conditions like inflammation and pain, but also may make it possible to stop further progress or even reverse the damage caused by RA.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
- A. Mayada, E. Dina, S. Marwa, and E. H. Wessam, “Serum leptin levels in rheumatoid arthritis and relationship with disease activity,” The Egyptian Rheumatologist, vol. 36, no. 1, pp. 1–5, 2014.
- G. S. Samar, E. K. Tarek, E. H. Ghada, and M. Waleed, “Significance of serum levels of angiopoietin-2 and its relationship to Doppler ultrasonographic findings in rheumatoid arthritis patients,” The Egyptian Rheumatologist, vol. 36, no. 1, pp. 15–20, 2014.
- R. Baron, “Polarity and membrane transport in osteoclasts,” Connective Tissue Research, vol. 20, no. 1–4, pp. 109–120, 1989.
- R. H. Straub and J. R. Kalden, “Stress of different types increases the proinflammatory load in rheumatoid arthritis,” Arthritis Research and Therapy, vol. 11, no. 3, article 114, 2009.
- I. B. McInnes and G. Schett, “The pathogenesis of rheumatoid arthritis,” The New England Journal of Medicine, vol. 365, no. 23, pp. 2205–2219, 2011.
- E. H. S. Choy and G. S. Panayi, “Cytokine pathways and joint inflamation in rheumatoid arthritis,” The New England Journal of Medicine, vol. 344, no. 12, pp. 907–916, 2001.
- J. C. Roldán, J. Amaya-Amaya, J. Castellanos-de la Hoz et al., “Autoimmune thyroid disease in rheumatoid arthritis: a global perspective,” Arthritis, vol. 2012, Article ID 864907, 15 pages, 2012.
- J. Cadena, S. Vinaccia, A. Pérez, M. I. Rico, R. Hinojosa, and J.-M. Anaya, “The impact of disease activity on the quality of life, mental health status, and family dysfunction in colombian patients with rheumatoid arthritis,” Journal of Clinical Rheumatology, vol. 9, no. 3, pp. 142–150, 2003.
- A. Rojas-Villarraga, J. Bayona, N. Zuluaga, S. Mejia, M.-E. Hincapie, and J.-M. Anaya, “The impact of rheumatoid foot on disability in Colombian patients with rheumatoid arthritis,” BMC Musculoskeletal Disorders, vol. 10, no. 1, article 67, 2009.
- A. N. DeMaria, “Relative risk of cardiovascular events in patients with rheumatoid arthritis,” The American Journal of Cardiology, vol. 89, no. 6, pp. 33–38, 2002.
- Y. Alamanos and A. A. Drosos, “Epidemiology of adult rheumatoid arthritis,” Autoimmunity Reviews, vol. 4, no. 3, pp. 130–136, 2005.
- T. K. Kvien, T. Uhlig, S. Ødegård, and M. S. Heiberg, “Epidemiological aspects of rheumatoid arthritis: the sex ratio,” Annals of the New York Academy of Sciences, vol. 1069, pp. 212–222, 2006.
- J. R. Kirwan, “The effect of glucocorticoids on joint destruction in rheumatoid arthritis,” The New England Journal of Medicine, vol. 333, no. 3, pp. 142–146, 1995.
- S. S. Lim, D. L. Conn, M. T. Galloway et al., “The use of low-dose prednisone in the management of rheumatoid arthritis,” Bulletin on the Rheumatic Diseases, vol. 50, no. 12, pp. 1–4, 2001.
- A. Kavanaugh, “Current treatments for rheumatoid arthritis,” The American Journal of Orthopedics, vol. 36, no. 3, pp. 4–7, 2007.
- M. C. Allison, A. G. Howatson, C. J. Torrance, F. D. Lee, and R. I. Russell, “Gastrointestinal damage associated with the use of nonsteroidal antiinflammatory drugs,” The New England Journal of Medicine, vol. 327, no. 11, pp. 749–754, 1992.
- C. O. Okoli, P. A. Akah, and S. V. Nwafor, “Anti-inflammatory activity of plants,” Journal of Natural Remedies, vol. 3, no. 1, pp. 1–30, 2003.
- D. T. Cowan, “Chronic non-cancer pain in older people: current evidence for prescribing,” British Journal of Community Nursing, vol. 7, no. 8, pp. 420–425, 2002.
- D. T. Cowan, “Pandemonium over painkillers persists,” British Journal of Community Nursing, vol. 12, no. 4, pp. 166–169, 2007.
- K. Eamlamnam, S. Patumraj, N. Visedopas, and D. Thong-Ngam, “Effects of Aloe vera and sucralfate on gastric microcirculatory changes, cytokine levels and gastric ulcer healing in rats,” World Journal of Gastroenterology, vol. 12, no. 13, pp. 2034–2039, 2006.
- K. L. Soeken, S. A. Miller, and E. Ernst, “Herbal medicines for the treatment of rheumatoid arthritis: a systematic review,” Rheumatology, vol. 42, no. 5, pp. 652–659, 2003.
- G. J. Visser, L. Peters, and J. J. Rasker, “Rheumatologists and their patients who seek alternative care: an agreement to disagree,” British Journal of Rheumatology, vol. 31, no. 7, pp. 485–490, 1992.
- J. K. Rao, K. Mihaliak, K. Kroenke, J. Bradley, W. M. Tierney, and M. Weinberger, “Use of complementary therapies for arthritis among patients of rheumatologists,” Annals of Internal Medicine, vol. 131, no. 6, pp. 409–416, 1999.
- J. D. Phillipson, “Phytochemistry and medicinal plants,” Phytochemistry, vol. 56, no. 3, pp. 237–243, 2001.
- D. Grindlay and T. Reynolds, “The Aloe vera phenomenon: a review of the properties and modern uses of the leaf parenchyma gel,” Journal of Ethnopharmacology, vol. 16, no. 2-3, pp. 117–151, 1986.
- J. M. Kong, N. K. Goh, L. S. Chia, and T. F. Chia, “Recent advances in traditional plant drugs and orchids,” Acta Pharmacologica Sinica, vol. 24, no. 1, pp. 7–21, 2003.
- WHO, Traditional Medicine Strategy Launched, vol. 80 of 610, WHO News, Geneva, Switzerland, 2002.
- S. Benowitz, “As war on cancer hits 25-year mark, scientists see progress, challenges,” Scientist, vol. 10, no. 24, 1996.
- N. Mascolo, R. Jain, S. C. Jain, and F. Capasso, “Ethnopharmacologic investigation of ginger (Zingiber officinale),” Journal of Ethnopharmacology, vol. 27, no. 1-2, pp. 129–140, 1989.
- T. Mustafa and K. C. Srivastava, “Ginger (Zingiber officinale) in migraine headache,” Journal of Ethnopharmacology, vol. 29, no. 3, pp. 267–273, 1990.
- M. Feldmann and L. Steinman, “Design of effective immunotherapy for human autoimmunity,” Nature, vol. 435, no. 7042, pp. 612–619, 2005.
- W. B. van den Berg and P. Miossec, “IL-17 as a future therapeutic target for rheumatoid arthritis,” Nature Reviews Rheumatology, vol. 5, no. 10, pp. 549–553, 2009.
- P. Miossec, “Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy,” Arthritis and Rheumatism, vol. 48, no. 3, pp. 594–601, 2003.
- F. M. Brennan and I. B. McInnes, “Evidence that cytokines play a role in rheumatoid arthritis,” Journal of Clinical Investigation, vol. 118, no. 11, pp. 3537–3545, 2008.
- S. Tanaka, “Regulation of bone destruction in rheumatoid arthritis through RANKL-RANK pathways,” World Journal of Orthopedics, vol. 4, no. 1, pp. 1–6, 2013.
- L. E. Theill, W. J. Boyle, and J. M. Penninger, “RANK-L and RANK: T cells, bone loss, and mammalian evolution,” Annual Review of Immunology, vol. 20, pp. 795–823, 2002.
- E. Lubberts and W. B. van den Berg, “Cytokines in the pathogenesis of rheumatoid arthritis and collagen-induced arthritis,” Advances in Experimental Medicine and Biology, vol. 52, pp. 194–202, 2003.
- S. Mathis, V. R. Jala, and B. Haribabu, “Role of leukotriene B4 receptors in rheumatoid arthritis,” Autoimmunity Reviews, vol. 7, no. 1, pp. 12–17, 2007.
- B. White, “Ginger: an overview,” The American Family Physician, vol. 75, no. 11, pp. 1689–1691, 2007.
- S. Kumar, K. Saxena, U. N. Singh, and R. Saxena, “Anti-inflammatory action of ginger: a critical review in anemia of inflammation and its future aspects,” International Journal of Herbal Medicine, vol. 1, no. 4, pp. 16–20, 2013.
- R. D. Altman and K. C. Marcussen, “Effects of a ginger extract on knee pain in patients with osteoarthritis,” Arthritisam and Rheumatism, vol. 44, no. 11, pp. 2531–2538, 2001.
- T. Feng, J. Su, Z.-H. Ding et al., “Chemical constituents and their bioactivities of “tongling White Ginger” (Zingiber officinale),” Journal of Agricultural and Food Chemistry, vol. 59, no. 21, pp. 11690–11695, 2011.
- M. Thomson, K. K. Al-Qattan, S. M. Al-Sawan, M. A. Alnaqeeb, I. Khan, and M. Ali, “The use of ginger (Zingiber officinale Rosc.) as a potential anti-inflammatory and antithrombotic agent,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 67, no. 6, pp. 475–478, 2002.
- F. Kiuchi, M. Shibuya, and U. Sankawa, “Inhibitors of prostaglandin biosynthesis from ginger,” Chemical and Pharmaceutical Bulletin, vol. 30, no. 2, pp. 754–757, 1982.
- F. Kiuchi, S. Iwakami, M. Shibuya, F. Hanaoka, and U. Sankawa, “Inhibition of prostaglandin and leukotriene biosynthesis by gingerols and diarylheptanoids,” Chemical and Pharmaceutical Bulletin, vol. 40, no. 2, pp. 387–391, 1992.
- S. Ribel-Madsen, E. M. Bartels, A. Stockmarr et al., “A synoviocyte model for osteoarthritis and rheumatoid arthritis: response to ibuprofen, betamethasone, and ginger extract—a cross-sectional in vitro study,” Arthritis, vol. 2012, Article ID 505842, 9 pages.
- D. L. Flynn, M. F. Rafferty, and A. M. Boctor, “Inhibition of human neutrophil 5-lipoxygenase activity by gingerdione, shogaol, capsaicin and related pungent compounds,” Prostaglandins Leukotrienes and Medicine, vol. 24, no. 2-3, pp. 195–198, 1986.
- H. Shimoda, S.-J. Shan, J. Tanaka et al., “Anti-inflammatory properties of red ginger (Zingiber officinale var. Rubra) extract and suppression of nitric oxide production by its constituents,” Journal of Medicinal Food, vol. 13, no. 1, pp. 156–162, 2010.
- H.-Y. Young, Y.-L. Luo, H.-Y. Cheng, W.-C. Hsieh, J.-C. Liao, and W.-H. Peng, “Analgesic and anti-inflammatory activities of -gingerol,” Journal of Ethnopharmacology, vol. 96, no. 1-2, pp. 207–210, 2005.
- J. A. O. Ojewole, “Analgesic, antiinflammatory and hypoglycaemic effects of ethanol extract of Zingiber officinale (Roscoe) rhizomes (Zingiberaceae) in mice and rats,” Phytotherapy Research, vol. 20, no. 9, pp. 764–772, 2006.
- J. L. Funk, J. B. Frye, J. N. Oyarzo, and B. N. Timmermann, “Comparative effects of two gingerol-containing Zingiber officinale extracts on experimental Rheumatoid arthritis,” Journal of Natural Products, vol. 72, no. 3, pp. 403–407, 2009.
- J. N. Sharma, K. C. Srivastava, and E. K. Gan, “Suppressive effects of eugenol and ginger oil on arthritic rats,” Pharmacology, vol. 49, no. 5, pp. 314–318, 1994.
- K. C. Srivastava and T. Mustafa, “Ginger (Zingiber officinale) in rheumatism and musculoskeletal disorders,” Medical Hypotheses, vol. 39, no. 4, pp. 342–348, 1992.
- R. B. van Breemen, Y. Tao, and W. Li, “Cyclooxygenase-2 inhibitors in ginger (Zingiber officinale),” Fitoterapia, vol. 82, no. 1, pp. 38–43, 2011.
- R. Grzanna, L. Lindmark, and C. G. Frondoza, “Ginger—an herbal medicinal product with broad anti-inflammatory actions,” Journal of Medicinal Food, vol. 8, no. 2, pp. 125–132, 2005.
- E. Nurtjahja-Tjendraputra, A. J. Ammit, B. D. Roufogalis, V. H. Tran, and C. C. Duke, “Effective anti-platelet and COX-1 enzyme inhibitors from pungent constituents of ginger,” Thrombosis Research, vol. 111, no. 4-5, pp. 259–265, 2003.
- S. Tripathi, D. Bruch, and D. S. Kittur, “Ginger extract inhibits LPS induced macrophage activation and function,” BMC Complementary and Alternative Medicine, vol. 8, no. 1, article 1, 2008.
- P. V. Phan, A. Sohrabi, A. Polotsky, D. S. Hungerford, L. Lindmark, and C. G. Frondoza, “Ginger extract components suppress induction of chemokine expression in human synoviocytes,” Journal of Alternative and Complementary Medicine, vol. 11, no. 1, pp. 149–154, 2005.
- R. C. Lantz, G. J. Chen, M. Sarihan, A. M. Sólyom, S. D. Jolad, and B. N. Timmermann, “The effect of extracts from ginger rhizome on inflammatory mediator production,” Phytomedicine, vol. 14, no. 2-3, pp. 123–128, 2007.
- M. Haghighi, A. Khalvat, T. Toliat, and S. Jallaei, “Comparing the effects of ginger (Zingiber officinale) extract and ibuprofen on patients with osteoarthritis,” Archives of Iranian Medicine, vol. 8, no. 4, pp. 267–271, 2005.
- M. Yoshikawa, S. Hatakeyama, N. Chatani, Y. Nishino, and J. Yamahara, “Qualitative and quantitative analysis of bioactive principles in Zingiberis Rhizoma by means of high performance liquid chromatography and gas liquid chromatography. On the evaluation of Zingiberis Rhizoma and chemical change of constituents during Zingiberis Rhizoma processing,” Yakugaku Zasshi, vol. 113, no. 4, pp. 307–315, 1993.
- E. Tjendraputra, V. H. Tran, D. Liu-Brennan, B. D. Roufogalis, and C. C. Duke, “Effect of ginger constituents and synthetic analogues on cyclooxygenase-2 enzyme in intact cells,” Bioorganic Chemistry, vol. 29, no. 3, pp. 156–163, 2001.
- M. H. Pan, M. C. Hsieh, P. C. Hsu et al., “6-Shogaol suppressed lipopolysaccharide-induced up-expression of iNOS and COX-2 in murine macrophages,” Molecular Nutrition and Food Research, vol. 52, no. 12, pp. 1467–1477, 2008.
- M. K. Eun, J. K. Hye, S. Kim et al., “Modulation of macrophage functions by compounds isolated from Zingiber officinale,” Planta Medica, vol. 75, no. 2, pp. 148–151, 2009.
- S. J. Pragasam, S. Kumar, M. Bhoumik, E. P. Sabina, and M. Rasool, “6-Gingerol, an active ingredient of ginger suppresses monosodium ureate crystal-induced inflammation: an in vivo and in vitro evaluation,” Annals of Biological Research, vol. 2, no. 3, pp. 200–208, 2011.
- C. Ospelt and S. Gay, “TLRs and chronic inflammation,” International Journal of Biochemistry and Cell Biology, vol. 42, no. 4, pp. 495–505, 2010.
- H. Shen, B. M. Tesar, W. E. Walker, and D. R. Goldstein, “Dual signaling of MyD88 and TRIF is critical for maximal TLR4-induced dendritic cell maturation,” Journal of Immunology, vol. 181, no. 3, pp. 1849–1858, 2008.
- P. A. Baeuerle and D. Baltimore, “IκB: a specific inhibitor of the NF-κB transcription factor,” Science, vol. 242, no. 4878, pp. 540–546, 1988.
- J. DiDonato, F. Mercurio, C. Rosette et al., “Mapping of the inducible IκB phosphorylation sites that signal its ubiquitination and degradation,” Molecular and Cellular Biology, vol. 16, no. 4, pp. 1295–1304, 1996.
- M. Karin and Y. Ben-Neriah, “Phosphorylation meets ubiquitination: the control of NF-κB activity,” Annual Review of Immunology, vol. 18, pp. 621–663, 2000.
- B. Tian and A. R. Brasier, “Identification of a nuclear factor kappa B-dependent gene network,” Recent Progress in Hormone Research, vol. 58, pp. 95–130, 2003.
- T. Y. Lee, K. C. Lee, S. Y. Chen, and H. H. Chang, “6-Gingerol inhibits ROS and iNOS through the suppression of PKC-α and NF-κB pathways in lipopolysaccharide-stimulated mouse macrophages,” Biochemical and Biophysical Research Communications, vol. 382, no. 1, pp. 134–139, 2009.
- H. Y. Lee, S. H. Park, M. Lee et al., “1-Dehydro--gingerdione from ginger inhibits IKKβ activity for NF-κB activation and suppresses NF-κB-regulated expression of inflammatory genes,” British Journal of Pharmacology, vol. 167, no. 1, pp. 128–140, 2012.
- R. K. Mishra, A. Kumar, and A. Kumar, “Pharmacological activity of Zingiber officinale,” International Journal of Pharmaceutical and Chemical Sciences, vol. 1, no. 3, pp. 1073–1078, 2012.
- D. W. Connell and M. D. Sutherland, “A re-examination of gingerol, shogaol and zingerone, the pungent principles of Ginger (Zingiber officinale Roscoe),” Australian Journal of Chemistry, vol. 22, no. 5, pp. 1033–1043, 1969.
- Z. Yang, W. Yang, Q. Peng et al., “Volatile phytochemical composition of rhizome of ginger after extraction by headspace solid-phase microextraction, petrol ether extraction and steam distillation extraction,” Bangladesh Journal of Pharmacology, vol. 4, no. 2, pp. 136–143, 2009.
- Y. L. Hsu, C. Y. Chen, M. F. Hou et al., “6-dehydrogingerdione, an active constituent of dietary ginger, induces cell cycle arrest and apoptosis through reactive oxygen species/c-Jun N-terminal kinase pathways in human breast cancer cells,” Molecular Nutrition and Food Research, vol. 54, no. 9, pp. 1307–1317, 2010.
- E.-K. Ahn and J. S. Oh, “Inhibitory effect of galanolactone isolated from Zingiber officinale roscoe extract on adipogenesis in 3T3-L1 cells,” Journal of the Korean Society for Applied Biological Chemistry, vol. 55, no. 1, pp. 63–68, 2012.
- M. Yoshikawa, S. Yamaguchi, K. Kunimi et al., “Stomachic principles in ginger. III. An anti-ulcer principle, 6- gingesulfonic acid, and three monoacyldigalactosylglycerols, gingerglycolipids A, B, and C, from Zingiberis Rhizoma originating in Taiwan,” Chemical and Pharmaceutical Bulletin, vol. 42, no. 6, pp. 1226–1230, 1994.
Copyright © 2014 Abdullah Al-Nahain et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.