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-1?, IL-6,
TNF? 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. TNF? is obviously the key inflammatory mediator and also induces
apoptosis. Importantly, the genes encoding TNF? 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).
Herbals with potential anti-arthritic activities via NF kB
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).
well-established that IL-1?, 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-1? induced MMP-13 secretion in OA chondrocytes (Kim S. R., 2013. ) (Tsutsumi R.,
2008. ). Also, Imamura et al. proved that IL-1? and
TNF-? 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?B? induced by IL-1?, which subsequently
mitigated p65 nuclear translocation and the transcriptional activity of NF-?B.
Furthermore, our results indicated that IL-1? treatment resulted in a
significant increase in expression of TNF-? 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
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-1?, IL-6, and
TNF- ? 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-1?, IL-12p40, TNF-?, AKT and p38
mitogen-activated protein kinase (MAPK), and attenuated I?B? 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-?, NO, ROS, NF-?B and phosphorylation of p38 MAPKs, ERK1/2,
I?B-? and p65 (Kim J, 2013. ). GLD significantly inhibited NO and IL-1? 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 23 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-? 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 .