Nawarathne Kalka: Antiinflammatory Actions and Potential Usage for Arthritic Conditions

CHAPTER 19

Nawarathne Kalka: Antiinflammatory Actions and Potential Usage for Arthritic Conditions Pathirage Kamal Perera*, Diyathi Tharindhi Karunaratne† * Institute of Indigenous Medicine, University of Colombo, Colombo, Sri Lanka College of Chemical Sciences, Institute of Chemistry Ceylon, Rajagiriya, Sri Lanka

†

ABBREVIATIONS PAF COX HPET PLA2 AA TX PG

platelet activating factor Cyclooxyganase Hydroperoxy-eicosatetraenoic acid Phospholipase A2 Arachidonic acid Thromboxane Prostaglandin

1. INTRODUCTION Traditional medicine in Sri Lanka have been practiced for >3000 years. Ayurveda, as defined in the Act, encompasses all medical systems indigenous to Asia, including Siddha and Unani in Sri Lanka.1 As people are becoming aware of the potency and side effects of synthetic drugs, there has been an increasing interest in natural product remedies with a basic approach toward nature. Throughout the history of mankind, many infectious diseases have been treated with herbals.2 Ayruveda is a traditional medicine system that originated in India approximately 6000 years ago. In Sanskrit, “Ayu” means “life” and “Veda” means “knowledge” or “science.” Ayurveda can therefore be interpreted as the “science of life.”3 Ayruveda has a strong logical, philosophical basis. It is not only limited to body or physical symptoms but also gives a broad knowledge about spiritual, mental, and social health.4 Ayurveda practices the theory of balance of Tridosha: Kapha, Pitta, and Vata.5 It demands that one herb or one drug cannot cure the imbalance of inflammatory mediators. Therefore, in most of the cases, a combination of herbs and plants (which are even parts of staple foods) are recommended for treatments.6 The most important among traditional systems of medicine in Sri Lanka is Ayurveda, which also forms part of the national health services provided by the government of Sri Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases https://doi.org/10.1016/B978-0-12-813820-5.00019-2

© 2019 Elsevier Inc. All rights reserved.

323

324

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Lanka, including a separate ministry for indigenous medicine. About 60%–70% of the rural population relies on traditional and natural medicine for their primary healthcare.1,7 Therefore, herbal drugs are a necessity as components of the primary healthcare system in Sri Lanka. Mainly, four systems of traditional medicine have been adopted in Sri Lanka: Ayurveda, Siddha, Unani, and Deshiya Chikitsa (Sri Lankan traditional medicine). The plants are extensively used singly or as mixtures in these systems. The traditional systems of medicine have a vast literature, mainly in the form of manuscripts, including medicinal scripts of ola leaves. Nawarathnekalka is a very old formula with >100 years of evidence included in the gold standard traditional medicine book, Vatika Prakarana, in Sri Lanka.8 Most of the formulas of this book include an essential Ayurveda drug list. NK is an excessively used antiinflammatory and immune-enhancing essential Ayurveda drug.

2. PATHOGENESIS OF RHEUMATOID ARTHRITIS In early rheumatoid arthritis, the synovial membrane becomes thickened. In the normal knee joint, the synovium has a synovial membrane (usually one or two cells thick). Synovial-lining cells are designated type A or type B. A pannus formation or a new network of new blood vessels is formed in the synovium. T cells (predominantly CD4 +) and B cells (plasma cells) infiltrate the synovial membrane. These cells are also found in the synovial fluid along with large numbers of neutrophils, and the synovial membrane begins to invade the cartilage. In established rheumatoid arthritis, the synovial membrane becomes transformed into inflammatory tissues.9 The joints of RA patients are characterized by an infiltration of immune cells into the synovium, leading to chronic inflammation, pannus formation, and subsequent irreversible joint and cartilage damage.10 Destruction of the tissue is mediated by intracellular signaling pathways involving transcription factors, such as nuclear factor kappa B, cytokines (such as IL-1, IL-6, TNF-α, and IL-18), chemokines (such as IL-8 and RANTES), growth factors, cellular ligands, metabolic proteins (such as COX-1, COX-2, and iNOS), and adhesion molecules.11 As a key proinflammatory cytokine, TNF-α, along with the other cytokines, activates immune cells, including macrophages and other cells such as synovial fibroblasts. In a key step, activated macrophages and synovial fibroblasts release proinflammatory cytokines, including TNF-α, IL-1, IL-6, and mediators of vascular growth, including VEGF (VEGF is essential to blood vessel proliferation or angiogenesis, which facilitates the influx of activated cells).12 These cells contribute to the growth of the pannus and villous projections from the pannus, allowing better access to the cartilage and bone. Activated cells and macrophages release matrix metalloprotenases (MMPs), which induce cartilage destruction that results in irreversible cartilage damage and joint space narrowing. This also induces the activation of osteoclasts, resulting in bone resorption and finally leading to the pathogenesis of RA. Recent advances in understanding the inflammation seen in rheumatoid arthritis have led to the successful use of therapies.13 Inflammation types are differentiated by

Nawarathne Kalka and Arthritis

the tissue that it occurs and arthritis are the inflammation that occurs in muscles, skin, joints respectively.14 And it is defined as the sum of the host’s defenses to infectious or noxious stimuli (e.g., pathogens or toxins). Based on visual observation, the ancients characterized inflammation by five cardinal signs: heat (calor), redness (rubor), swelling (tumor), pain (dolor), and loss of function (functio laesa).15 The first four of these signs were named by Celsus in ancient Rome and the last by Galen.16 When a pathogen or inflammatory stimuli (IS) enters one’s body, a cascade of events takes place. Every pathogen cell has an expression of proteins on their cell membranes called pathogen-associated molecular patterns (PAMPs). They are a diverse set of microbial molecules that share a number of different recognizable biochemical features (entire molecules or, more often, part of molecules or polymeric assemblages) that alert the organism to intruding pathogens.17 Most of the responses triggered by PAMPs fall into the general categories of inflammation and immunity, such as activation of immune cells to destroy the pathogen and/or pathogen-infected cells, and triggering an immunological response in order to produce and select specific T cell receptors and antibodies that are best suited to recognize the pathogen in the future.18 Inflammatory mediators, upon identifying the intruders, later take charge of the other defense mechanisms leading to inflammation. IMs found in blood vessels are generally two types (plasma IMs, cell-derived IMs). Plasma IMs that are kinases produced by the liver are usually found in the plasma of blood vessels that consist of a combination of complement proteins (C3a and C5a) and antibodies. These plasma IMs are helpful in a process called “opsonization.” Opsonization is the immune process of any molecule that enhances phagocytosis by marking an antigen for an immune response. Recognition of PAMPs is critically important in proper activation of the immune system, and toll-like receptors (TLR) are the signaling network responsible for innate immune response.19 Whereas cell-derived IMs are cytokines secreted by macrophages such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-α), arachidonic acid (AA) metabolites such as prostaglandins and leukotrienes, and histamine released by mast cells. IMs cause the most important characteristics of inflammation, such as vasodilatations (usually occur due to recruitment of new immune cells) and vascular permeability that leads to tumor and calor. The leakage of the plasma fluids and proteins from the blood vessels into the tissue causes tumor. Similarly, the sensory nerve fibers firing and certain cytokines and AA precursors such as prostaglandins that promote pain and fever promote dolor. The fifth characteristic of inflammation, loss of function, is usually seen only in cases of chronic inflammation.

3. ROLE PLAYED BY THE AA METABOLISM PATHWAY ON INFLAMMATION Figures 19.1 and 19.2 show the evaluation of the AA metabolism pathways, which lead to the production of eicosanoids that are IMs (such as LTs, thromboxane [TX], PGs) and

325

326

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Phospholipds

PLA2

Lyso-PAF

Promotes inflammation

PLA2 (Inhibited by Lypocortin)

AA Cyclooxyganase pathway (COX-1 and COX-2)

Lypooxyganase pathway

TX2 synthase

PGG2 (very unstable)

LTs

TX2 Vasoconstriction Platelet aggregation Bronco constriction

Peroxyganase

PGH2 F2a

e thas

syn

PGD2 synthase

PG

PGH2a Myometral constriction Bronoco constriction

PGH2 Vasoconstriction Platelet aggregation

PGF2a, PGD2, PGE2, PGI2 and PGH2 are similar in structures

PGE

2

syn

PGI2 synt

thas

e

PGE2 Vasodilation Hyperalgesic

hase

PGI2 Vasodilation Hyperalgesic Inhibits platelet aggregation

Figure 19.1 Cylooxyganse pathway.

the production of antiinflammatory mediators such as lipoxins. Although TXs, LTs, and PGs are generally called eicosanoids, TXs and PGs are called prostonoids. Reactive oxygen species (ROS), together with prostonoids, leukotrienes, and proteases, are also believed to be the mediators of inflammation and responsible for the pathogenesis of tissue destruction in RA. Antioxidant (AO) activity is one of the mechanisms by which many conventional drugs used in day-to-day treatment of RA alleviate the painful symptoms associated with this disease.20 Because ROS produced in the body is composed of many species, such as oxygen ions, peroxides, hydroxyl radicals, etc., one would require a combination of antioxidants to quench them altogether. Plant polyphenolics, though, are a good source of antioxidants, but they differ in their abilities to quench different species of ROS.21 Therefore, one may need to use a combination of phytochemicals and multieffective, polyherbal medicinal systems against inflammations.

4. SPECIFICATIONS FOR NAWARATHNA KALKA (TABLE 19.1)8,22 4.1 Honey The precise composition of honey varies according to the plant species on which the bee forages, but the main constituents are the same in all honeys: 95% of the solids in honey are carbohydrates with a highly complex mixture of sugars.23 Antibacterial activity and wound-healing property of honey can be taken as the key mechanisms to ease

Lypooxyganase pathway (Lypooxyganase) HOOC-15-HPETE-COOH

AA

15-Lypooxyganase

5-Lypooxyganase

HO-15-HETE-COOH

12-Lypooxyganase 5-Lypooxyganase Lypoxin A & B

HOOC-5-HPETE-COOH

HOOC-12-HPETE-COOH

Pauses the action of Pro-inflammatory stimuli

HO-12-HETE-COOH Inflammation LTA4

HO-5-HETE-COOH Inflammation sis

LTC4

ly dro Hy

H2O

LTD4

LTB4 Chemotaxis

LTE4

LTF4

Figure 19.2 Lypooxyganase pathway.

Constriction of Bronco muscles Vasodilation of most Vessels but coronary Vessels uses Vasoconstriction Asthma

328

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Table 19.1 Specifications for Nawarathna Kalka8,22 Ingredients of Nawarathne Kalka

Part of the plant used

Proportions (weight basis)

1. Cedrus deodara (Vernacular name (VN): Devadara) 2. Cuminum cyminum (VN: Suduru) 3. Eugenia caryophylla (VN: Karabu) 4. Ferula asafetida (VN: Perunkayam) 5. Glycyrrhiza glabra (VN: Valmi) 6. Myristica fragrans (VN: Sadikka)

Bark

1

Seeds Flower bud Resin Stem Dried kernel of the seed Seeds Roots Dried fruit Seeds

1 1 1 1 1

Seeds Rhizome Fruit (outer cover) Fruit (outer cover) –

1 1 13 26 50

7. Nigella sativa (VN: Kaluduru) 8. Picrorhiza kurroa (VN: Katukarosana) 9. Piper longum (VN: Thippili) 10. Trachyspermum roxburghianum (VN: Asamodagum) 11. Vernonia anthelmintica (VN: Sanninayam) 12. Zingiber officinale (VN: Inguru) 13. Terminalia bellirica (VN: Bulu) 14. Terminalia chebula (VN: Aralu) 15. Honey

1 1 1 1

rheumatoid arthritis. Before a wound-healing process can begin, the wound bed must have similar properties to those in the extracellular matrix.24,25 The association of an acid called hyaluronic with collagens and fibrins has proved to create an environment that encourages cell migration and proliferation as well as developing a similar environment to the extracellular matrix.26 Because the presence of sugar or honey can assist the formation of similar structures, hyaluronic acid consists of disaccharide chains made from modifications of monosaccharide glucose called glucuronic acid and N-acetyl glucosamine, in which case honey can act as a substitute for hyaluronic acid.27 Because RA patients suffer excessively from degradation of cartilage and bone damage, this develops an environment similar to a normal wound, which can be reversed by an occasional intake of honey due to its wound-healing ability.

4.2 Cedrus deodara (Devadara) The wood of C. deodara has been used since ancient times in Ayurvedic medicine for the treatment of inflammations, rheumatoid arthritis, and cancer as well as a potent disinfectant, antifungal, and analgesic.28 It also shows that the antiinflammatory activity of C. deodara wood oil could be attributed to its mast cell stabilizing activity and therefore

Nawarathne Kalka and Arthritis

inhibition of leukotriene synthesis (by inhibition of the lypooxyganase enzyme),28 causing the proinflammatory mediators to be inhibited. C. deodara on adjuvant-induced arthritis (AIA) and complete Freund’s adjuvant-induced arthritis (CFA) in rats showed that it effectively inhibited the polyarthritis phase and the acute phase of the induced methods, respectively, confirming its activity against both acute and chronic inflammatory response.

4.3 Cuminum cyminum (S. Suduru) Cumin seeds (Cuminum cyminum L.) are largely used as a condiment or spice in Indian food. They are also medicinally useful to treat hoarseness of voice, gonorrhea, dyspepsia, and chronic diarrhea. Cumin supplementation significantly reduces the incidence and number of tumors in the colon while preventing the accumulation of lipids in tissues and optimizing the excretion of fecal sterols and bile acids.29 Also, C. cyminum treatments are found to result in significant reductions in plasma and tissue cholesterol, phospholipids, free fatty acids, and triglycerides,30 decreasing the excessive lipid oxidations/ metabolism. A treatment of cumin can lead to elevated levels of cytochrome P-450 (cyt P-450), cytochrome b5 (cyt b5), cyt P-450 reductase, and cyt b5 reductase (the significance level of the phase II enzymes activity can be increased as well). In the antioxidant system, significant elevation of the specific activities of superoxide dismutase and catalase is usually observed while lipid peroxidation measured as a formation of MDA production showed significant inhibition in a recent study. The results strongly suggest that the cancer chemopreventive potential and the antioxidant properties of cumin seeds could be attributed to their ability to modulate the carcinogen metabolism as well as their antiarthritic properties.31

4.4 Eugenia caryophylla (S. Karabu) E. caryophylla (cloves) are proved to possess good antioxidant properties, suggesting that in addition to imparting flavor to the food, they possess potential health benefits by inhibiting lipid peroxidation32 and thus suppressing the production of LTs and PGs by the inhibition of excessive lipid peroxidation that can lead to inflammation. In human nutrition and biology, advanced glycation end products, known as AGEs, are substances that can be a factor in the development or worsening of many degenerative diseases.33 Active oxygen has been suggested to be involved in the process of formation of AGE,34 therefore causing elevation of oxidative stress. AGE (pentosidine) and AGE-modified IgG have been shown to correlate with RA disease activity,35 thus acting as an oxidative modification of proteins in autoimmune disease. According to Oya et al., Eugenia caryophylla possessed the ability to decrease the oxidative stress by suppression of

329

330

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

formation of AGE and forming an antiinflammation environment. Although Eugenia caryophylla may prove to be important in the treatment of RA with its antistress activity on behalf of the assumption that the unnecessary excitements of nuclear factors such as kappa can lead to stress-induced inflammation, further research is needed.36

4.5 Ferula asafetida (S. Perumkayam) An analysis of F. asafetida showed that it has 40%–64% of resinous materials of 267 of its caloric content. One of the most important components from its resinous material was found to be ferulic acid (FA), which has the multipharmacological activity of being anticancer, antiinflammatory, antimutagenic, antineoplastic, antitumor, antiviral, antibacterial, antispasmodic, antinitrosaminic, antioxidant, antiarthritic, and an immunestimulant.37 FA’s ability to decrease the levels of hydrogen peroxide-induced IL-1β, TNF-α, MMP-1, and MMP-13 were discussed in earlier studies to showcase it’s discouragement on bone destruction synovitis and the erosion of cartilage in antigen-induced arthritis,38 as well as its effect on the expression levels of chondrogenic genes such as type II collagen (COLIIA1) and SOX9.39 Other than FA, another important compound isolated from Ferula assafoetida is Farnesiferol C (FC)3 and it contributes in the antiinflammation process by inhibition of vascular endothelial growth factor (VEGF)-induced cell proliferation, migration, invasion, tube formation, and the expression of MMP-2.40 F. asafetida’s protective effect on joints appears to occur through multiple ways due to the various antiarthritic effects exerted by its constituent bioactive compounds.

4.6 Glycyrrhiza glabra (S. walmi) It has been known that the G. glabra (GG) roots (licorice) contain a host of phytochemicals, including flavanoids, saponins, and triterpenoids, that can significantly encourage the antioxidant and antiinflammatory effects.41 Licorice’s flavonoid constituents mainly include flavones, flavonals, and isoflavones.42 Among the constituents, glycyrrhizic acid (GA) or glycyrrhizin is a triterpenoid saponin normally considered to be the main biologically active component of GG.43 The other important constituent of GG is an isoflavan called glabridin.44 Later in this review, we will only discuss the roles of the two components, GA and glabridin, to reflect the GG’s antiarthritic effect. In a recent study, GA in licorice was found to have the ability to act as a neuroprotective agent by promoting downstream PI3K/Akt signaling and reducing inflammatory cytokine production and its resulting antiinflammation via the PI3K/Akt/GSK3β pathway.45 Martin et al. established that the PI3K-Aktdependent inhibition of GSK3β activity in human monocytes, stimulated with lipopoly saccharide (LPS), differentially affected the nature and magnitude of the inflammatory response through the activation

Nawarathne Kalka and Arthritis

of TLR2. This in turn resulted in the production of the antiinflammatory cytokine IL-10 while production of proinflammatory cytokines IL-1β, IL-6, TNF, IL-12, and IFN-α fell substantially. Inhibition of GSK3β negatively modulated the inflammatory response because it differentially affected the nuclear activity of NF-κB (p65 subunit)46 whereas the inhibitory effect of the licorice isoflavane (glabradin) on oxidation of LDL mediated by macrophages exhibits its antioxidant activity.47 Further, the antioxidant activity was directly correlated to the structures of glabaradin and its derivatives, which appeared to reside mainly on their 20 hydroxyl groups.48

4.7 Myristica fragrans (S. Sadikka and S. Vasawasi) Two important fruit spices are derived from the fruit–nutmeg and mace, where nutmeg is the dried kernel of the seed and mace is the dried aril surrounding it.49 It is studied that among the many chemical compositions of M. fragrans fruit, eugenol (EUG), myristicin (MYRS), safrole (SAFR), trimyristicin,50 and neolignans51 are in importance of its many pharmacological activities such antibacterial,52 anticancer,53 antiinflammatory,54 antioxidant,55 psychoactive,56 hepatoprotective, and hypolipidemic and antiatherosclerotic effects.57 Although no direct correlations were found with antiarthritic effects and M. fragrans, the antiinflammatory and antioxidant properties of its constituents such as myristicin showed antiinflammatory and antioxidant properties that could account for its antiarthritic-like effect. In a recent study, the antiinflammatory effect of myristicin on double-stranded RNA (dsRNA)-stimulated macrophages was examined to show the inhibition of the production of calcium, nitric oxide (NO), interleukin (IL)-6, IL-10, interferon-inducible protein-10, monocyte chemotactic protein (MCP)-1, MCP-3, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein (MIP)-1α, MIP-1β, and leukemia inhibitory factor in dsRNA [polyinosinic-polycytidylic acid]-induced RAW 264.7 cells. In conclusion, it showed that the myristicin has an antiinflammatory property related with its inhibition of NO, cytokines, chemokines, and growth factors in dsRNAstimulated macrophages via the calcium pathway.58

4.8 Nigella sativa (S. Kaluduru) Thymoquinone (TQ), dithymoquinone (DTQ), thymohydroquinone (THQ), and thymol (THY) are the most important pharmacologically active constituents/quinones in Nigella sativa (NS).59 And tyhymoquinone (C10H12O2; molecular weight: 164.2), the main bioactive component of the volatile oil of the black seed (NS, Ranunculaceae family), has been used as antioxidant, antiinflammatory, and antineoplastic medicines for >2000 years.60 The antioxidant and antiarthritic activity of TQ resulted in significantly reduced levels of proinflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ, and PGE2) and increased levels of IL-10. Likewise, the protective effects of TQ against

331

332

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

RA were evaluated in a recent study, showing the decrease in arthritis scoring and bone histology61 on TQ treatments. A comparative study between TQ and methotrexate, a well-known disease-modifying antirheumatic drug (DMARD) in RA, showed similarities on behalf of their effects against the pathogenesis of RA.62 However, in another study TQ was reported to inhibit histamine release from rat peritoneal mast cells in vitro, suggesting that the mechanism of action is mainly due to the ability of TQ’s remarkable stimulation of histamine secretion through phosphatidylserine on calcium transport across the plasma membranes by inhibition of protein kinase C and partly due to its ability to inhibit the oxidative energy metabolism.63

4.9 Picrorhiza kurroa (S. Katukarosana) The extracts from roots and rhizomes of this plant (commonly called katuka, kutki, or kutaki in India) are used to treat a variety of ailments, including fever, hepatitis, allergies, asthma, and other inflammatory diseases.3 The active constituent is known as kutkin, which is a mixture of kutkoside and picroside while its other constituents are apocynin, andorsin, and cucurbitacin glycosides.64 The active constituent kutkin, picroside-1, and kutkoside demonstrated high antiinflammatory activity in a variety of test models, showing significant antiinflammatory activity in adjuvant-induced arthritis and formaldehyde arthritis in rats and mice.65 Among these constituents, apocynin was found to have NADPH oxidase inhibition ability, therefore inhibiting production of ROSs by polymorphonuclear leukocytes (PMNs), thus acting as an antioxidant and antiinflammatory mediator.66 A study by Lafeber et al. (1999)67 showed that the potential of apocynin in the treatment of RA by pheriphertal blood mononuclear cells (PBMNC)-induced arthritis resulted in a decrease in IL-1 and TNF-α production by the MNC while IFN-gamma, IL-4, and T-cell-derived IL-10 were strongly diminished. While apocynin did not show any direct adverse effects on the chondrocyte metabolism, it diminished the release of proteoglycan from the cartilage matrix, which may be due to its ability to inhibit the effect of NADPH oxidase that results in the downregulation of the activities of the MNCs/PMNs and PBMNCs. Therefore, it reduces the production of proinflammatory cytokines.

4.10 Piper longum (S. Thippili) Piper longum (Long pepper) is a flowering vine in the family Piperaceae. It is cultivated for its fruit, which is usually dried and used as a spice and seasoning. The fruits contain the alkaloid piperine. P. longum is a component of Indian traditional medicine, reported to be used as a remedy for treating gonorrhea, menstrual pain, tuberculosis, sleeping problems, respiratory tract infections, chronic gut-related pain, and arthritis.3 Piperine plays a huge role in contributing to the antiarthritic property of P. longum as a whole, and that is done by the inhibition of the IL6 and PGE2 response to the already existing proinflammatory mediators. Piperine also inhibits the protein and mRNA expression levels of IL6 COX-2

Nawarathne Kalka and Arthritis

and MMP13 by blocking the MAPK/ERK1/2 pathway.68 The analgesic effect of piperine should also be noted here because of piperine’s ability to inhibit the production of PGE2 and the protein levels of COX-2.

4.11 Terminalia bellirica (S.Bulu) and Terminalia chebula (S. Aralu) Haritaki (T.chabula) and Vibhitaki (T.belerica) are two important components of many ayurvedic polyherbal formulations69 with antiarthritic effects, including Nawarathne Kalka, triphala, and triphala gugulu (TG). “Triphala” (T) (Sanskrit tri ¼ three and phala ¼ fruits) is composed of three medicinal fruits: Phyllanthus emblica L. or Emblica officinalis Gaertn., T. chebula, and T. belerica.70 The combination of Triphala and Gugulu (Myrrh oleoresin) is called tripahala guggulu, which is reported to have a chondroprotective property of antiarthritic effects.71 Pharmacological activities of NK, T, and TG greatly depend on their constituents as mentioned above, such as T. chebula is shown to be a potent hyaluronidase and collagenase inhibitor that prevents degradation of cartilage. And it’s also reported to contain hydrolysable tannins such as chebuline, chebulagic acid, and gallic acid that have produced an antiarthritic effect. From the studies of Ramani, 2012, chebulagic acid from immature seeds of Terminalia chebula suppressed the onset and progression of collagen-induced arthritis in mice and produced immune suppression via induction of transforming growth factor beta (TGFβ) and CD4 + CD25 + T cells. Note: CD4 + CD25 + T cells have been identified as a population of immune regulatory T cells that mediates suppression of CD4 + CD25  T cells by cell–cell contact and not secretion of suppressor cytokines. Also, CD4 + CD25 + T cells produce high levels of transforming growth factor (TGF)-β1 and interleukin (IL)-10 compared with CD4 + CD25  T cells, demonstrating an antiinflammatory property via immune suppression by a cell–cell interaction involving cell surface TGF-β.72 Among the many constituents of T. bellirica bellericanin and gallic acid (GA1) are important in inflammation conditions in arthritis.73 GA1can selectively inhibits COX by binding to its active site of the nonsteroidal antiinflammatory drug (NSAID) binding site, showing a competitive inhibitory action for both COX-1 and COX-2 with more affinity toward COX-2 causing an antiinflammation environment.74

4.12 Trachyspermum roxburghianum (S. Asamodagum) Limonene, from the essential oils obtained by steam distillation of the seeds of Trachyspermum roxburghianum (TR), yields 40.9%–47.2% of the bulk as its main constituent. Other notable constituents are sabinene (20.3% and 8.5%, respectively), terpinen-4-ol (8.6% and 12.2%), (Z)-ligustilide (5.1% and 8.0%), and γ-terpinene (5.6% and 6.7%).75 TR’s ability to disregard inflammation-induced disease to some extent could be attributed to its constituents’ (terpinen-4-ol) ability to suppress the production of TNF-α, IL-1β, IL-8, and PGE2. Because a specific mechanism isn’t suggested

333

334

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

yet on how this is modulated, the fact that it reduces the stimulatory effect on PMA initially indicates that it may affect the rate of synthesis of ROS modulating the PMA transduction pathway or/and could exert a scavenging effect on the ROS produced.76,77

4.13 Vernonia anthelmintica (S. Sanninayam) Vernonia anthelminitica (VA) is composed of fatty acids (Trivernolin, 1,3-divernolin, and Vernolic/Epoxyoleic),78 flavonoids,79 sterols,80 glycosylated triterpenes, saponins, and steroids. It shows properties such as antibacterial, larvicidal, analgesic, antipyretic, diuretic agent, antihyperglycemic, antibacterial, antifungal, anti-inflammatory, and antiarthritic.81 VA as an antiinflammatory and antiarthritic drug has no ulcerative side effect, and this may be speculated due to the combined interactions of phytochemicals such as flavonoids, tannins, gallic acid, and the earlier mentioned constituents. VA may possibly act by preventing production of nitric oxide from nitric oxide synthase or by preventing neutrophilic infiltration, thereby decreasing the generation or release of chemotactic factors and inflammatory T cell mediators such as IL, TNF-α, and LTs. These effects may be attributed to phytochemicals present in VA. In order to evaluate a better mechanism of action of VA on antiarthritis and antiinflammatory properties, further studies are needed.82

4.14 Zingiber officinale (S. Inguru) Traditionally, Zingiber officinale (ZO)/ginger has been used to treat a wide range of ailments including gastrointestinal disorders such as stomachaches, abdominal spasms, nausea, and vomiting as well as in arthritis and motion sickness. Phytochemical studies showed that the plant is rich in a large number of substances, including gingerols and shogaols. These compounds display diverse biological activities such as antioxidant, antiinflammatory, and anticarcinogenic properties.3 According to a study on peroxidation in a rat liver microsomes showed that the eugenol had the ability to efficiently inhibit lipid peroxidation. Inhibit lipid peroxidation of eugenol is not known and it could be subjected to their free radical scavenging acitivity/inhibition of lipid peroxidation or ability of suppression of the activities of oxygen free radicals and metal ions that mediate complex process of lipids peroxidation,83 and inhibition of inflammatory mediators such as PGE2 is another remarkable evaluation by Shen et al., 2003 84 on OZ extracts which contributed to the study of its antiinflammatory property. Various powders, formulations, and extracts have, however, been commercially used and tested, both in vitro and in vivo, in animal models. In these models, ginger has been shown to act as a dual inhibitor of both cyclooxygenase (COX) and lipooxygenase, to inhibit leukotriene synthesis, and to reduce caregeenan-induced rat-paw edema, an animal model of inflammation (Table 19.2).85

Nawarathne Kalka and Arthritis

Table 19.2 Summary of the actions of the components present in NK Ingredients of Active Nawarathne Kalka compound/s Inhibitory action

Ref.

Honey

Carbohydrates/ highly complex mixture of sugars

24, 25

Cedrus deodara (S. Devadara)

Extract/oil

Cuminum cyminum (S. Suduru)

Extract/oil

Eugenia caryophylla (S. Karabu)

Extract/oil

Ferula asafetida (S. Perunkayam)

Ferulic acid/ Farnesiferol C

Glycyrrhiza glabra (S. Walmi)

Glycyrrhizic acid (GA) Glycyrrhizin/ Glabridin

Presence of sugar and carbohydrate can assist the formation of similar structures hyaluronic acid consists of disaccharide chains made from modifications of monosaccharide glucose called glucuronic acid and N-acetyl glucosamine in which case honey can act as a substitute for hyaluronic acid which encourage to create an environment that encourages cell migration, proliferation and developing a similar environment to extracellular matrix Mast cell stabilizing activity and therefore inhibition of leukotriene synthesis By inhibition of lipid peroxidation and activities of superoxide dismutase and catalase enzymes. Decreasing the oxidative stress by suppression of formation of AGEs (Advanced glycation end products) Decreases the levels of hydrogen peroxide-induced IL-1β, TNFα, MMP-1, and MMP-13/ inhibition of vascular endothelial growth factor (VEGF)-induced expressions of MMP-2 Encouragement of production of the antiinflammatory cytokine IL-10 while production of proinflammatory cytokines IL-1β, IL-6, TNF, IL-12, and IFN-α suppr ession by PI3K/ Akt/GSK3β pathway and by competitive inhibition of LDL peroxidation

28

30, 31

32, 34, 35

38–40

45–47

Continued

335

336

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

Table 19.2 Summary of the actions of the components present in NK—cont’d Ingredients of Active Nawarathne Kalka compound/s Inhibitory action

Myristica fragrans (S. Sadikka)

Myristicin

Nigella sativa (S. Kaluduru)

Thymoquinone

Picrorhizakurroa (VN: Katukarosana)

Apocynin

Piper longum (S. Thippili)

Piperine

Terminalia bellirica/ Terminalia chebula (S. Aralu) (S. Bulu & S. Aralu)

Extract/Gallic acid/, Chebulagic acid

Inhibition of the production of calcium, nitric oxide (NO), interleukin (IL)-6, IL-10, interferon inducible protein-10, monocyte chemotactic protein (MCP)-1, MCP-3, granulocytemacrophage colony-stimulating factor, macrophage inflammatory protein (MIP)-1α, MIP-1β, and leukemia inhibitory factor in dsRNA [polyinosinicpolycytidylic acid]-induced RAW 264.7 cells Maintaining reduced levels of proinflammatory mediators (IL1β, IL-6, TNF-α, IFN-γ, and PGE2) and increased level of IL-10 NADPH oxidase inhibition ability therefore inhibiting production of ROSs Inhibition of the IL6 and PGE2 response to the already existing proinflammatory mediators. Piperine also inhibits the protein and mRNA expression levels of IL6 COX-2 and MMP13 by blocking the MAPK/ERK1/2 pathway Immune suppression via induction of transforming growth factor beta (TGFβ) and CD4 + CD25+ T cells are found to produce high levels of transforming growth factor (TGF)-β1 and interleukin (IL)-10 compared with CD4 + CD25  T cells/Gallic acid can selectively inhibit COX by binding to its active site of the nonsteroidal antiinflammatory drug (NSAID) binding site showing competitive inhibitory action for both COX-1 and COX-2

Ref.

58

58, 63

66

68

72, 74

Nawarathne Kalka and Arthritis

Table 19.2 Summary of the actions of the components present in NK—cont’d Ingredients of Active Nawarathne Kalka compound/s Inhibitory action

Ref.

Trachyspermum roxburghianum (S. Asamodagum) Vernonia anthelmintica (S. Sanninayam)

terpinen-4-ol

Suppress the production of TNF-α, IL-1β, IL-8, and PGE2

76, 77

Extract

82

Zingiber officinale

Eugenol

Prevention of the production of nitric oxide from nitric oxide synthase or by preventing neutrophilic infiltration thereby decreasing the generation or release of chemotactic factors and inflammatory T cell mediators such as IL, TNF-α, and LTs Inihibition of lipid peroxidation inflammatory mediators such as PGE2 and dual inhibition of cyclooxygenase (COX) and lipooxygenase

83–85

5. DISCUSSION Inhibition of a single kinase or pathway is unlikely to treat a disease, therefore it requires multitargeted, polyherbal medicinal systems. Medications that are used to treat rheumatoid arthritis are divided into three main classes: nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, and DMARDs (both synthetic and biologic).13 A study done in Sri Lanka has shown that NK has potential free radical scavenging property and inhibition of advanced glycation end products in RA patients.22 In order to approach therapy for RA, many research have taken in order to seek for better medicine with long term use and less side effects through traditional medicine systems. In this study, as we evaluate the effects of the individual components of polyherbals, NK showed a remarkable variety of mechanisms and a better therapeutic approach toward many diseases other than RA, suggesting that the many problems faced in modern medicine can be solved with the introduction of such polyherbal systems.

REFERENCES 1. Organization WH. Legal Status of Traditional Medicine and Complementary/Alternative Medicine: A Worldwide Review. Geneva: World Health Organization; 2001. 2. Verma S, Singh SP. Current and future status of herbal medicines. Vet World. 2008;1(11):347–350. 3. Aggarwal B, Prasad S, Reuter S, et al. Identification of novel antiinflammatory agents from Ayurvedic medicine for prevention of chronic diseases: “reverse pharmacology” and “bedside to bench” approach. Curr Drug Targets. 2011;12(11):1595–1653.

337

338

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

4. Behere PB, Das A, Yadav R, Behere AP. Ayurvedic concepts related to psychotherapy. Indian J Psychiatry. 2013;55(Suppl 2):S310–S314. https://doi.org/10.4103/0019-5545.105556. 5. Patwardhan B. Ayurveda: the designer medicine. Indian Drugs. 2000;37:213–227. 6. Garodia P, Ichikawa H, Malani N, Sethi G, Aggarwal BB. From ancient medicine to modern medicine: ayurvedic concepts of health and their role in inflammation and cancer. J Soc Integr Oncol. 2007;5 (1):25–37. 7. Perera PK. Current scenario of herbal medicine in Sri Lanka. In: Conference Proceeding, ASSOCHAM, 4th Annual Herbal International Summit Cum Exhibition on Medicinal & Aromatic Products, Spices and Finished Products (Hi-MAPS), NSIC, Okhla Industrial Estate, New Delhi, India; 2012. 8. Illiyakperuma A. Vatika Prakarana/Deshiya Beheth Guli Kalka Potha. Panadura, Sri Lanka: Modern Press; 1879. 9. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344(12):907–916. https://doi.org/10.1056/NEJM200103223441207. 10. M€ uller-Ladner U, Pap T, Gay RE, Neidhart M, Gay S. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nat Clin Pract Rheumatol. 2005;1:102. https://doi.org/10.1038/ncprheum0047. 11. Simmonds RE, Foxwell BM. Signalling, inflammation and arthritis NF-κB and its relevance to arthritis and inflammation. Rheumatology. 2008;47(5):584–590. https://doi.org/10.1093/rheumatology/ kem298. 12. Houssiau FA. Cytokines in rheumatoid arthritis. Clin Rheumatol. 1995;14(2):10–13. 13. O’Dell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med. 2004;350(25):2591–2602. https://doi.org/10.1056/NEJMra040226. 14. Aronson J. When I use a word … Is it inflammation? It is!. QJM An Int J Med. 2009;102(12):895–896. https://doi.org/10.1093/qjmed/hcp039. 15. Taqweem M, Kan H, Takreem A, Alam I. Intra-articular (I/A) methotrexate in rheumatoid arthritis. Int J Rheumatol. 2008;6(1):231–235. 16. Hurley JV. Acute Inflammation. Churchill Livingstone; 1972. 17. Janeway Jr CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20(1):197–216. 18. Bianchi ME. DAMPs, PAMPs and alarmins: All we need to know about danger. J Leukoc Biol. 2007;81 (1):1–5. https://doi.org/10.1189/jlb.0306164. 19. Oda K, Kitano H. A comprehensive map of the toll-like receptor signaling network. Mol Syst Biol. 2006;2(1): http://msb.embopress.org/content/2/1/2006.0015.abstract. 20. Ira Thabrew M, Senaratna L, Samarawickrema N, Munasinghe C. Antioxidant potential of two polyherbal. Preparations used in Ayurveda for the treatment of rheumatoid arthritis. J Ethnopharmacol. 2001;76(3):285–291. https://doi.org/10.1016/S0378-8741(01)00213-6. 21. Stevenson DE, Hurst RD. Polyphenolic phytochemicals—just antioxidants or much more? Cell Mol Life Sci. 2007;64(22):2900–2916. 22. Fernando CD, Karunaratne DT, Gunasinghe SD, et al. Inhibitory action on the production of advanced glycation end products (AGEs) and suppression of free radicals in vitro by a Sri Lankan polyherbal formulation Nawarathne Kalka. BMC Complement Altern Med. 2016;16(1):197. https://doi.org/ 10.1186/s12906-016-1178-x. 23. Jeffrey AE, Echazarreta CM. Medical uses of honey. Rev Biomed. 1996;7(1):43–49. 24. Cohen IK, Diegelmann RF, Lindblad WJ. Wound Healing: Biochemical and Clinical Aspects. Philadelphia: WB. Saunders Company; 1992. 25. Gallo RL. Proteoglycans and cutaneous vascular defense and repair. J Investig Dermatology Symp Proc. 2006;5(1):55–60. https://doi.org/10.1046/j.1087-0024.2000.00008.x. 26. Hollander D, Schmandra T, Windolf J. Using an esterified hyaluronan fleece to promote healing in difficult-to-treat wounds. J Wound Care. 2000;9(10):463–466. 27. Topham J. Why do some cavity wounds treated with honey or sugar paste heal without scarring? J Wound Care. 2002;11(2):53–55. 28. Shinde UA, Phadke AS, Nair AM, Mungantiwar AA, Dikshit VJ, Saraf MN. Studies on the antiinflammatory and analgesic activity of Cedrus deodara (Roxb.) Loud. wood oil. J Ethnopharmacol. 1999;65 (1):21–27. https://doi.org/10.1016/S0378-8741(98)00150-0.

Nawarathne Kalka and Arthritis

29. Nalini N, Manju V, Menon VP. Effect of spices on lipid metabolism in 1,2-dimethylhydrazine-induced rat colon carcinogenesis. J Med Food. 2006;9(2):237–245. 30. Dhandapani S, Subramanian VR, Rajagopal S, Namasivayam N. Hypolipidemic effect of Cuminum cyminum L. on alloxan-induced diabetic rats. Pharmacol Res. 2002;46(3):251–255. https://doi.org/10.1016/ S1043-6618(02)00131-7. 31. Gagandeep, Dhanalakshmi S, Mendiz E, Rao AR, Kale RK. Chemopreventive effects of Cuminum cyminum in chemically induced forestomach and uterine cervix tumors in murine model systems. Nutr Cancer. 2003;47(2):171–180. https://doi.org/10.1207/s15327914nc4702_10. 32. Shobana S, Akhilender NK. Antioxidant activity of selected Indian spices. Prostaglandins, Leukot Essent Fat Acids. 2000;62(2):107–110. https://doi.org/10.1054/plef.1999.0128. 33. Vistoli G, De Maddis D, Cipak A, Zarkovic N, Carini M, Aldini G. Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radic Res. 2013;47(Supp. 1):3–27. https://doi.org/10.3109/10715762.2013.815348. 34. Oya T, Osawa T, Kawakishi S. Spice constituents scavenging free radicals and inhibiting Pentosidine formation in a model system. Biosci Biotechnol Biochem. 1997;61(2):263–266. https://doi.org/ 10.1271/bbb.61.263. 35. Kurien BT, Hensley K, Bachmann M, Scofield RH. Oxidatively modified autoantigens in autoimmune diseases. Free Radic Biol Med. 2006;41(4):549–556. https://doi.org/10.1016/j. freeradbiomed.2006.05.020. 36. Singh AK, Dhamanigi SS, Asad M. Antistress activity of hydro-alcoholic extract of Eugenia caryophyllus buds (clove). Indian J Pharmacol. 2009;41(1):28–31. https://doi.org/10.4103/0253-7613.48889. 37. Mahendra P, Bisht S. Ferula asafoetida: Traditional uses and pharmacological activity. Pharmacogn Rev. 2012;6(12):141–146. https://doi.org/10.4103/0973-7847.99948. 38. Zhu H, Liang Q-H, Xiong X-G, et al. Antiinflammatory effects of the bioactive compound ferulic acid contained in oldenlandia diffusa on collagen-induced arthritis in rats. Evid Based Complement Altern Med. 2014;2014. 39. Chen MP, Yang SH, Chou CH, et al. The chondroprotective effects of ferulic acid on hydrogen peroxide-stimulated chondrocytes: inhibition of hydrogen peroxide-induced proinflammatory cytokines and metalloproteinase gene expression at the mRNA level. Inflamm Res. 2010;59 (8):587–595. https://doi.org/10.1007/s00011-010-0165-9. 40. Lee J-H, Choi S, Lee Y, et al. Herbal compound farnesiferol C exerts antiangiogenic and antitumor activity and targets multiple aspects of VEGFR1 (Flt1) or VEGFR2 (Flk1) signaling cascades. Mol Cancer Ther. 2010;9(2):389–399.http://mct.aacrjournals.org/content/9/2/389.abstract. 41. Nomura T, Fukai T. Phenolic Constituents of Licorice (Glycyrrhiza Species) BT - Fortschritte der Chemie Organischer Naturstoffe/Progress in the Chemistry of Organic Natural Products. In: Nomura T, Herz W, et al. Fukai T. Vienna: Springer Vienna; 1998:1–140. https://doi.org/ 10.1007/978-3-7091-6480-8_1. 42. Xing G-X, Li N, Wang T, Yao M-Y. Advances in studies on flavonoids of licorice. China J Chinese Mater Medica. 2003;28(7):593–597.http://www.ncbi.nlm.nih.gov/pubmed/15139098. 43. Khanahmadi M, Naghdi Badi H, Akhondzadeh S, et al. A review on medicinal Plant of Glycyrrhiza glabra L. J Med Plants. 2013;2(46):1–12. 44. Hatano T, Fukuda T, Liu YZ, Noro T, Okuda T. Phenolic constituents of licorice. IV. Correlation of phenolic constituents and licorice specimens from various sources, and inhibitory effects of licorice extracts on xanthine oxidase and monoamine oxidase. Yakugaku zasshi J Pharm Soc Japan. 1991;111 (6):311–321. 45. Kao T-C, Shyu M-H, Yen G-C. Glycyrrhizic acid and 18β-Glycyrrhetinic acid inhibit inflammation via PI3K/Akt/GSK3β signaling and glucocorticoid receptor activation. J Agric Food Chem. 2010;58 (15):8623–8629. https://doi.org/10.1021/jf101841r. 46. Cortes-Vieyra R, Bravo-Patin˜o A, Valdez-Alarco´n JJ, Jua´rez MC, Finlay BB, Baizabal-Aguirre VM. Role of glycogen synthase kinase-3 beta in the inflammatory response caused by bacterial pathogens. J Inflamm. 2012;9(1):23. https://doi.org/10.1186/1476-9255-9-23. 47. Kent UM, Aviram M, Rosenblat M, Hollenberg PF. The licorice root derived isoflavan glabridin inhibits the activities of human cytochrome P450S 3A4, 2B6, and 2C9. Drug Metab Dispos. 2002;30 (6):709–715.http://dmd.aspetjournals.org/content/30/6/709.abstract.

339

340

Bioactive Food as Dietary Interventions for Arthritis and Related Inflammatory Diseases

48. Belinky PA, Aviram M, Mahmood S, Vaya J. Structural aspects of the inhibitory effect of glabridin on LDL oxidation. Free Radic Biol Med. 1998;24(9):1419–1429. https://doi.org/10.1016/S0891-5849(98) 00006-9. 49. Parthasarathy VA, Chempakam B, Zachariah TJ. Chemistry of Spices. Cabi; 2008. 50. Nagore DH, Kuber V, Patil P, Deshmukh T. Simultaneous assessment and validation of reverse phasehigh performance liquid chromatography method for quercetin, eugenol, myristicin, and safrole from nutmeg, fruit and mace. Chronicles Young Sci. 2013;4(1):9–17. 51. Kasahara H, Miyazawa M, Kameoka H. Absolute configuration of 8-O-40 -neolignans from Myristica fragrans. Phytochemistry. 1995;40(5):1515–1517. https://doi.org/10.1016/0031-9422(95)00510-E. 52. Orabi KY, Mossa JS, El-Feraly FS. Isolation and characterization of two antimicrobial agents from Mace (Myristica fragrans). J Nat Prod. 1991;54(3):856–859. https://doi.org/10.1021/np50075a017. 53. Plengsuriyakarn T, Viyanant V, Eursitthichai V, et al. Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models. BMC Complement Altern Med. 2012;12(1):23. https://doi.org/10.1186/1472-6882-12-23. 54. Jin H, Zhu Z-G, Yu P-J, et al. Myrislignan attenuates lipopolysaccharide-induced inflammation reaction in murine macrophage cells through inhibition of NF-κB Signalling pathway activation. Phyther Res. 2012;26(9):1320–1326. https://doi.org/10.1002/ptr.3707. 55. Damien Dorman HJ, Deans SG, Noble RC, Surai P. Evaluation in vitro of plant essential oils as natural antioxidants. J Essent Oil Res. 1995;7(6):645–651. https://doi.org/10.1080/10412905.1995. 9700520. 56. Forrest JE, Heacock RA, Forrest TP. Diarylpropanoids from nutmeg and mace (Myristica fragrans Houtt.). J Chem Soc Perkin Trans 1. 1974;(0):205–209. https://doi.org/10.1039/P19740000205 57. Latha PG, Sindhu PG, Suja SR, Geetha BS, Pushpangadan P, Rajasekharan S. Pharmacology and chemistry of Myristica fragrans Houtt.-a review. J Spices Aromat Crop. 2005;14(2):94–101. 58. Lee JY, Park W. AntiInflammatory effect of myristicin on RAW 264.7 macrophages stimulated with polyinosinic-polycytidylic acid. Mol. 2011;16(8)https://doi.org/10.3390/molecules16087132. 59. Ghosheh OA, Houdi AA, Crooks PA. High performance liquid chromatographic analysis of the pharmacologically active quinones and related compounds in the oil of the black seed (Nigella sativa L.). J Pharm Biomed Anal. 1999;19(5):757–762. https://doi.org/10.1016/S0731-7085(98)00300-8. 60. Yi T, Cho S-G, Yi Z, et al. Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways. Mol Cancer Ther. 2008;7(7):1789–1796.http://mct.aacrjournals.org/content/7/7/1789.abstract. 61. Umar S, Zargan J, Umar K, Ahmad S, Katiyar CK, Khan HA. Modulation of the oxidative stress and inflammatory cytokine response by thymoquinone in the collagen induced arthritis in Wistar rats. Chem Biol Interact. 2012;197(1):40–46. https://doi.org/10.1016/j.cbi.2012.03.003. 62. Budancamanak M, Kanter M, Demirel A, Ocakci A, Uysal H, Karakaya C. Protective effects of thymoquinone and methotrexate on the renal injury in collagen-induced arthritis. Arch Toxicol. 2006;80(11):768–776. https://doi.org/10.1007/s00204-006-0094-0. 63. Chakravarty N, Yu W. Regulatory role of calcium on histamine secretion. Agents Actions. 1986;18 (1):57–60. https://doi.org/10.1007/BF01987982. 64. Singh AP. Kutkins—a review of chemistry and pharmacology. Ethnobot Leafl. 2004;2004(1):9. 65. Singh GB, Bani S, Singh S, et al. Antiinflammatory activity of the iridoids kutkin, picroside-1 and kutkoside from Picrorhiza kurrooa. Phyther Res. 1993;7(6):402–407. https://doi.org/10.1002/ ptr.2650070604. 66. van den Worm E. Investigations on Apocynin, a Potent NADPH Oxidase Inhibitor. Faculteit Farmacie: Universiteit Utrecht; 2001. 67. Lafeber FPJG, Beukelman CJ, van den Worm E, et al. Apocynin, a plant-derived, cartilage-saving drug, might be useful in the treatment of rheumatoid arthritis. Rheumatology. 1999;38(11):1088–1093. https:// doi.org/10.1093/rheumatology/38.11.1088. 68. Bang JS, Oh DH, Choi HM, et al. Antiinflammatory and antiarthritic effects of piperine in human interleukin 1β-stimulated fibroblast-like synoviocytes and in rat arthritis models. Arthritis Res Ther. 2009;11 (2):R49. https://doi.org/10.1186/ar2662. 69. Ganjiwale R, Wadher S, Yeole P, Polshettiwar S. Spectrophotometric estimation of total tannins in some ayurvedic eye drops. Indian J Pharm Sci. 2007;69(4):574. https://doi.org/10.4103/0250474X.36949.

Nawarathne Kalka and Arthritis

70. Baliga MS. Triphala, Ayurvedic formulation for treating and preventing cancer: A review. J Altern Complement Med. 2010;16(12):1301–1308. 71. Sumantran VN, Kulkarni AA, Harsulkar A, et al. Hyaluronidase and collagenase inhibitory activities of the herbal formulation Triphala guggulu. J Biosci. 2007;32(4):755–761. https://doi.org/10.1007/ s12038-007-0075-3. 72. Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by Cd4 + Cd25 + regulatory T cells is mediated by cell surface-bound transforming growth factor β. J Exp Med. 2001;194 (5):629–644. https://doi.org/10.1084/jem.194.5.629. 73. Sabina EP, Rasool M. Therapeutic efficacy of Indian ayurvedic herbal formulation triphala on lipid peroxidation, antioxidant status and inflammatory mediator TNF-α in adjuvant-induced arthritic mice. Int J Biol Chem. 2007;1(3):149–200. 74. Chandramohan Reddy T, Aparoy P, Kishore Babu N, Anil Kumar K, Kumar Kalangi S, Reddanna P. Kinetics and docking studies of a COX-2 inhibitor isolated from Terminalia bellerica fruits. Protein Pept Lett. 2010;17(10):1251–1257. 75. Choudhury S, Rajkhowa A, Dutta S, Kanjilal PB, Sharma RK, Leclercq PA. Volatile seed oils of Trachyspermum roxburghianum Benth. Ex. Kurz. from India. J Essent Oil Res. 2000;12(6):731–734. https://doi.org/10.1080/10412905.2000.9712203. 76. Hart PH, Brand C, Carson CF, Riley TV, Prager RH, Finlay-Jones JJ. Terpinen-4-ol, the main component of the essential oil of Melaleuca alternifolia (tea tree oil), suppresses inflammatory mediator production by activated human monocytes. Inflamm Res. 2000;49(11):619–626. https://doi.org/ 10.1007/s000110050639. 77. Caldefie-Chezet F, Fusillier C, Jarde T, et al. Potential antiinflammatory effects of Melaleuca alternifolia essential oil on human peripheral blood leukocytes. Phyther Res. 2006;20(5):364–370. https://doi.org/ 10.1002/ptr.1862. 78. Krewson CF, Ard JS, Riemenschneider RW. Vernonia anthelmintica (L.) Willd. Trivernolin, 1,3-divernolin and vernolic (Epoxyoleic) acid from the seed oil. J Am Oil Chem Soc. 1962;39 (7):334–340. https://doi.org/10.1007/BF02638798. 79. Tian G, Zhang U, Zhang T, Yang F, Ito Y. Separation of flavonoids from the seeds of Vernonia anthelmintica Willd by high-speed counter-current chromatography. J Chromatogr A. 2004;1049(1):219–222. https://doi.org/10.1016/j.chroma.2004.07.072. 80. Akihisa T, Hayashi Y, Patterson GW, Shimizu N, Tamura T. 4α-methylvernosterol and other sterols from Vernonia anthelmintica seeds. Phytochemistry. 1992;31(5):1759–1763. https://doi.org/ 10.1016/0031-9422(92)83142-L. 81. Srivastava R, Verma A, Mukerjee A, Soni N. Phytochemical, pharmacological and pharmacognostical profile of Vernonia anthelmintica: an overview. Res Rev J Pharmacognsoy Phytochem. 2014;2(2):22–28. https://pdfs.semanticscholar.org/6f8e/dbaabaac186656008eb90ad888cb3dd0c5a6.pdf. 82. Otari KV, Shete RV, Upasani CD, Adak VS, Bagade MY, Harpalani AN. Evaluation of antiinflammatory and antiarthritic activities of ethanolic extract of Vernonia anthelmintica seeds. J Cell Tissue Res. 2010;10(2):2228–2269. 83. Reddy ACP, Lokesh BR. Studies on the inhibitory effects of curcumin and eugenol on the formation of reactive oxygen species and the oxidation of ferrous iron. Mol Cell Biochem. 1994;137(1):1–8. https:// doi.org/10.1007/BF00926033. 84. Shen C-L, Hong K-J, Kim SW. Effects of ginger ( Zingiber officinale Rosc.) on decreasing the production of inflammatory mediators in sow Osteoarthrotic cartilage explants. J Med Food. 2003;6(4):323–328. https://doi.org/10.1089/109662003772519877. 85. Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum. 2001;44(11):2531–2538. https://doi.org/10.1002/1529-0131(200111)44:11<2531:: AID-ART433>3.0.CO;2-J.

341