Nuclear Factor Kappa B Inhibition as a Therapeutic Target of Nutraceuticals in Arthritis, Osteoarthritis, and Related Inflammation

CHAPTER 25

Nuclear Factor Kappa B Inhibition as a Therapeutic Target of Nutraceuticals in Arthritis, Osteoarthritis, and Related Inflammation Hazem M. Shaheen*, Abdelwahab A. Alsenosy† *

Department of Pharmacology, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt Department of Biochemistry, Faculty of Veterinary Medicine, Damanhour University, Damanhour, Egypt

†

1. INTRODUCTION Rheumatoid arthritis (RA) is a disease of chronic autoimmunity with an extensive inflammation of the synovial membrane, resulting in erosions of articular cartilage and marginal bone and causing inflammatory joint destruction. Arthritis is chiefly a disease of the joints with a proinflammatory disorder, thus a full understanding of the inflammatory character of arthritis is essential for the success of therapeutic trials.1 Bone tissue primarily contains osteocytes, osteoblasts and matrix osteoid proteins with deposition of salts mainly inorganic mineral. Osteoprotegerin (OPG) and receptor activator of nuclear factor kappa B (NF-κB) ligand (RANKL) played a key role in osteoclast differentiation via its receptor RANK located on the osteoclast membrane. So, diseases such as osteoporosis and arthritis could be regulated by osteoclast differentiation.2 The present molecular biological technologies have extended useful approaches for RA research. Nowadays, gene expression is a prime tool used to investigate pathogenesis in RA, and it provides useful information for understanding RA.3 RA susceptibility loci were discovered through candidate gene, linkage, and genome-wide association studies. The gene signatures in the synovial tissues of rheumatoid arthritis and osteoarthritis have been found using microarray approaches.4 Lately, it is accepted that NF-κB provides a central inflammatory mediator that responds to large varieties of immune receptor signals. Because deregulated NF-κB activation is involved in various inflammatory diseases, targeting the NF-κB signaling pathway is a prominent application for antiinflammatory therapies. Several kinds of inhibitors have been developed to block the different steps of NF-κB signaling.5

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases https://doi.org/10.1016/B978-0-12-813820-5.00025-8

© 2019 Elsevier Inc. All rights reserved.

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2. RHEUMATOID ARTHRITIS Arthritis is an endothelial dysfunction that could be termed a systemic disorder, indicating an inflammation in rheumatoid arthritis with chronic stages.6 The role of chemokines and enzymes of inflammation such as cyclooxygenase-2, 5-lipoxygenase, matrix metalloproteinase, interleukin-1β, IL-6, cytokines, TNF-α, and adhesion molecules in arthritis has been documented. Most of the inflammatory mediators involved in arthritis have been approved to be regulated by NF-κB.7 The multifarious relations between genetic vulnerability and deregulated genes generate rheumatoid arthritis. The clinical signs in arthritic patients are the formation of pannus with atypical proliferation of synovial tissue. Early diagnosis could heighten the prognosis and the quality of life of RA patients. However, the pathogenetic mechanism of RA is indefinite without reasonable biomarkers for early diagnosis in clinical practice.8 The course of action of RA involves a variety of cells containing innate immune cells such as monocytes/macrophages, T and B cells, and synovial fibroblasts. NF-κB mediates the induction of proinflammatory cytokines such as TNF-α, IL-1, and IL-6 in monocytes/macrophages. The canonical and noncanonical NF-κB pathways also mediate RANK ligand-induced differentiation of monocytes/ macrophages into the bone-resorbing osteoclasts, whose deregulation adds to an inflammatory bone loss followed by RA.9 In between the lymphocyte subsets of T cells, Th17 cells are predominantly important for the advancement of RA. NF-κB promotes Th17 segregation indirectly through induction of inflammatory cytokines, IL-1, IL-6, and IL-23, of cellular immune and directly regulates transcription factors of Th17 lineage in T cells.10 Deregulated activation of NF-κB also contributes to atypical survival of self-reactive B cells and autoantibody stimulation that donates to RA pathogenicity.11 Particularly, RA patients often display higher levels of B-cell activating factor in serum belonging to the TNF family associated with unsynchronized stimulation of the NF-κB noncanonical type.12 Therefore, NF-κB mediates the pathogenesis of RA by functioning in various cell types, as shown in Figure 25.1.

3. NF-κB MEDIATOR IN RHEUMATOID ARTHRITIS NF-κB is an initiator in RA pathogenesis and is essential for the production of inflammatory mediators in the synovium. However, while much is recognized about the pathways that result in NF-κB stimulation in transformed cells and in lab animals, these events often differ in the RA linked cells, such as human myeloid cells and cells of the synovium. These events are only being fully explored now, using new approaches such as adenoviral infection. Doubtlessly, cutting-edge technologies such as small inhibiting RNA will also give great insight into the functional roles of these proteins in prospect studies. This will be important to help identify new therapeutic targets of RA and validate those therapies already under development. The exquisitely specific NF-κB response induced by

Nuclear Factor Kappa B Inhibition as a Therapeutic Target

Figure 25.1 Osteoarthritis pathophysiology with attachment of the synovium. Products of cartilage breakdown released into the synovial fluid are phagocytized by synovial cells, intensifying synovial inflammation. In turn, the productions of proinflammatory mediators initiate a surplus production of the proteolytic enzymes, leading to cartilage breakdown. Additionally, the inflamed synovium facilitate the osteophyte assembly via BMPs.

different stimuli in different cells gives hope that treatments can be developed to specifically target NF-κB in the inflamed synovium with no harmful effects on the innate immunity.13 In the synovial cells with RA, activation of the NF-κB pathway could transactivate a responsive gene of the inflammatory phenotype, containing TNF-α from macrophages, matrix metalloproteinases from synovial fibroblasts, and chemokines that hire immune cells to the inflamed pannus. Despite these differences at the molecular level, the significance of NF-κB in inflammation is approved and inhibition of the pathway is widely believed to have great potential as a treatment target in RA. Commercial effort has been exerted into developing inhibitors of NF-κB activation. However, inactivation of the NF-κB leads to an exacerbation of inflammation if TNF-α production by macrophages is not controlled.14 The data gained from arthritic patients suggest that NF-κ B activation is thoroughly involved in the chronic inflammation of the RA synovium. Accordingly, inhibitors of NF-κB are a potential approach as therapeutics for RA. The successful trials for treatments that directly target the products of NF-κB focused genes, such as TNF-α, IL-6, and IL-1, are a major advance in the treatment of RA patients that do not respond to the pattern treatment.15 The useful intensifying evidence is that NF-κB is a major transcription factor controlling inflammation. The activation of the NF-κB pathway is concerned with the progress of chronic inflammatory disorders, including rheumatoid arthritis and inflammatory disease of the bowel.16 An inhibitor of the NF-κB kinase complex formed by the NF-κ kinase inhibitor and IKKb and subunit IKKg that is a regulatory regulates NF-κB proteins. This inhibitor kinase phosphorylates IkB is then ubiquitinated and degraded, leading to the NF-κB activation.17 Moreover, a family of nucleotide-binding domain and leucine-rich repeat containing including NOD1, NOD2, NLR pyrin domain containing (NLRP) 3, and NLRP2 regulate the

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Figure 25.2 Genes targeted by NF-κB in inflammation series and development. NF-κB is an inducible transcription factor. Once activated, it can trigger transcription of a series of genes regulating inflammation. In addition, NF-κB targets inflammation by increasing the induction of inflammatory cytokines, chemokines, and adhesion molecules. It also regulates the cell survival and proliferation, apoptosis, and angiogenesis.

activation process of NF-κB.18 A common signaling event is initiation of the canonical NF-κB pathway, which regulates transcriptional induction of proinflammatory cytokines, chemokines, and additional inflammatory mediators in different types of innate immune cells (Figure 25.2).

4. NFKB IN MODELS OF RA Many studies in rheumatoid arthritis propose that NF-κB is essential for the expression of inflammatory mediators such as cytokines and tissue-degrading enzymes. Consistently, NF-κB activation is approved in synovial tissue from arthritic patients, and this emerges as a relation to clinical manifestation. Uncontrolled regulation of proteins that direct the NF-κB pathway contributes to the susceptibility or severity of inflammation during diseases.19 The joints of rheumatic patients’ synovia are infiltrated by immune cells, leading

Nuclear Factor Kappa B Inhibition as a Therapeutic Target

to chronic inflammation, pannus formation, and consequent joint and cartilage damage. The RA synovium is known to possess basically macrophages (30%–40%), T cells (30%), and synovial fibroblast alongside B cells, dendritic cells, other immune cells, and the endothelium.20, 21 RA synovial fluid has been analyzed, and it contains a broad variety of effector molecules including proinflammatory cytokines (such as IL-1β, IL-6, TNFα, and IL-18), chemokines (such as IL-8, IP-10, MCP-1, MIP-1, and RANTES), matrix metalloproteinases (MMPs, such as MMP-1, -3, -9, and -13), and metabolic proteins (such as COX-1, COX-2, and iNOS).22 These correlate in a complex manner that is assumed to cause a malicious cycle of proinflammatory signals, resulting in frequent and chronic inflammation. TNFα is obviously the key inflammatory mediator and also induces apoptosis. Importantly, the genes encoding TNFα and many other listed factors are well known to be controlled by NF-κB transcription factors, suggesting that NF-κB could be a central key of inflammatory cytokine production in RA. Indeed, the activated NF-κB transcription factors have been verified in cultured fibroblasts of the synovium.16 The joints of arthritic humans and animals with experimentally induced RA. Immunohistochemistry has demonstrated the presence of both p50 and p65 in the nuclei cells lining the synovial tissue and macrophages.23 Furthermore, cellular extracts have verified a facility to attach the NF-κB consensus sequence. A practice such as in vivo imaging has been used to demonstrate the bustle of NF-κB in a mouse model of inflammation. By placing the luciferase gene controlled by NF-κB, a marked increase in luminescence was observed in the mice joints. These findings are investigated in mice that carried an NF-κB family member’s c-Rel knockouts genes.24

5. HERBALS WITH POTENTIAL ANTIARTHRITIC ACTIVITIES VIA NF-κB 5.1 Capsicum Genus Natives have traditionally used Capsicum annum fruit for many centuries. It contains chemicals that cause highly selective anesthesia by the breakdown of the capsaicin-sensitive nociceptive nerve endings. It is known to be potent in the stimulation 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-κB activation for generating the antiinflammatory effect.25 The herb is often mixed with other antiarthritic herbals. It is also used for peripheral neurone disorders and chronic musculoskeletal pain.26

5.2 Curcuma Genus Several members of the Curcuma genus are used in traditional medicine, with the most important being Curcuma longa (CL), or turmeric. Its rhizome has a centuries-long use as a dietary spice as well as a herb for its antiinflammatory properties, hence its utility in arthritic conditions, including RA.27 In an animal arthritis model, a preparation from Curcuma lacking essential oil strongly suppressed joint inflammation and periarticular

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damage with decreased activation of NF-κB and of the resultant cascade of events (involving mediators of inflammation such as chemokines, cyclooxygenase 2, and the receptor activator of NF-κB ligand).28 The ability to prevent the negative changes in joints and bone appears to be comparable to that of betamethasone.29 Liposomal encapsulation may help overcome the poor bioavailability problem generated by the low water solubility. The osteoclast-osteoblast balance is tilted for bone building while halting the osteoarthritis progression.30 In a ratinduced arthritis model, applying ginger and turmeric rhizomes was better than indomethacin (a potent NSAID) regarding the facility to improve both joint histopathological changes and the extraarticular manifestations, including systemic inflammation, malnutrition, and iron deficiency anemia, with no intolerance to kidney function and lessen the cardiovascular risk factors.31 In human clinical studies, a combination of Curcuma longa has been shown to be more efficient than a standard dose of celecoxib in the treatment of osteoarthritis, improving the condition of the patients with no toxicity detectable by laboratory tests.32 Curcuma domestica extracts are useful in knee osteoarthritis, reducing the pain with an efficiency equivalent to ibuprofen, but with low side effects.33 A metaanalysis found related scientific confirmation for the efficacy of turmeric as a therapeutic option in arthritis, but more studies are necessary to definitively fasten it.34 The active ingredient phenolic 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 signaling pathways and mediators.35 In a rat model of arthritis, Curcuma improved joint inflammation in the few hours after the arthritis-inducing event.36

5.3 Garlic It is well established that IL-1β, once bound to its type 1 receptor, activates NF-κB dimers by triggering phosphorylation and subsequent reduction of the inhibitory IκB proteins. Activation of NF-κB was a necessity for IL-1β-induced MMP-13 secretion in OA chondrocytes.37 Also, Imamura et al. proved that IL-1β and TNF-α inhibited chondrogenesis via the pathway of NF-κB in human mesenchyme stem cells.38 Various garlic products have been studied in osteoarthritis where garlic has demonstrated that it suppressed arthritis through inhibition of NF-κB DNA-binding activity and expression of iNOS and COX-2.39 However, there are few studies on the garlic effect on osteoarthritis. In addition, a previous study revealed that DATS suppressed MMP2–9 expression, which was dependent on NF-κB and ERK-MAPK signaling pathways.40 Mechanistically, garlic was found to be related to the increased levels of IκBα induced by IL-1β, which subsequently mitigated p65 nuclear translocation and the transcriptional activity of NF-κB. Furthermore, a result indicated that IL-1β treatment increased the expression of TNF-α at both the transcription and translation. The combination of these findings suggests that garlic can potentially be applied in OA treatment.

Nuclear Factor Kappa B Inhibition as a Therapeutic Target

5.4 Ginger Zingiber officinalis (ZO), also known as ginger, is a common spice used in Asian cuisine and a traditional remedy for joint diseases in ethnomedicine.27 Nevertheless, the ginger extract inconsistently increased the synthesis of proinflammatory cytokines (TNF-α, IL-6, and monocyte chemotactic protein-1) in cell culture. The exogenous administration of the ginger extract had a twofold effect on TNF-α synthesis in mice in peritoneal cells: ZO extract primarily improved it, but with repeated administrations reduced it.41 In addition, it augmented the serum corticosterone level and this may contribute to the antiinflammatory effect of ZO. A recent human clinical study found that ZO powder supplementation can reduce the serum level of nitric oxide and high-sensitivity reactive protein hs-CRP in OA patients. The inflammatory markers started to decrease after 3 weeks of treatment.42 Several studies showed a clinical improvement in OA patients with ZO extract as evaluated by the pain score with VA and a reduction in intake of free medication, having mostly mild gastrointestinally adverse events. Sharp-tasting constituents of ZO were thought to contribute to the antiinflammatory activity of this medicinal plant. For instance, ginger inhibited kB kinase activity required for NF-κB activation and suppressed NF-κB-regulated expression of inflammatory genes in the lipopolysaccharide S-activated macrophage.43 6-Dehydrogingerdione attenuated iNOS, COX-2, IL-1β, IL-6, and TNF-α gene expression in vitro in RAW 264.7 macrophages.44

5.5 Licorice About 300 polyphenols have been isolated from licorice, including phenolic acids, flavonoids, flavans, chalcones, isoflavan, and isoflavonoids. Thus far, the main antiinflammatory active polyphenols in licorice are chalcones, isoflavan, and isoflavonoids. The mechanisms for the antiinflammatory 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.45, 46 Furthermore, LCC decreased the expression of iNOS and modulated the antioxidant system activity of SOD, catalase, and glutathione peroxidase.47 LCE efficiently inhibited PKC/JNK and ERK1/2; reduced the expression of iNOS, COX-2, IL-6, IL-1β, IL-12p40, TNF-α, AKT, and p38 mitogen-activated protein kinase (MAPK); and lessened IκBα degradation and NF-κB activities as well as the transcriptional activity of activator protein AP-1.48 Besides chalcones, other flavonoids in licorice, including DGC, DGD, ISOA, GLD, LID, and LIA, also revealed tremendous antiinflammatory activities. DGC, DGD, and ISOA all showed well-built ferric reducing activities and effectively scavenged DPPH, ABTS+, and singlet oxygen radicals.49 Furthermore, DGC increased the expression of haemeoxygenase-1 and MAPK phosphatase-1, suppressed the inflammationmediated neurodegeneration, production of TNF-α, NO, ROS, NF-κB and phosphorylation of p38 MAPKs, ERK1/2, IκB-α, and p65.50 GLD significantly inhibited NO

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and IL-1β release51 and decreased the iNOS mRNA expression under high-glucose levels, which indicated that GLD could be applied to diabetes-induced vascular dysfunction.52 LID and LIA inhibited the secretion of IL-6, chemokine (C-C motif) ligand 5, and MMP-7, -8, and -9. The suppression of cytokine and MMP secretion by LID and LIA was associated with the inhibition of NF-κB p65 in periodontitis therapeutic trials.53

5.6 Pomegranate In vivo studies have defined a clear role for NF-κB in the modulation of inflammation by pomegranate extracts, findings that have been confirmed in vitro. Pomegranate juice, POMxTM extract,54 and their bioactive compounds punicalagin55 or delphinidin56 all suppressed NF-κB activation in different cells. It was found that pomegranate inhibited the expression of NF-κB target genes, including IL-6 and interleukin 8 (IL-8), upon exposure to proinflammatory stimuli in intestinal cells.57 Also, EA and POMxTM58 declined NF-κB activation in various subsets of immune cells, and anthocyanin delphinidin reduced inflammation in rheumatoid arthritis cells. Taken together, these results suggest that pomegranate and other bioactive compounds present in its juice show antiinflammatory effects in vitro, and that the mechanisms involved appear to be related to inactivation of NF-κB signaling. Administration of pomegranate-derived products has been shown to reduce inflammation in a respiratory inflamed model of mice59 and in the joints of RA model mice.60 There also exists data support suggesting that pomegranate extract exerts antiinflammatory effects that may alleviate the symptoms of IBD and inflammation were all recovered by pomegranate fruit supplementation in rodent models of IBD.61 The mechanisms involved appear to be related to the inhibition of NF-κB,62 c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase, and signal transducer and activator of transcription 3 phosphorylation.63

5.7 Resveratrol Resveratrol has a variety of concentrations in different plants and the higher concentrations are believed to be derived from knotweed or Polygonum cuspidatum and red wine grapes. In plants, it is located in the skin, which serves as a phytoalexin in the protection of the plant against infection and UV radiation as well as a broad plant defense system. It is known to acquire antimutation, antioxidant, antiinflammatory, and DNA protection entities when consumed by animals and humans. Numerous studies have been established in neuro and cardio protection. This is used in the management of arthritic joint pain. Intraarticular injections of resveratrol showed protective effects on the cartilage through the reduction of the inflammatory reactions caused by osteoarthritis in the knees. This has also been justified with the reduction of the edema in experimental animal models supposedly related to the inhibition of production of the prostaglandins.64 It is also a powerful inhibitor of the TNF-α and IL-1β-induced NF-κB activation. Similarly, the

Nuclear Factor Kappa B Inhibition as a Therapeutic Target

antiinflammatory activities may be suppressing the COX-2 pathways through blocking NF-κB activation in the joints. Resveratrol is extracted from many sources. However, when administered, it is converted to transresveratrol, which is the active form, with no significant side effects and no safety issues in numerous studies of resveratrol.65

5.8 Sesamum Oil Sesame oil (SO) extracted from Sesamum indicum has been used in various Asian traditional medicines to lighten pain in inflammatory conditions of the various tissues such as joints, teeth, and skin.66 In rat-induced arthritis, SO was tested and was capable of reducing the biochemical consequences of oxidative stress: lower plasma thiobarbituric acid reactive substance levels and reduced gamma-glutamyltransferase activity in the joints.67 In a rat model of destructive arthritis, SO strongly delayed the inflammatory reaction and lowered the levels of inflammatory mediators, hindering the NF-κB activity within the mast cells and the activation of complement systems.66 In another arthritic model, SO alleviated the inflammatory pain by inhibiting oxidative aggression via falling lipid peroxidation and production of superoxide anion and peroxynitrite in the muscles.68 SO is active in experimentally induced arthritis through its minor constituents which without it is inactive, decreasing the clinically visible joint inflammation, in addition to its serum markers including oxidative stress related molecules, RA markers, inflammatory eicosanoids and cytokines and the activity of hydrolytic enzymes; additionally, bone loss was also diminished.69 In a study on knee OA patients, orally administrated sesame produced better outcomes in terms of objective and subjective manifestations in comparison to standard therapy alone.70 In OA patients, a placebo trial on sesame seed management was associated with a noticed drop in serum levels of malondialdehyde and of high-sensitivity C-reactive protein (hs-CRP); it also significantly lowered levels of IL6 after treatment.71 The ability of SI to protect from the forward consequences of inflammation and oxidative stress is due to the presence of lignans. It contains sesamin and its hydroxylated counterpart, sesamolin. Similar biological activity has a phenolic compound, sesamol (3,4-methylene-dioxy-phenol), which results from the degradation of sesamolin.72 Sesamol has been approved to alleviate joint inflammation and cartilage degradation in an adjuvant-induced arthritis animal model. This action was paralleled by a drop in the level of proinflammatory cytokines and in the activity of tissue-destructive enzymes.73 In addition, restorations of the oxidant homeostasis reflected in decreased oxidative stress markers and a boost in the activity of protective enzymes were noticed, which leads to the inhibition of this inflammation-promoting enzyme.72

5.9 Whitania somnifera Withania somnifera (WS) also called ashwagandha, is a powerful antiosteoarthritic and antiinflammatory plant.74 WS extract was studied in vitro, and it was observed to inhibit

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liposaccharide S-induced production of proinflammatory mediators (TNF-α, IL-1β, and IL-12) in mononuclear cells from rheumatoid arthritis in humans.75 The WS extract also showed inhibitory effects on collagenase activity in the Achilles tendon that may be useful in joint disease treatment.76 In an experimental rat-induced arthritis model, WS root powder had shielding effect on bone collagen.77 The aqueous extract of WS produced a significant reduction of scores for pain, stiffness, and disability in patients with knee joint inflammation in a randomized, double-blind, placebo study.78 Withaferin A suppresses NF-κB activation by targeting a crucial cysteine 179 in IKKβ, a kinase, and by inhibition of the NF-κB essential modulator complex formation, according to molecular studies.79, 80

6. NUTRACEUTICALS TARGET THE NF-κB PATHWAY IN ARTHRITIS 6.1 Camel Milk Camel milk revealed various antiinflammatory effects via downregulation of TNF-α, COX-2, iNOS, and its upstream effector NF-κB, together with enhancing the IL-10 antiinflammatory pathway. These antiinflammatory mechanisms are described additionally in further studies, which reported that camel milk possesses marked antiinflammatory actions in experimental models.81, 82 The observed downregulation of activated NF-κB p65 in the pouch lining confirms the effectual antiinflammatory performance of camel milk.83 Meanwhile, the observed downregulation of iNOS, TNF-α, and COX-2 in arthritic rats is prone to the downregulation of their upstream NF-κB transcription factor.84, 85

6.2 Glucosamine Glucosamine is a building block of polysaccharide chain glycosaminoglycans correlated to a protein in proteoglycan molecules called aggrecans, forming a component of the cartilage matrix. Glucosamine administration exerts specific outcomes on chondrocytes and cartilage in osteoarthritis.86 Glucosamine affects the molecular expression of arthritic cartilage, and its therapeutic effects are linked to its anticatabolic activities.87 Glucosamine is given in vitro to reduce PGE2 production and inactivation of the NF-κB pathway, thus inhibiting the cytokine intracellular signaling cascade in chondrocytes and synovial cells. In osteoarthritis, glucosamine induces a setback of the inflammation and jointdegenerating drawbacks of IL-1.86 Interleukin-1β is a persuasive proinflammatory cytokine produced in the arthritic joint, where it triggers the upregulation of inflammatory mediators such as COX-2, iNOS, IL-6, and TNF-α. IL-1β also induces cells to produce more IL-1β and matrix degradation factors, such as metalloproteinases (MMPs) and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member TSs (ADAMTSs). Most of these genes are under the transcriptional control of NF-κB.

Nuclear Factor Kappa B Inhibition as a Therapeutic Target

Glucosamine at appropriate concentrations lessens the gene expression of COX-2, iNOS, and microsomal prostaglandin Esynthase-1 (mPGEs1) and PGE2 synthesis after IL-1β induction, signifying that glucosamine can regulate the triggered cascade by inflammatory stimuli.88 Transcription of IL-6, IL-8, IL-24, and TNF-α genes is controlled by multiple transcription factors, such as NF-κB.89 Attractively, the functions of NF-κB are controlled by OGlcNAc modification.90 Furthermore, GlcN inhibits the TNF-α-induced chemokine expression by rat smooth muscle cells via the O-GlcNAc modification of NF-κB p65.91 Moreover, it was previously revealed that GlcN inhibits the expression of chemokine and the adhesion molecule by endothelial cells via O-GlcNAc modification of NF-κB p65.89 GlcN had been confirmed to enhance the O-GlcNAc modification of NF-κB p65 but suppresses the expression of cytokines in MH7A cells. These observations likely suggest that the expression of proinflammatory cytokine genes may be regulated by the mechanism involving the O-GlcNAc modification of NF-κB.

6.3 Chondroitin and Glucosamine Combination The chondroitin and glucosamine combination restrained the IL-1-induced gene upregulation of iNOS, COX- 2, m PGEs, and NF-κB in inflamed cartilage. This led to decreased NO and PGE2 production, which is the mediator for chondrocyte cell death and inflammatory reactions.92 Both in a mixture could diminish production of the COX2 enzyme. One way is the reduction of the IL-1β-induced NF-κB pathway by glucosamine results in reduced synthesis of the COX-2 enzyme.93 A further way in which glucosamine inhibits COX-2 is the downregulation of COX-2 N-glycosylation and the facilitation of COX-2 protein yield.94 Chondroitin alone reduces the nuclear translocation of NF-κB, which lessens the production of proinflammatory cytokines IL-1β and TNF-α and enzymes such as COX-2 and NOS-2.95 The antiinflammatory capability of CS was a reduction of the proinflammatory molecules C-reactive protein and IL-6 and the expression of MCP-1 and COX-2 in the mononuclear cells. It also inhibited NF-κB that initiates induction of inflammatory processes.96 Furthermore, the metalloproteinase-3 (TIMP-3), a potent inhibitor of ADAMTS, was upregulated. Glucosamine alone inhibited the activation process of MMP-2 and MMP-9 expression via inhibition of the NF-κB pathway.97 Inflammatory mediators are keys for narrowed biosynthesis of cartilage material. In rats, chondrocytes models have shown that IL-1β inhibits the key enzyme in the biosynthesis of cartilage GAG chains and a dosedependent glucosamine could reduce this inhibition.98

6.4 Omega 3 Fatty Acids Omega-3 polyunsaturated fatty acids such as linolenic acid and eicosapentaenoic acid are found in plant and fish oils.51 Their antiinflammatory action has been approved in several

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studies. It has been successfully used in clinical trials, mainly to treat rheumatoid arthritis. In vitro studies on omega-3 fatty acids revealed that they can augment collagen synthesis and diminish the inflammatory mediator PGE2.99 Omega-3 fatty acids decrease IL-1induced aggrecanase and collagenase activity and reduce mRNA transcription of ADAMTS-4, COX-2, IL-1α, and TNF-α. Furthermore, they decline the levels of numerous MMP proteins.100 Inflammatory diseases are regularly related with activation of NF-κB transcription factor and release of inflammatory cytokines and therefore, this is an important target for n-3 PUFAs. Associations between dietary fats and DNA methylation in the NF-κB pathway, measured using the Infinium 450 k array, were observed in the Greek preadolescent cross-sectional cohort. Therefore, this may provide valuable targets within intervention studies.101

7. CONCLUSION Because dysregulated NF-κB activation is implicated in various inflammatory diseases, targeting the NF-κB signaling pathway represents a striking application for antiinflammatory trials in arthritis. It’s noticed that the use of nutrients in rheumatology is atypical and eventually, the enhanced interest in arthritic patients in the nutrient approach will be a reality. Therefore, rheumatologists should advise their patients with scientific tools and the finest data available. In this sense, the antiarthritic ability of nutrients sets its position, which supports precise scientific evaluation on all approaches that improve the therapy of rheumatic diseases. At present, the nutrient approaches are possibly advantageous for RA patients, although there is still a long way ahead in terms of research to draw firm conclusions. Until now, no long-term studies, nor studies to assess series of joint damage; conversely some complementary therapies may signify a prospect to broaden the worth of our patient’s life, may be along with integrated management of arthritic patients in the future.

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