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Many of studies propose that NF-kB is essential for the expression of inflammatory cytokines and tissue damaging enzymes in rheumatoid arthritis (Lawrence, 2009). Consistently, activation of NF-kB has been shown in synovial tissue from RA patients, and this appears to be related to clinical manifestation. Uncontrolled regulation of proteins that direct the NF-kB pathway is likely to contribute to susceptibility or severity of chronic inflammatory diseases (Lawrence, 2009).
The joints of rheumatic patients are characterised by synovial infiltration of immune cells, leading to chronic inflammation, pannus formation and consequent joint and cartilage damage. The RA synovium is known to posses basically of macrophages (30-40%), T cells(~30%) and synovial fibroblast alongside of B cells, dendritic cells, other immune cells and synovial cells such as endothelium (Choy, 2012 ; Gibofsky, 2012.). RA synovial fluid has been analyzed which contains a broad variety of effector molecules including proinflammatory cytokines (such asIL-1ß, IL-6, TNFa and IL-18), chemokines (such asIL-8, IP-10, MCP-1, MIP-1, and RANTES), matrix metalloproteinases (MMPs, such as MMP-1, -3, -9and -13) in addition to metabolic proteins (such as Cox-1, Cox-2 and iNOS) (Herkenham M., 2011).
These correlate in a complex manner that is assumed to cause a vicious cycle of proinflammatory signals resultant in frequent and chronic inflammation. TNFa is obviously the key inflammatory mediator and also induces apoptosis. Importantly, the genes encoding TNFa and many other listed factors are well-known to be under the control of NF-kB transcription factors, suggesting that NF-kB could be a master regulator of inflammatory cytokine production in RA. Indeed, the existence of activated NF-kB transcription factors have been verified in cultured fibroblasts of synovium (Hayden MS., 2011. -).
Human arthritic joints and the joints of animals with experimentally induced RA. Immunohistochemistry has demonstrated the presence of both p50 and p65in the nuclei cells lining the synovial membrane and macrophages (Giopanou I. , 2014),. Furthermore, nuclear extracts of cells have verified an ability to bind the NF-kB consensus sequence. A recent practice such as in vivo imaging has also been used to demonstrate the activity of NF-kB in a mouse model of chronic inflammation. By placing the luciferase gene under the control of NF-?B, a marked increase luminescence was observed in the joints of mice (Mann, 2002. ). These findings are supported by a study that investigated experimentally induced arthritis in mice that carried knockouts genes for the NF-kB family member’s p50 or c-Rel. The two experimental models used were collagen induced arthritis (a model of chronic RA where disease development involves both T and B cells) and an acute/destructive model induced by methylated BSA and IL-1 (involving exclusively T cells).
Capsicum annum fruit is used traditionally by the native of the American tropics for many centuries. It was originally grown in the tropics of the United States of America. It is known to contain high chemicals that cause highly selective anesthesia by the breakdown of the capsaicin sensitive nociceptive nerve endings. It is known to be potent in the activation of the receptor potential for vanilloid-1. This is believed to be the main receptor for nociception. It is also suggested to have ability in the inhibition of NF-kB activation as a mechanism of action for generating the ant-inflammatory effect. The herb is often mixed with other natural anti-arthritic herbal preparations. It is also used for peripheral neurone disorders and chronic musculoskeletal pain (Caterina MJ; Surh YJ).
Several members of the Curcuma genus are used in traditional medicine, most important being Curcuma longa (CL); turmeric. Its rhizome has a centuries-long use as a dietary spice as well as herb for its anti-inflammatory properties, hence its utility in arthritic conditions including RA (Sharma, 2006b). Animal studies. In an animal arthritis model a preparation from CL lacking essential oil strongly suppressed joint inflammation and periarticular damage in correlation with decreased activation of NF-kB and of the ensuing cascade of events (involving mediators of inflammation and injury such as chemokines, cyclooxygenase 2, and receptor activator of nuclear factor kappa-B ligand (Funk, 2006).
The ability to prevent the destructive changes in joints and periarticular bone seems to be comparable to that of betamethasone (Kamarudin, 2012; Taty Anna, 2011). Liposomal encapsulation may help overcome the poor bioavailability problem generated by the low water-solubility. The osteoclast-osteoblast balance is tipped in favor of bone building, while halting the OA progression (Chang, 2015). In a rat-induced arthritis model, applying of ginger and turmeric rhizomes were better than indomethacin (a potent NSAID) regarding the ability to improve both joint histopathological changes, and the extra-articular manifestations, including systemic inflammation, malnutrition and iron deficiency anemia, with no intolerance to kidney function and reduced risk of cardiovascular disease (Ramadan, 2013).
In human clinical studies, a combination of Curcuma longa and Boswellia serrata has been shown to be more efficient than a standard dose of celecoxib (a selective COX-2 inhibitor) in the treatment of osteoarthritis, improving the condition of the patients, with no toxicity detectable by clinical examination and laboratory tests (Kizhakkedath, 2013). Curcuma domestica extracts have been shown to be useful in knee osteoarthritis, reducing the pain and functionally with an efficiency equivalent to ibuprofen, but with less side effects (Kuptniratsaikul, 2014). A recent meta-analysis found relevant scientific evidence for the efficacy of turmeric as a therapeutic option in arthritis, but concluded that more studies are necessary in order to definitively pin it down (Daily, 2016). The diferuloylmethane, is the active ingredient phenolic pigment commonly known as curcumin, which has a complex beneficial action in various fields of pathology due to its ability to favorably influence a variety of signalling pathways and mediators (Ghosh, 2015). In a rat model of arthritis, it has been shown to improve the joint inflammation, in the first few hours after the arthritis-inducing event being even more effective than a low dose of prednisone (Nonose, 2014).
It is well-established that IL-1ß, once bound to its type 1 receptor, activates NF-?B dimers by triggering phosphorylation and subsequent degradation of the inhibitory I?B proteins. Activation of NF-?B was a necessity for IL-1ß induced MMP-13 secretion in OA chondrocytes (Kim S. R., 2013. ) (Tsutsumi R., 2008. ). Also, Imamura et al. proved that IL-1ß and TNF-a inhibited chondrogenesis through NF-?B pathway in human mesenchyme stem cells (Imamura M., 2014). Various garlic products have been studied in osteoarthritis (Williams F. M. K., 2010. ). A sulfur compound isolated from garlic has demonstrated that it suppressed arthritis through inhibition of NF-?B DNA-binding activity and expression of iNOS and COX-2 (Ban J. O., 2009.). Though, there are a few studies on SAMC effect on osteoarthritis. In addition, previous study has revealed that DATS suppressed MMP2-9 expression which was dependent on NF-?B and ERK-MAPK Signalling Pathways (Liu Y., 2015.). Mechanistically, SAMC was found to be related to the increased levels of I?Ba induced by IL-1ß, which subsequently mitigated p65 nuclear translocation and the transcriptional activity of NF-?B. Furthermore, our results indicated that IL-1ß treatment resulted in a significant increase in expression of TNF-a at both the mRNA and protein levels, which was ameliorated by treatment with SAMC. The combination of these findings suggests that SAMC can potentially be applied in OA treatment.
Zingiber officinalis, also known as ginger, is a common spice used in Asian cuisine, and a traditional remedy for joint diseases in ethnomedicine (Sharma, 2006a). Ginger is thought to have anti-inflammatory effects, possibly by inhibiting COX-1,COX-2 and LOX (Grzanna, 2005, ). Nevertheless, the squeezed ginger extract paradoxically increased the synthesis of pro-inflammatory cytokines (TNF-a, IL-6, and monocyte chemotactic protein-1) in RAW264 cell culture (Ueda, 2010). The oral administration of the ginger extract had a double effect on TNF-a synthesis in mice, in peritoneal cells: ZO extract initially augmented it, but with repeated administrations reduced it (Ueda, 2010). In addition, it augmented the serum corticosterone level, and this may contribute to the anti-inflammatory effect of ZO.
A recent human clinical study found that ZO powder supplementation for three months can reduce the serum level of nitric oxide and high-sensitivity reactive protein hs-CRP in patients with knee OA. The inflammatory markers started to decrease after three weeks of treatment (Naderi, 2016). Several other studies showed a clinical improvement in OA patients with ZO extract as evaluated by the pain score with VAS, reduction in intake of rescue medication, having mostly mild gastrointestinal adverse events, and similar or even better efficacy and satisfaction score than the standard treatment prescribed by the orthopedic specialist. Sharp-tasting constituents of ZO were thought to contribute to the anti-inflammatory activity of this medicinal plant. For instance, ginger inhibited kB kinase _ activity required for NF-kB activation and suppressed NF-kB-regulated expression of inflammatory genes in lipopolysaccharide S-activated macrophage (Lee, 2012). 6-Dehydrogingerdione attenuated iNOS, COX-2, IL-1ß, IL-6, and TNF- a gene expression in vitro, in RAW 264.7 macrophages. (Huang, 2014, ).
About 300 polyphenols have been isolated from licorice, including phenolic acids, flavonoids, flavans, chalcones, isoflavan and isoflavonoids. Thus far, the main anti-inflammatory active polyphenols in licorice are chalcones, isoflavan and isoflavonoids. The mechanisms for the anti-inflammatory activities of chalcones have been fully investigated. LCA, LCB, ISL and EC all inhibited the production of NO, IL-6 and PGE2, while LCA, LCB and LCD all exhibited potent inhibition of lipid peroxidation (Fu Y, 2013. ) (Honda H, 2014. ). LCB and LCD both strongly inhibited superoxide anion production in the xanthine oxidase system, showed potent scavenging activity on DPPH radical and inhibited phosphorylation of NF-?B p65 (Furusawa J, 2009. ). Furthermore, LCC decreased the expression and activity of iNOS, and modulated the antioxidant network activity of SOD, catalase and glutathione peroxidase (Wang Z, 2013.). LCE effectively inhibited PKC/JNK, ERK1/2, reduced the expression of iNOS, COX-2, IL-6, IL-1ß, IL-12p40, TNF-a, AKT and p38 mitogen-activated protein kinase (MAPK), and attenuated I?Ba degradation and NF-?B activities, as well as transcriptional activity of activator protein AP-1 (Cho YC, 2010 . ) (Lee HN, 2013. ).
Besides chalcones, other flavonoids in licorice, including DGC, DGD, ISOA, GLD, LID and LIA, also showed excellent anti-inflammatory activities. DGC, DGD and ISOA all showed strong ferric reducing activities and effectively scavenged DPPH, ABTS + and singlet oxygen radicals (Kim HJ, 2012. ). Furthermore, DGC increased the expression of haemeoxygenase-1 and MAPK phosphatase-1, suppressed the inflammation-mediated neurodegeneration, production of TNF-a, NO, ROS, NF-?B and phosphorylation of p38 MAPKs, ERK1/2, I?B-a and p65 (Kim J, 2013. ). GLD significantly inhibited NO and IL-1ß release (Thiyagarajan P, 2011. ), attenuated colonic inflammation in mice with dextran sulphate sodium-induced colitis, and decreased the iNOS mRNA expression under high-glucose levels, which indicated that GLD could be applied to diabetes-related vascular dysfunction (Yehuda I, 2015.). LID and LIA inhibited the secretion of IL-6, chemokine (C-C motif) ligand 5, MMP-7, -8 and -9. The suppression of cytokine and MMP secretion by LID and LIA was associated with the reduced activation of NF-?B p65 in periodontitis treatment (La VD, 2011. ).
As mentioned above, in vivo studies have defined a clear role for NF-kB in the modulation of inflammation by pomegranate extracts, a finding that appears to be confirmed in vitro. Pomegranate juice (Velagapudi, 2016, ), POMxTM extract (Rasheed, 2009), and their bioactive compounds punicalagin (Y. E. H. Kim, C.J.; Lee, H.P.; Kim, C.S.; Son, D.J.; Ham, Y.W.; Hellström, M.; Han, S.B.; Kim, H.S.; Park, E.K.; et al. , 2017, ) or delphinidin (Seong, 2011) all suppressed NF-kB activation in various types of cells. It was found that ET reduced the expression of NF-kB target genes, including IL-6 and interleukin 8 (IL-8), upon exposure to pro-inflammatory stimuli in intestinal cells (Hollebeeck, 2012, ), while EA (Promsong, 2015, ) and POMxTM (Rasheed, 2009 #187) reduced NF-kB activation in various subsets of immune cells, and anthocyanin delphinidin reduced inflammation in rheumatoid arthritis cells (Seong, 2011). Taken together, these results suggest that ET and other bioactive compounds present in pomegranate juice show anti-inflammatory effects in vitro, and that the mechanisms involved appear to be related to inactivation of NF-kB signalling.
Administration of pomegranate-derived products has been shown to reduce local inflammation in the bronchoalveolar tissue of COPD model mice (Husari, 2016,) and in the joints of RA model mice (Shukla, 2008,). There also exists a strong base of evidence suggesting that pomegranate extract exerts anti-inflammatory effects that may alleviate the symptoms of IBD (H. B. Kim, N.; Ivanov, I.; Pfent, C.M.; Prudhomme, K.R.; Bisson, W.H.; Dashwood, R.H.; Talcott, S.T.;Mertens-Talcott, S.U. , 2016, ) and inflammation  were all ameliorated by pomegranate fruit supplementation in rodent models of IBD. The mechanisms involved appear to be related to the inhibition of NF-_B (M. A. S.-H. Rosillo, M.; Cárdeno, A.; Aparicio-Soto, M.; Sánchez-Fidalgo, S.; Villegas, I.; & de la Lastra, 2012,; Shah, 2016, ), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase, and signal transducer and activator of transcription 3 phosphorylation (M. A. S.-H. Rosillo, M.; Cárdeno, A.; de la Lastra, C.A. , 2011, ).
Resveratrol has a variety of concentrations in different plants and the higher concentrations are believed to be derived from Knot weed or Polygonum cuspidatum and from red wine grapes. In plants, it is located in the skin of plant which serves as a phytoalexin in the protection of the plant against infection, UV radiation and broad plant defense system. It is known to acquire anti-mutation, antioxidant and anti-inflammatory and DNA protection entities when consumed by animals and humans.
Many of the studies have been demonstrated in neuro and cardioprotection. This is used in the management of RA in management of arthritic joint pain. Using intra articular injections of resveratrol showed protective efects on the cartilage through the reduction of the inflammatory reactions caused by the osteoarthritis in the knees. This has also been justified with the reduction of the edema in experimental animal models supposed to be related to the inhibition of production of the prostaglandins (Elmali N, (2007)). It is also a potent inhibitor of the TNF-a and IL-1b-induced NF-kB activation. Similarly, the anti-inflammatory activities may be suppress the COX -2 pathway through the blocking of NF-kB activation in the joints. Resveratrol is extracted from many sources. However, when administered, it is converted to trans-resveratrol which is the active form with no significant side effects have been recorded and no safety issues have also been indicated in many of the studies involving use of resveratrol. Possible anti-platelet effect is suggested, hence, there is need for proper care when using other key prescription drugs or coagulation interfering products.
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