Research Paper a Review on the Efficacy of Phytomedicines For

Research Paper

A review on the efficacy of phytomedicines for Rheumatoid arthritis.

Accepted 9th November, 2020

ABSTRACT

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease marked by inflamed joints causing articular tissue damage and joint dysfunction by triggering the production of auto antibodies. In response to the self epitopes, activation of defense cells, macrophages, occurrence of acute and chronic inflammation of the synovium become major mediators in the progression of RA thereby holds an important prospect for its treatment. As a consequence of the emerging side effects of the popular synthetic drugs like Non-steroidal anti- inflammatory drugs (NSAIDs) and Disease modifying anti rheumatic drugs (DMARDs) available for RA therapy, alternative interventions like herbal therapy or phytomedicines come into play with limited side effects and equivalent effectiveness. Therefore, the discoveries of potential anti-rheumatoid herbal drugs Deeksha Kaloni1, Debolina Chakraborty1,2,, are under great consideration. These herbal interventions are being able to inhibit Sagarika Biswas1* inflammation, would exhibit substantial benefits including accessibility, less or no 1Department of Integrative and Functional toxicity and affordability. The current review retrieved the toxic and chronic side Biology, CSIR- Institute of Genomics and effects of the drugs currently administered for RA therapy along with the need for Integrative Biology, Mall Road, Delhi- herbal therapy as an effective alternative approach. Anti inflammatory, anti 110007, India 2Academy of Scientific and Innovative oxidant and other medicinal properties of some of the easily available herbal Research (AcSIR), Ghaziabad- 201002, plants possessing active phytoconstituents are also been elaborated with India scientific evidences collected from various literatures proceeding towards a new pavement for natural drug therapy for RA. *Corresponding author. E-mail: [email protected] or [email protected], Tel: 91-11- Key words: Rheumatoid arthritis, inflammation, risks, herbal therapy, medicinal 27662581 plants.

INTRODUCTION

Rheumatoid arthritis (RA) is a chronic systemic disease peripheral neuropathy and other physical disturbances that is delineated by the inflammation of joints in mostly (Smolen and Steiner, 2003; Firestein and McInnes, 2017). elderly people. RA is associated with production of auto- Complications associated with RA include pain, swelling, antibodies such as “rheumatoid factor” (RF) and anti- stiffness and loss of function of joints. Due to the citrullinated protein antibodies (ACPA) which causes dysregulated immune system resulting in inflammation, cartilage and bone damage as well as disability by affecting the disease is not confined to joints only but is affecting the synovial joints (Smolen and Steiner, 2003). Other multiple organs like lungs, heart, eyes, kidney and even modulator of the immune system including various skin (Abhishek et al., 2017). The contributory factors signaling pathways, cytokines and chemokines plays an responsible for the progression of this disease are mainly essential role in the progression of the disease. Multi-joint genetic, epigenetic and environmental. Prevalence of RA is symmetry, invasive arthritis and involvement of extra- more frequent in women population than in men, occurring articular organ are some of the common manifestations of between the ages of 35-50 years as reported in 80% of the RA. In addition to this, patients also experience drowsiness, total cases (Fishman and Bar-Yehuda, 2010). According to fever, depression, pleuritis subcutaneous nodules, the World Health Organization (WHO), the prevalence of Academia Journal of Medicinal Plants; Kaloni et al. 180

disease varies between 0.3% to 1% in developed countries. medication than NSAIDs, but they come with greater side For curing this chronic illness, several synthetic drugs effects. DMARDs are considered as the second line including DMARDs are currently been used. These treatment drug. The mainstay of DMARD therapy is conventional drugs are effectual but usually associated methotrexate, which is administered weekly, either orally with critical and life threatening adverse effects which or subcutaneously. Hydroxychloroqyine (Plaquenil), diverted the focus towards utilizing phytomedicines as a Sulfasalazine (Azulfidine), Gold salts, such as potential herbal product with minimal side effects. aurothioglucose (Solganal), auranofin (Ridaura), gold Plants are the prime sources of medicines since a long sodium thiomalate (Myochrysine) and D-penicillamine time and most of the prescribed medicines have at least (Depen and Cuprimine) are few other DMARDs that are one plant derived ingredient in it. In this modern world this used in RA therapy (Bullock et al., 2019). Biologics, also utilization of plant extracts and their useful phytochemical known as biological DMARDs, acts rapidly and are very compounds gave rise to a new trend of medication known effective in retarding the progression of the joint damage as phytomedicine. This practice of using herbal remedies caused by RA. They are considered to be a more “direct, was known to emerge initially from China followed back defined and targeted” method of treatment (Shiel, 2017). then by Indian, Egyptian, Greek, Roman and Syrian. The Biologic medications such as etanercept (Enbrel), world is now progressing towards the implementation of infliximab (Remicade), adalimumab (Humira), golimumab herbal medicine or phytomedicines to combat various (Simponi), and certolizumab pegol (Cimzia) are all TNF diseases by repairing and reinforcing the bodily systems inhibitors that prevent the recruitment of the cells that specifically the immune system without toxic side effects cause inflammation, bringing rapid symptom relief (Roux (Pandey et al., 2011). Recently phytomedicines emerge to et al., 2006). They are recommended if other second-line be a promising alternative for treating various diseases medications are not effective. Unfortunately, these including RA and their efficacy is relatively comparable medications tend to be very expensive and their role in with that of commonly used popular drugs. In several in treating patients at various stages of RA and with various vivo and in vitro experiments, the phytomedicines proved mechanisms of action is a matter of continuous to be effective in RA conditions but their mechanism of investigation. action is quite elusive. Moreover there is a scarcity of their Despite the advancement in the techniques, the potency in clinical studies which needs to be elucidated treatment of these drugs are slow progressing and exhibit further. Since a long time traditional herbal medicine are limited efficiency and have adverse effects (some drugs being utilized in several diseases but a clear idea of their along with their associated complications are listed in mechanistic role need to be explored. Phytomedicines with Table 1). RA itself confers an elevated risk of infection, and their various medicinal properties including anti- DMARD and biologic therapies suppress the immune inflammatory, anti-oxidative, anti-proliferative, system through various targets, also increasing this risk immunosuppressive proved to be effective in attenuating (Mushtaq et al., 2010) making the body susceptible to RA progression in various experiments. These medicinal various infections. Bacterial infections particularly plants contain different phyto compounds which targets pneumonia and soft-tissue infections are increased with different signaling pathways reducing the severity of this the use of methotrexate and this are increased 2–4-fold disease. This review will discuss some selected potential with the addition of an anti-TNF medication (Emery et al., herbal plant species which are considered as potent 2008). Similar infectious risks have been found with other phytomedicine in suppressing RA pathogenesis. biologic DMARDs as well (Emery et al., 2008; Genovese et al., 2008). A significant risk of reactivation of tuberculosis has also been noted with anti-TNF medication. An CURRENT TREATMENT FOR RA AND ITS LIMITATIONS increased risk of viral infections with traditional or biologic DMARDs, including varicella-zoster virus, Epstein-Barr The treatment for RA involves medication in coalition with virus and cytomegalovirus has been documented (Kim, proper rest, exercise, adequate knowledge and in severe 2010). Hepatitis B and C reactivation have also occurred cases surgery. Currently available treatment includes with biologic DMARDs, so screening prior to treatment and mainly NSAID’s, DMARD’s and Anti-TNF (Tumor necrosis vaccination when possible is recommended (Roux et al., factor) biologics (which are a class of DMARDs). NSAIDs 2006; Kim, 2010). Progressive multifocal and corticosteroids are the first line treatment drugs, they leukoencephalopathy, an infection caused by reactivation reduce pain and inflammation. NSAIDs include of the John Cunningham (JC) virus, has also been reported acetylsalicylate (Aspirin), naproxen (Naprosyn), ibuprofen in RA patients treated with Rituximab (Fleischmann, (Advil and Motrin) and etodolac (Lodine) (Bullock et al., 2009). Immuno suppression also can lead to a theoretical 2019). The newer NSAID, celecoxib (Celebrex) is a selective risk of malignancy, as tumor surveillance by the immune cyclooxygenase-2 (Cox-2) inhibitor that poses lower risk of system may be affected (Kahlenberg and Fox, 2011). Since GI (Gastrointestinal) side effects (Ong et al., 2007). RA patients have an increased risk of lymphoma secondary Corticosteroids are a more potent anti-inflammatory to the disease itself, the extent of the increased risk of Academia Journal of Medicinal Plants; Kaloni et al. 181

Table 1: Adverse effects associated with various drugs.

DRUGS COMPLICATION Methotrexate Pneumonitis, Mouth ulcers, Alopecia (Luo et al., 2013) Retinal toxicity, Heamolytic anemia, skin discolouration Nausea, Diarrhea, Vomiting, Hydroxychloroquine Loss of appetite, Skin rash(Luo et al., 2013) Gastrointestinal disorder, myelosuppression, rashes, Heamolytic anemia (Sun et al., Sulfasalazine 2013) Corticosteroids Adrenal suppression (Lis et al., 2014) Tuberculosis, hepatic reactions, including acute liver failure, jaundice and hepatitis (Lis Infliximab et al., 2014) Etanercept Multiple sclerosis, inflammation of spinal cord and optic nerves (Lis et al., 2014) Adalimumab Hypersensitivity reactions, Anemia Golimumab Pneumonia, fungal infection, tuberculosis, hepatitis B, malignancies (Brady et al., 2015) Glucocorticoid Peptic ulcer, cataract, muscle atrophy (Joseph et al., 2016)

Figure 1: Side effects exerted by commonly used synthetic drugs for RA

developing a cancer such as lymphoma while taking Owing to these limitations there is a need to revolutionize immunosuppressive medications remains debatable the RA therapy using natural products. Herbal products are (Askling, 2008). The side effects exerted by these synthetic the source of various bioactive components with drugs for RA are illustrated in Figure1. Therefore an therapeutic activity that could potentially be used for the extensive research on the formulation of herbal drug is development of new drugs. The structures of bioactive under great attention. Many plants are already known for compounds which exert medicinal implication for RA their potential anti-inflammatory activity but their prevention are illustrated in Figure2. The aggressive role of molecular mechanism still remains unknown. Therefore, inflammation which is associated with various diseased the review concentrates majorly on managing RA with conditions needs to be reduced in order to prevent the herbal interventions. inflammatory diseases. So to subdue this, different kind of safe and effective anti-inflammatory agents are available such as aspirin and other non-steroidal anti-inflammatory HERBAL ALTERNATIVES FOR RA THERAPY drugs. These anti-inflammatory agents are advantageous to cure the disease but they also possess certain severe side The main stream drugs for RA have various adverse effects effect, costly and are effective on a limited proportion of RA and moreover some of the drugs are quite expensive. patients (Dudics et al., 2018). Over the past years, herbal Academia Journal of Medicinal Plants; Kaloni et al. 182

Figure 2: Structures of plant compound with medicinal implications found in the phytomedicines (Created with Chemsketch software).

medicines are used for the treatment of various diseases. stinging nettle belongs to the Urticaceae family. It is widely According to WHO report, around 80% of world’s distributed throughout the temperate and tropical areas population counts on the traditionally known medicines around the world, particularly in the Himalayas from (WHO 2002). These could be a potential alternative that Kashmir to Kumaon (Joshi et al., 2014). The plant has been could replace these synthetic drugs. Herbal medicines are known for its various pharmacological activities such as reducing the risks of side effects and is also cost effective antioxidant, anti-inflammatory, antiulcer, anti-colitis, than the biological agents (Xia et al., 2020). Moreover, antiviral, anticancer, antibacterial, antimicrobial, herbal products can control arthritic inflammation through antifungal, anti-androgenic, insecticide, immune- various pathways, for example, inhibition of effectors modulatory, hypo-cholesterolemic, hypoglycemic, anti- molecules (e.g., pro-inflammatory cytokines and arrhythmic effects (Joshi et al., 2014). It shows anti- chemokines), induction of anti-inflammatory mediators inflammatory effect by inhibiting activation of Nuclear (e.g., IL-4, IL-10), regulation of the Th17/Treg balance, and Factor kappa-light-chain-enhancer of activated B cells (NF- modulation of the osteo-immune cross-talk (Nanjundaiah ĸB) by interfering with its DNA binding activity (Joshi et al., et al., 2012; Astry et al., 2015; Venkatesha et al., 2016). This 2014). A similar study has attributed the potential of Urtica review summarizes some of the potential common herbs dioica to inhibit the pro-inflammatory transcription factors which were proved to be beneficial for reducing RA by suppressing the activation of NF-ĸB (Riehmaan et al., pathogenesis contributing minimal side effects. 1999). Inhibition of the transcription factor NF-ĸB was Mechanistic pathways of these herbal plants in inhibiting demonstrated in different cell types including T-cells, RA progression are also been discussed, focusing majorly macrophages, fibrosarcoma and epithelial cells. Inhibition on the reduction of inflammatory and other disease was also demonstrated in response to several stimuli by progressing molecules which directs toward detrimental stinging nettle leaf extracts as the extracts stabilize the symptoms of RA. inhibitor IκBα by preventing its proteolytic degradation (Riehmaan et al., 1999). Methanolic root extract of Urtica dioica was used in preparation of a herbal gel and was Urtica dioica applied in a carrageenan-induced hind rat paw edema model. Approximately 55.05% inhibition of paw edema Urtica dioica L. is a perennial plant commonly known as and 58.21% analgesia were observed after 24 hr compared Academia Journal of Medicinal Plants; Kaloni et al. 183

with a standard indomethacin gel. Moreover the herbal gel collagen content in the Freunds adjuvant induced arthritic has been found to be safe as no skin irritation was rats. It may be due to its membrane-stabilizing action and observed in the model after primary skin irritation test. As suppression of the collagenases that destroys collagen and a result this gel has been suggested to be used as an bone (Ekambaram et al., 2011). Thus, it can be a potent effective and safe treatment for rheumatoid arthritis and alternative in the treatment of RA. can be an alternative to NSAIDs (Liao et al., 2016). Therefore due to the potential to inhibit the pro- inflammatory transcription factors it can be an effective Cinnamomum cassia alternative therapy to treat RA. Cinnamomum cassia of Lauraceae family is an ancient spice, commonly known as cinnamon (Bansode, 2012). Its Strychnos potatorum cultivation is distributed in China, India, Vietnam, Indonesia and other countries. It exhibit anti-cancer, anti- Strychnos potatorum L. belongs to Loganiaceae family, also ulcer, anti-inflammatory, heptoprotective, anti-microbial, known as clearing nut tree (Yadav et al., 2014). It is anti-fungal and anti-HIV activity and are potent inhibitors commonly found in Sri Lanka, Burma and Central parts of of nitric oxide (NO) and cyclooxegenase (COX) (Bansode, India. It is a deciduous tree having height up to 12m. 2012). The essential oil of cinnamon bark inhibits the Traditionally it is used for the treatment of diseases like synthesis of pro-inflammatory cytokines such as monocyte diabetes, chronic diarrhea, gonorrhea, bronchitis, chemoattractant protein 1, Interferon gamma (IFN-γ), leukeorrhea, gastropathy, dysentery, renal and vesicle interferon inducible T-cell alpha chemoattractant and calculi, conjunctivitis, scleritis, ulcers and other eye monokine induced by gamma interferon (MIG) (Han and diseases (Sanmuga Priya and Venkataraman, 2007). It also Parker, 2017). Studies on the hydroalcoholic extract of C. possesses anti-diabetic, anti-inflammatory, cassia bark have shown significant reduction in swelling of heptoprotective, anti-oxidant and anti-ulcerogenic joint as well as IL-1β and TNF-α level in Complete Freund's potential (Yadav et al., 2014). It inhibits Cyclooxygenase adjuvant (CFA) induced arthritis. TNF-α receptor (COX) enzyme thereby inhibiting the production of expression was reported to get decreased in rats treated prostaglandins (PG) on carrageenin induced inflammation with Indomethacin or C. cassia hydroalcoholic extract in rats (Sanmuga Priya and Venkataraman, 2007). A (CCHE) (Sharma et al., 2018). A study demonstrated that significant decrease in rat paw edema and body weight cinnamic aldehyde, cinnamic alcohol, cinnamic acid, and were observed in Freund’s complete adjuvant (FCA) coumarin, the constituent of C. cassia inhibit the levels of induced arthritic rats upon treatment with Strychnos NO, tumor necrosis factor (TNF-α), and prostaglandin E2 potatorum aqueous extract (SPE) and the Strychnos (PGE2) in lipopolysaccharide (LPS)-stimulated mouse potatorum whole seed powder (SPP). These SPP and SPE macrophage (RAW264.7) and carrageenan (Carr)-induced treatment at the dose of 200 mg/kg/p.o recovers the mouse paw edema model(Liao et al., 2012). Recent study hematological parameters like Hemoglobin (Hb), Red blood by Liu et al. in 2020 reported that Cinnamaldehyde (CA), an cell (RBC), White blood cells (WBC) and Erythocyte essential component of Cinnamomum cassia have the sedimentation rate (ESR) and biochemical parameters potential to impart anti inflammatory effects against (RA). (blood urea, serum creatinine, total proteins and acute Moreover in-vitro studies proved that the expression of phase proteins) in the arthritic rats (Ekambaram et al., succinate receptor GPR91 was suppressed by CA followed 2010). Crude powder (SPP) and aqueous extract (SPE) of S. by the inhibition of Hypoxia-inducible factor 1-alpha (HIF- potatorum Linn were proved to be effective in antioxidant 1α) activity. The study also demonstrated that CA inhibited defense system against Freund’s complete adjuvant (FCA) the expression of NLRP3, usually gets activated by HIF-1α induced arthritis in rats at the dose of 200 mg/kg/p.o for leading to the inhibition of inflammasome (a multiprotein 14 and 28 days and also induces in vitro antioxidant oligomer in the cytosol that activates the inflammatory activity against Ferrous thiocyanate (FTC) and response) assembly and IL-1β processing (Liu et al., 2020). Thiobarbiturate (TBA) induced lipid peroxidation. These findings prove that Cinnamomum cassia can be a Oxidative stress was significantly reduced in SPP and SPE herbal alternative for RA. treated arthritic rats compared to control arthritic rats as the drugs SPP and SPE have scavenged the free radicals by various antioxidant phytochemicals like steroids, Allium sativum triterpenes and polyphenolics present in it either by individual or by combined actions. Moreover it was Allium sativum L. of Liliaceae family is commonly known as observed that SPE has higher antioxidant activity garlic, native to Asia but is also cultivated in Europe, China, compared to SPP (Ekambaram et al., 2011). Another study Egypt and Mexico (Mikaili et al., 2013). Leaves and cloves showed that the SPE and SPP normalized the lysosomal of A. sativum are used as traditional medicines and are enzymes and glycoproteins and increased the altered known for various therapeutic properties including Academia Journal of Medicinal Plants; Kaloni et al. 184

antibacterial, cardioprotective, antiviral, anti-parasitic, sativum seeds acts as an analgesic and provide anti- anti-inflammatory and anticancer (Mikaili et al., 2013). inflammatory activities in Carrageenan induced paw Presence of sulfur compound thiacremonone inhibits edema (Bhat et al., 2014). inflammation of nervous tissues and amyloidogenesis via inhibition of NF-κB activity (Mikaili et al., 2013). A. sativum have shown to inhibit the level of IL-17 cytokine without Curcuma longa affecting cell proliferation in human peripheral blood mononuclear cells (PBMCs). Synovium and synovial Curcuma longa L. native to Southwest India, known as cultures from RA patients contains increased levels of IL- turmeric or Haldi commonly belongs to the Zingiberaceae 17 (Moutia et al., 2016). A study conducted on female family (Ashraf and Sultan, 2017). It is known for its wide patients (n=70) sufferring from RA supplemented with spectrum of medicinal properties like anti-fungal 1000 mg of garlic for 8 weeks resulted in improvement of properties, anti-inflammatory, hepatoprotective, anti- clinical symptoms like fatigue, serum level of C-reactive tumor, anti-viral, anti-depressant and anti-cancer activities, protein (CRP), tumor necrosis factor-α (TNF-α), and and is also used as a drug in Ayurvedic system (Ashraf and erythrocyte sedimentation rate (ESR) at the end of the Sultan, 2017). It has the ability to inhibit inflammation by study (Moosavian et al., 2020). Treatment of Aged garlic directly binding to TNF-α thereby suppressing its extract (AGE) with or without Methotrexate (MTX) in CIA production and also decreases the production of various models resulted in increased antioxidants, total glutathione other interleukins by inhibiting NF-κB. Tsou et al. studies and superoxide dismutase (SOD) and catalase (CAT) revealed the inhibition of NF-κB activation induced by enzymes activities and decreased malondialdehyde (MDA) Protein kinase B or AKT and IL-1β with curcumin, levels in comparison to only Collagen induced arthritis mediated by down-regulation of COX-2 and Matrix (CIA) and CIA-MTX treated groups. Simultaneously, there is metalloproteinases (MMP-9) and reducing nuclear factor of a significant inhibition of cytokines (CRP and TNF) and kappa light polypeptide gene enhancer in B-cells inhibitor, interleukins (IL-17, IL-6, and IL-1) expression in AGE alpha (IκBα) phosphorylation in IL-1β- and TNF-α- treated groups compared to control rats which supports stimulated human articular chondrocytes (Tsou et al., the fact that Allium sativum has potent anti inflammation 2012). In case of RA, Lee et al. found that under in vitro property and also diminishes hepatotoxicity when given in conditions, a curcumin like compound diarylpentanoid 2, combination with MTX (Badr and Arafa, 2020). 6-bis (2, 5-dimethoxybenzylidene) cyclohexanone eradicated the p65 NF-κB nuclear translocation. Additionally it suppresses the binding activity of NF-κB Coriander sativum DNA in the Phorbol 12-myristate 13-acetate (PMA) which is a direct activator of protein kinase C stimulated synovial Coriander sativum, an annual herb commonly known as fibroblasts through inhibition of COX-2, IL-6, MMP-3, coriander belongs to the Apiaceae family (Jinous, 2012). It collagenase and pro-gelatinase B (pro-MMP-9) (Lee et al., is native to the Mediterranean but cultivated worldwide as 2014). Study on patients (n=18) provided with a culinary herb. It is used as a herb, possesses anti- 1200 mg/day of curcumin, showed significant bacterial, anti-oxidant, anti-diabetic, hepatoprotective, improvement from baseline in morning stiffness, walking anti-bacterial, and anti-fungal activities (Asgarpanah and time and joint swelling (Deodar et al., 1980). Joint swelling Kazemivash, 2012). It significantly lowers the production was dramatically (90-100%) inhibited in female rats with of NO, Prostaglandon E2 (PGE2), inducible nitric oxide streptococcal cell wall (SCW) induced arthritis by synthase (iNOS), cyclooxygenase-2, and pro-interleukin-1β administering Crude or refined turmeric essential oils expression, indicating to have a strong anti-inflammatory (TEO) extracts (Funk et al., 2010). Significant mean property by restraining NF-κB activation and Mitogen difference in Erythrocyte sedimentation rate (ESR), activated protein kinase (MAPK) signal transduction Arthritic score(AS) and radiological scores were observed pathway in Lipopolysacharide (LPS)-induced in (CIA) induced Sprague-Dawley rats after treatment macrophages(Wu et al., 2010). The hydroalcoholic extract with 110 mg/ml/kg CL compared to vehicle treated group of C. sativum (CHSE) was studied in adult wistar rats and (Anna et al., 2011). Induction of apoptosis and growth the expression of TNF-R1, IL-1 β and IL-6 in the synovium inhibition, suppression of anti-apoptotic Bcl-2 and X-linked was observed to be down regulated (Nair et al., 2012). inhibitor of the apoptosis protein, increase of pro- CSHE at a dose of 32 mg/kg causes significant reduction in apoptotic Bax expression were observed in synovial paw edema and dry granuloma weight in carrageenan- fibroblasts of RA patients when they were treated with induced paw edema model. Moreover there was a curcumin, a polyphenolic compound from the rhizome of significant reduction of serum IL-6 and IL-1 β levels and Curcuma longa. Moreover the occurrence of proteolytic Tumor necrosis factor receptor 1 (TNF-R1) expression on activation of caspase-3 and caspase-9, and the concomitant peritoneal macrophages (Nair et al., 2012). Studies have degradation of poly(ADP-ribose) polymerase protein, been reported that the aqueous and ethanolic extracts of C. decrease in the expression levels of the COX-2 were Academia Journal of Medicinal Plants; Kaloni et al. 185

also reported which demonstrated the therapeutic anti-inflammatory, anti-microbial, antitumor, anti-viral, potential of C. longa against hyperplasia of the synovial anti-diabetic, anti-oxidant and anti-malarial properties fibroblasts in RA (Park et al., 2007). (Febrina et al., 2018). α-Mangostin compound present in G. mangostana lowers the expression level of TNF-α, MCP-1, and IL-6 (Kim et al., 2017). Peel extract of G. mangostana Zingiber officinalae studied by Wahyu et al exhibited the inhibition of COX-2, IL-6, IL-1β, and NO by G. mangostana peel extract (GMPE) Zingiber officinale, a species commonly known as ginger and its components α-mangostin, and γmangostin in LPS- belongs to Zingiberaceae family (Dhanik et al., 2017). It is induced RAW264.7 cells along with regulating the widely used in Chinese, Arabian, Caribbean and Ayurveda activation of macrophages (Widowati et al., 2016). A study medicine systems. It is known for its anti-oxidant, anti- reported that mangosteen and its ingredients inhibited the microbial, anti-cancer, anti-diabetic, analgesic, anti-pyretic, secretion of TNF-α from cells with IC50 range from 2 μg/ml anti-inflammatory and anti-platelet aggregating activities to 11 μg/ml. It also inhibited the secretion of TNF-α and IL- (Dhanik et al., 2017). Gingerol, shogaol, and other 6 in LPS-stimulated mice with ED50 (median effective structurally-related substances present in Z. officinalae dose) less than 100 mg/kg (Lee et al., 2013). Zuo et al. commonly known as ginger inhibits the biosynthesis of (2018) showed the effect of G. mangostana pericarp prostaglandin and leukotriene by suppressing 5- ethanol extract in CIA rats and reported a significant lipoxygenase or prostaglandin synthetase. They also down reduction in anti-cyclic citrullinated peptide antibody, IL- regulate the production of pro-inflammatory cytokines (IL- 17 and TLR4 expression in CIA rats along with increase in 1, TNF-α, and IL-8). Another study by Pan et al. (2008) FOXP3, CD25þ cells distribution and IL-10 secretion (Zuo reported the potential of shogaol to reduce levels of et al., 2018). A study by Fu et al. (2014) first reported the inflammatory inducible nitric oxide synthase (iNOS) and immuno suppressing action of isogarcinol, a natural COX-2 gene expression (Pan et al., 2008). Jung et al. (2009) compound extracted from Garcinia mangostana L.. Oral indicated that rhizome hexane fraction extract of Z. administration of isogarcinol on CIA showed significant officinale hampers the over production of NO, PGE2, TNF-α, decrease in clinical scores, cytokines level in serum like IL - and IL-1beta (Jung et al., 2009). The alcoholic and aqueous 2 diminishing cartilage and bone erosion. This study also extract of rhizome of Z. officinale have shown significant reported the decrease of iNOS, COX-2 mRNA expression, anti arthritic activity against form aldehyde induced COX-2 mRNA expression, activity of NFAT (Nuclear factor arthritis in rats but the pathway still remains unclear of activated T-cells) and NF-κB expression (Fu et al., 2014) (Prakash and Katiyar, 2016). Inhibition of joint swelling in demonstrating its effectiveness to decrease the progression streptococcal cell wall-induced arthritis model by both RA. It may therefore be considered for a phytomedicine for crude dichloromethane ginger extract and fractions RA. containing only gingerol and their derivatives was reported in the study by Funk et al. (2009), however the crude extract was found to be more effective (Funk et al., 2009). Emblica officinalis Another study by Funk et al. in 2016 showed the anti- inflammatory effects of other secondary metabolites of Emblica officinalis of Euphorbeaceae family is also known ginger, the essential oils, which contain terpenes and is as the Indian gooseberry or Amla (Khan, 2009). It is native reported to have phytoestrogenic activity in female Lewis to India, also growing in Sri Lanka, Uzbekistan, South East rats with SCW-induced arthritis (Funk et al., 2016). Fouda Asia, and China. Various preclinical studies have and Berika, (2009) reported the anti-inflammatory manifested the cardioprotective, antipyretic, wound potential of Zingiber officinale rhizomes with doses more healing, analgesic, anti-tussive, anti-diarrheal, anti- than 50 mg/kg/day in CIA rat model by demonstrating the atherogenic, adaptogenic, gastroprotective, anti-anemic, amelioration of disease incidence, clinical scores, joint hepatoprotective, anti-hypercholesterolemic, anti- swelling, destruction of cartilage and also reduction of atherosclerotic, nephroprotective, and neuroprotective cytokines like IL1β, IL-6, TNF-α and anti CII (collagen type potential of E. officinalis (Khan, 2009). It significantly II) antibodies (Fouda and Berika, 2009). Zingiber officinale lowered the expression of pro-inflammatory cytokines IL- can be an advantageous herbal option in the treatment of 6, TNF-α and suppresses the phosphorylation of NF-κB in RA. rats (Malik et al., 2016). E. officinalis fruits have the potential to trigger programmed cell death of human primary osteoclasts that are involved in the pathogenesis Garcinia mangostana of RA (Penolazzi et al., 2008). A study from Golechha et al. (2014) reported the management of acute and chronic Garcinia mangostana L. of family Clusiaceae is a type of inflammation in rats with hydroalcoholic extract of Emblica fruit native to Southeast Asia region (Febrina et al., 2018). officinalis (HAEEO) (Golechha et al., 2014). Finding the It is commonly known as mangosteen and known for its potential of Emblica officinalis, can be drawn as a beneficial Academia Journal of Medicinal Plants; Kaloni et al. 186

reception for patients suffering from RA. 2007) Methanolic extract of Moringa oleifera also showed anti-arthritic activity against turpentine oil, formaldehyde and CFA induced arthritis which proves that M.oleifera has Psidium guajava the potential to be a potent phytomedicine for RA (Kumar et al., 2013). Psidium guajava, the common fruit guava belongs to Myrtaceae family, majorly found in the tropical and temperate regions (Gutiérrez et al., 2008). It is known to Periploca forrestii show the following pharmacological properties like antioxidant, hepatoprotection, anti-allergy, anti-microbial, anti- Periploca forrestii belongs to the Apocynaceae family and is genotoxic, anti-plasmodial, cytotoxic, anti-spasmodic, widely used in Chinese medicine system (Dong et al., cardioactive, anti-cough, anti-diabetic, anti-inflammatory 2017). It is known for its anti-inflammatory and and anti-nociceptive activities (Gutiérrez et al., 2008). It is immunosuppressive potential. Ethanolic extract of P. known to reduce the levels of iNOS and COX-2 at the forrestii potentially inhibits the LPS-stimulated production transcription level (Jang et al., 2014). It also suppresses of NO, PGE2 and cytokines like TNF-α, IL-6 and IL-10. It extracellular signal-regulated kinases ERK1/2 of MAPK also suppresses the phosphorylation and degradation of pathway thereby acting as an anti-inflammatory agent inhibitor of NF-κB-α and the signaling pathway MAPK. The (Jang et al., 2014). Studies have demonstrated the anti-arthritic effect of the cardenolide-rich and inhibition of carrageenan-induced paw edema when caffeoylquinic acid-rich fractions (CDLFs and CQAFs) of P. treated with the ethanolic extract of P. guajava (Dutta and forrestii was studied in CIA rats. The results showed that Das, 2010). Similar study was carried out in CFA induced CDLF and CQAF could suppress the paw swelling in CIA arthritic rats upon treatment with ethanolic extract of rats and reduced the levels of RF, TNF-α, IL-6, IL-1β, PGE2, P.guajava, a significant suppression of paw swelling and NO, and MDA (Ting et al., 2018). Another study arthritic score with a dose of 250 mg/kg was observed. demonstrated the potential of Periplocin (an active Repair of knee joint, knee joint synovial membrane and compound of Periploca forrestii) to suppress pro- cartilage has also been reported (Baroroh et al., 2016). inflammatory cytokines levels of IL-6, IFN-γ, TGF-β1, IL-13 Another study reported the anti-arthritic effect of and IL-22 and transcription factor levels of T-bet, GATA3, hydroalcoholic extract of Psidium guyava Linn. in complete and C-Jun genes in adjuvant-induced arthritis (AIA) rats Freund’s adjuvant induced arthritic rats (Jahagirdar et al., (Liu et al., 2016). In a study by Huang et al. (2012), it was 2010). The studies therefore exhibit the efficacy of shown that there was a significant reduction in paw P.guajava in the management of RA. swelling and in the expression level of IL-1β, IL-6 and TNF- α in the serum and inflammatory tissue of AIA rats treated with P.forrestii extract compared to controls (Ming-jin et Moringa oleifera al., 2011). Moreover ethanol extract of P.forrestii was also proved to inhibit COX2 and PGE2 expression and restrained Native to India, Moringa oleifera commonly known as proliferation of rheumatoid arthritis synovial fibroblasts drumstick tree belongs to the Moringaceae family (RASF) at a concentration of 250 and 500 mg/ml (Jiang et (Gopalkrishnan et al., 2016). It has high nutritional as well al., 2015). Therefore it could be a favorable choice in as therapeutic values. It exhibits anti-diabetic, anti- treating RA. microbial, anti-cancer and anti-inflammatory activities (Gopalkrishnan et al., 2016). Earlier study reported that the ethanolic extract of Moringa leaves exhibits strong Anoectochilus roxburghii inhibition against inflammatory paw edema and decreases the arthritic index (Mahdi et al., 2018). Similar study Anoectochilus roxburghii belongs to Orchidaceae family and reported that the hydroethanolic leaves extract of M. is known as Jinxianlian in Chinese (Ye et al., 2017). The oleifera significantly suppressed the protein expression of Chinese herb, also called the “king medicine” known for inflammatory markers like cyclooxygenase-2, and nuclear anti-oxidant activity, anti-lipemic, anti-inflammatory, anti- factor kappa-light-chain-enhancer of activated B-cells p65 viral, liver protective, renal protective, immune- in LPS-induced RAW264.7 macrophages in a dose- modulatory, sedative, and anti-neoplastic effects (Ye et al., dependent manner (Fard et al., 2015). In 2007, a study by 2017). It also lowers the cytokine level and the production Mahajan et al. (2007) in female wistar rats with adjuvant of NO (Guo et al., 2019). Study by Guo et al. (2019) induced arthritis upon treatment with ethanolic extract of demonstrated that A.roxburghii polysaccharides (ARP) seeds of Moringa oleifera Lam. showed a significant significantly suppress the production of NO, down- reduction in RF, TNF-α, IL-1, and IL-6 expression level in regulating the mRNA expressions of IL-1β and IL-6 and serum, paw edema volume and arthritic index score and also phosphorylated IκB and p65 resulting in inhibition of also caused an alteration in oxidative stress (Mahajan et al., nuclear factor κB (NF-κB) pathway in Academia Journal of Medicinal Plants; Kaloni et al. 187

Table 2: The bioactive components present in the herbal products and their target.

ACTIVE COMPONENT PLANT SOURCE TARGET REFERENCES Quercetin Allium cepa (onions) NF-kβ, COX-2, TNF-α, 5LOX, TNF-α, IL- (Oliveira et al., 2014) 1β, AMs, RANKL Curcumin Curcuma longa NF-kβ, TNF-α, AMs, MMP-9, TL9, IL-6, (Shakibaei et al., 2007) IL-8, COX2, LOX Resveratrol Veratrum grandiflorum JNK, NF-kB, TNF-α, 5LOX, AMs, COX2, (Elmali et al., 2007) PGE2, MMP13 8-methoxy-7,3′,4′- Albizia myriophylla NO (Bakasatae et al., 2018) trihydroxyflavone Myristicin Trachydium roylei IL-6, IL-1β, TNF-α, NO, PGE2 (Wang et al., 2016)

Guggulosterone Commiphora mukul IFN-γ, IL-12, IL-1β, NO, NF-ĸB , COX- (Manjula et al., 2006) 2

Shagoal Zingiber officinale IL-1 β, IL-6, TNF-α, INF-γ, NO, PGE2 (Naderi et al., 2015) Cinnamic aldehyde, Cinnamomum cassia NO, TNF-α, PGE2 (Liao et al., 2012) Cinnamic alcohol, Cinnamic acid, & Coumarin Alpha-linolenic acid (ALA) Actinidia polygama iNOS, COX-2, TNF-α (Ren and Chung, 2007) α-Mangostin Garcinia mangostana IL-6, TNF-α, MCP-1 (Kim et al., 2017)

Tetrandrine Stephania tetrandra TNF-α, IL-1β, IL-6, COX-2 (Li et al., 2018) Thiacremonone Allium sativum NF-κB (Mikaili et al., 2013)

Lipopolysacharide(LPS)-stimulated RAW 264.7 cells (Guo by Tao et al. (2001) showed that ethyl acetate extract of et al., 2019). It can be beneficial in halting the symptoms of T.wilfordii dosage up to 570 mg/day are safe and doses RA. more than 360 mg/ day are beneficial for RA patients (Tao et al., 2001). More clinical studies carried out by the same group in the year 2002 on RA patients, Tripterygium Tripterygium wilfordii wilfordii proved to be beneficial in a study (Tao et al., 2002). Lv et al. (2015) showed through a clinical trial that Tripterygium wilfordii of the family Celastraceae is a T.wilfordii hook F (TWHF) monotherapy as well as TWHF Chinese herb (Di et al., 2008), used for the treatment of plus methotrexate therapy was much better than various autoimmune disorders and have potential methotrexate alone for RA patients (Lv et al., 2015). Some antitumor, immune modulating and anti-inflammatory of the known bioactive components of herbal products are ability. It is also known as thunder god vine (Di et al., listed in Table 2 and represented in Figure 2. 2008). It reduces the expression NF-κB gene and accumulation of NO in cultured RAW 267.4 macrophages (Wang et al., 2016). Studies conducted by Bao et al. (2011) CONCLUSION demonstrated that the extract of T. wilfordii inhibits the production of IL-2, TNF-α, IFN-γ, iNOS and COX-2. It also RA associated with inflammation of multiple joints that suppressed the secretion of MMP by synovial fibroblast ranges from pain to deformity presents hassles in and chondrocytes in CIA rats (Bao et al., 2011). Another diagnosis, often observed flare ups, polycyclical nature of study was reported on patients (n=70) who did not RA progression and inconsistent response to therapies. responded to NSAIDs for at least 2 months were Activation of several interrelated immune pathways and an administered with TWH (Tripterygium wilfodii Hook F), imbalance in the cytokine networks significantly 60 mg/day or identically appearing placebo tablets for contributes to RA pathogenesis and inflammatory 3 months (Tao et al., 1989). At the completion of treatment, response. The available treatment includes non-steroidal patients treated with TWH indicated significant anti-inflammatory drugs (NSAID’s) and steroids; these can improvement in joint tenderness score, swelling count, manage the disease to a certain degree. These conventional morning stiffness and grip strength. Another clinical trial treatments are associated with certain limitation including Academia Journal of Medicinal Plants; Kaloni et al. 188

the cost, safety and the long term efficacy. Herbal Astry B, Venkatesha SH, Laurence A, Christensen-Quick A, Garzino-Demo medicines could be a promising and effective treatment for A, Frieman MB, O’Shea JJ, Moudgil KD (2015). Celastrol, a Chinese Herbal Compound, Controls Autoimmune Inflammation by altering the curing diseases like RA. Naturally available balance of pathogenic and regulatory T Cells in the target organ. Clin. medicinalplants/could be an economically feasible Immunol. 157(2): 228-238. treatment and an alternative to the commercially available Badr GM, Arafa NS (2020). “Synergetic Effect of Aged Garlic Extract and therapy. This review expressed strong evidences showing Methotrexate on Rheumatoid Arthritis Induced by Collagen in Male Albino Rats.” Indian J. Exp. Biol. 58(1): 33-38. that the different extracts of these medicinal plants are Bakasatae N, Kunworarath N, Yupanqui CT, Voravuthikunchai SP, potential enough to be established into certain agents that Joycharat N (2018). Bioactive components, antioxidant, and anti- would possibly act as the prevention or treatment of RA. Inﬂammatory activities of the wood of Albizia myriophylla. Rev. Bras. Moreover this review will provide the traditional folk Farmacogn. 28(4): 444-450. Bansode VJ (2012). A Review on pharmacological activities of knowledge and the discovery of potential compounds Cinnamomum cassia Blume. Int. J. Green Pharm. 6(2): 102-108 having promising pharmacological characteristics which Bao J, Dai SM (2011). A Chinese Herb Tripterygium Wilfordii Hook F in the can be useful to sustain the remission of RA. The poor Treatment of Rheumatoid Arthritis: Mechanism, Efficacy, and Safety. bioavailability of the herbal products imposes a significant Rheumatol Int. 31(9): 1123-1129. Baroroh H, Utami E, Achmad A (2016). Psidium Guajava Leaves Decrease obstacle. In order to overcome this issue, researchers are Arthritic Symptoms in Adjuvant-Induced Arthritic Rats. Universa Med. looking for nano-particle delivery mechanism of such 34(3): 197-204 products and reported successful application of these Bhat SP, Rizwi W, Kumar A (2014). Coridandrum Sativum on Pain and methodologies. Nano-particles delivery system improves Inflammation. Int. J. Res. Pharm. Chem. 4(4): 939-45. Brady BL, Tkacz JP, Lofland J, Meyer R, Bolge SC (2015). Prescribing the pharmacological and therapeutic properties of the Patterns of Intravenous Golimumab for Rheumatoid Arthritis. Clin. Ther. drug. Moreover, they can protect the drug against 37(9): 2028-36. intracellular degradation and can efficiently deliver the Bullock J, Rizvi SAA, Saleh AM, Ahmed SS, Do DP, Ansari RA, Ahmed J drug to a specific target. In consequence, lower dose of the (2019). “Rheumatoid Arthritis: A Brief Overview of the Treatment. Med. Princ. Pract. 27(6): 501-507. drug is required to achieve the desired efficacy. Thus, nano- Deodar SD, Sethi R, Srimal RC (1980). Preliminary study on antirheumatic particles can also ensure controlled release of drug dosage activity of curcumin (diferuloyl methane). Indian J. Med. Res. 71: 632-4. and reduction in toxicity (Dudics et al., 2018). However, Dhanik J, Arya N, Nand V (2017). A Review on Zingiber Officinale. J. further research is mandatory for identification, isolation, Pharmacogn. Phytochem. 6(3): 174-184. Dong L, Zhang Y, Wang X, Dong YX, Zheng L, Li YJ, Ni JM (2017). In vivo and characterization of the bioactive component from crude in vitro anti-Inflammatory effects of ethanol fraction from Periploca plant extracts, investigating herb–target interactions, its Forrestii Schltr. Chin. J. Integr. Med. 23 (7): 528-534. bioefficacy and safety aspects of these phytochemical Dudics S, Langan D, Meka R, Venkatesha S, Berman B, Che C, Moudgil K agents for finding and developing novel natural drugs. (2018). Natural Products for the Treatment of Autoimmune Arthritis: Their Mechanisms of Action, Targeted Delivery, and Interplay with the Apart from this, global compliance of legislation is needed Host Microbiome. Int. J. Mol. Sci. 19 (9): 2508. for mass production and marketing of herbal medicines Dutta S, Das S (2010). A study of the anti-inflammatory effect of the leaves which would be beneficial for the treatment of disease. of Psidium guajava Linn. on experimental animal models. Pharmacognosy Res. 2(5): 313-317. Ekambaram S, Perumal S, Subramanian V (2010). Evaluation of antiarthritic activity of Strychnos potatorum Linn seeds in Freund’s ACKNOWLEDGEMENT adjuvant Induced arthritic rat model. BMC Complement. Altern. Med. 10: 56 Ekambaram S, Perumal S, Subramanian V (2011). Strychnos Potatorum We acknowledge Council of Scientific and Industrial Linn Seed Extract Enhances Lysosomal Membrane Stability and Research (CSIR) and Academy of Scientific and Innovative Collagen Formation in Freunds Complete Adjuvant-Induced Arthritic Research (AcSIR) for their support. Rats. J. Herbs, Spices Med. Plants 17(4): 392-402. Elmali N, Baysal O, Harma A, Esenkaya I, Mizrak B (2007). Effects of resveratrol in inflammatory arthritis. Inflammation. 30(1-2): 1-6. Emery P, Keystone E, Tony HP, et al (2008). IL-6 receptor inhibition with REFERENCES tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results Abhishek A, Doherty M, Kuo CF, Mallen CD, Zhang W, Grainge MJ (2017). from a 24-Week multicentre randomised placebo-controlled trial. Ann. Rheumatoid Arthritis Is Getting Less Frequent Results of a Nationwide Rheum. Dis. 67(11): 1516-1523 Population-Based Cohort Study. Rheumatology (Oxford). 56(5): 736- Fard MT, Arulselvan P, Karthivashan G, Adam SK, Fakurazi S (2015). 744. Bioactive extract from moringa oleifera inhibits the pro-inflammatory Anna KA, Suhana MRE, Das S, Faizah O, Hamzaini AH (2011). Anti-Infl mediators in lipopolysaccharide stimulated macrophages. Pharmacogn. Ammatory Effect of Curcuma Longa (Turmeric) on Collagen-Induced Mag. 11(Suppl 4):S556-63. Arthritis: An Anatomico-Radiological Study. Clin. Ter. 162(3): 201-207. Febrina D, Milanda T, Muchtaridi M (2018). Pharmacological activity Asgarpanah J, Kazemivash N (2012). Phytochemistry, pharmacology and garcinia mangostana linn: a review. Int. J. Curr. Med. Sci. 8(5): 430-433. medicinal properties of Coriandrum sativum L. Afr. J. Pharm. Firestein G, McInnes IB (2017). Immunopathogenesis of rheumatoid Pharmacol. 6(31): 2340-2345. arthritis. Immunity. 46(2): 183-196. Ashraf K, Sultan S (2017). A Comprehensive Review on Curcuma Longa: Fishman P, Bar-Yehuda S (2010). Rheumatoid Arthritis: History, Molecular Phytochemical, Pharmacological and Molecular Study. Int. J. Green Fleischmann RM (2009). Progressive multifocal leukoencephalopathy Pharm. 11(4): S671-685. following rituximab treatment in a patient with rheumatoid arthritis. Askling Ja, Bongartz Tb (2008). Malignancy and Biologic Therapy in Arthritis Rheum. 60(11): 3225-8. Rheumatoid Arthritis. Curr. Opin. Rheumatol. 20(3): 334-339 Fouda A, Berika M (2009). Evaluation of the effect of hydroalcoholic Academia Journal of Medicinal Plants; Kaloni et al. 189

extract ofzingiber officinalerhizomes in rat collagen-induced arthritis. in diversely induced arthritis in wistar rats with plausible mechanism. Basic Clin. Pharmacol. Toxicol. 104 (3): 262-271. Int. J. Pharm. Sci. Res. 4(10): 3894-3901. Fu Y, Zhou H, Wang M, Cen J, Wei Q (2014). Immune regulation and anti- Lee KH, Abas F, Mohamed Alitheen NBM, Shaari K, Lajis NH, Israf DA, inflammatory effects of isogarcinol extracted from Garcinia mangostana Syahida A (2014). Chemopreventive effects of a curcumin-like L. against collagen-induced arthritis. J. Agric. Food Chem. 62(18): 4127- diarylpentanoid [2,6-bis(2,5-dimethoxybenzylidene)cyclohexanone] in 4134.Funk J, Frye J, Oyarzo J, Chen J, Zhang H, Timmermann B (2016). cellular targets of rheumatoid arthritis in vitro. Int. J. Rheum. Dis. 18(6): Anti-Inflammatory effects of the essential oils of ginger (Zingiber 616-27. officinale roscoe) in experimental rheumatoid arthritis. Lee TL, Tsai YF, Hu NY, Wang CW, Huang KK , Hsiao JK, Shih YC, Munekazu PharmaNutrition. 4(3): 123-131. I (2013). Anti-arthritis effect of mangostins from G. Mangostana. Funk J, Frye J, Oyarzo J, Timmermann B (2009). Comparative effects of two Biomed. Prev. Nutr. 3: 227-232. gingerol-containing Zingiber officinale extracts on experimental Li X, Wu Z, He B, Zhong W (2018). Tetrandrine alleviates symptoms of rheumatoid arthritis. J. Nat. Prod. 72(3): 403-407. rheumatoid arthritis in rats by regulating the expression of Funk J, Frye J, Oyarzo J, Zhang H, Timmermann B (2010). Anti-Arthritic cyclooxygenase‐2 and inflammatory factors. Exp. Ther. Med. 16(3): effects and toxicity of the essential oils of turmeric (Curcuma longa L.). J. 2670-2676. Agric. Food Chem. 52(2): 842-49. Liao JC We, ZX, Ma ZP, Zhao C, Cai DZ (2016). Evaluation of a root extract Genovese MC, Schiff M, Luggen M, et al (2008). Efficacy and safety of the gel from Urtica dioica (urticaceae) as analgesic and anti-inflammatory selective co-stimulation modulator abatacept following 2 years of therapy in rheumatoid arthritis in mice. Trop. J. Pharm. Res. 15(4): 781- treatment in patients with rheumatoid arthritis and an inadequate 785. response to anti-tumour necrosis factor therapy. Ann. Rheum. Dis. Liao JC, Deng JS, Chiu CS, Hou WC, Huang SS, Shie PH, Huang GJ (2012). 67(4): 547-54 Anti-inflammatory activities of cinnamomum cassia constituents in vitro Golechha M, Sarangal V, Ojha S, Bhatia J, Arya DS (2014). Anti- and in vivo. Evid. Based Complement. Alternat. Med. doi: Inflammatory effect of emblica officinalis in rodent models of acute and 10.1155/2012/429320. chronic inflammation: involvement of possible mechanisms. Int. J. Lis K, Kuzawińska O, Bałkowiec-Iskra E (2014). Tumor necrosis factor Inflam. 6 pp. inhibitors–state of knowledge. Arch. Med. Sci. 10(6): 1175-1185. Gopalkrishnan L, Doriya K, Kumar DS (2016). Moringa olifera: A Review on Liu P, Wang J, Wen W, Pan T, Chen H, Fu Y, et al (2020). Cinnamaldehyde Nutritive Importance and Its Medicinal Application. Food Sci. Hum. suppresses NLRP3 derived IL-1β via activating succinate/HIF-1 in Wellness. 5: 49-52. rheumatoid arthritis rats. Int. Immunopharmacol. 84:106570. DOI: Guo Y, Ye Q, Yang S, Wu J, Ye B, Wu Y, Huang Z, Zheng C (2019). 10.1016/j.intimp.2020.106570. Therapeutic effects of polysaccharides from Anoectochilus roxburghii on Liu Y, Li M, He Q, Yang X, Ruan F, Sun G (2016). Periploca Forrestii Saponin type II collagen-induced arthritis in rats. Int. J. Biol. Macromolecules. Ameliorates Murine CFA-Induced Arthritis by Suppressing Cytokine 122: 882-892. Production.” Mediators Inflamm. 11pp. Gutiérrez RMP, Mitchell S, Solis RV (2008). Psidium guajava: a review of its Luo Q, Sun Y, Liu W, Qian C, Jin B, Tao F (2013). A novel disease modifying traditional uses, phytochemistry and pharmacology. J. Ethnopharmacol. anti-rheumatic drug, iguratimod, ameliorates murine arthritis by 117(1): 1-27. blocking IL-17 signaling, distinct from methotrexate and leflunomide. J. Han X, Parker TL (2017). Antiinflammatory activity of cinnamon Immunol 191(10): 4969-78. (Cinnamomum zeylanicum) bark essential oil in a human skin disease Lv QW, Zhang W, Shi Q, et al (2015). Comparison of Tripterygium wilfordii model. Phytother Res. 31(7): 1034-1038. Hook F with methotrexate in the treatment of active rheumatoid Jahagirdar K, Ghosh P, Adil SA, Ziyaurrahman AR (2010). Effect of arthritis (trifra): a randomised, controlled clinical trial. Ann. Rheum. Dis. hydroalcoholic extract of psidium guyava linn. On complete freund’s 74(6): 1078-1086. adjuvant induced arthritis in laboratory animals. Pharmacologyonline. Mahajan S, Mali R, Mehta A (2007). Protective effect of ethanolic extract of 3: 706-719. seeds of Moringa oleifera Lam. against inflammation associated with Jang M, Jeong SW, Cho SK, Ahn KS, Lee JH, Yang DC, Kim JC (2014). Anti- development of arthritis in rats. J. Immunotoxicol. 4(1): 39-47. inﬂammatory effects of an ethanolic extract of guava (Psidium Guajava Mahdi HJ, Khan NAK, Asmawi MZB, Mahmud R, Murugaiyah V A/L. (2018). L.) leaves in vitro and in vivo. J. Med. Food. 17(6): 678-685. In vivo anti-arthritic and anti-nociceptive effects of ethanol extract of Jiang L, Kai MW, Zheng-qi L, Yang AN, Xue-ming Y, Zhi-yu T (2015). Effects Moringa oleifera Leaves on complete Freund’s adjuvant (CFA)-induced of periploca forrestii ethanol extract (PFE) on proliferation, COX-2 arthritis in rats. Integr. Med. Res. 7(1): 85-94. expression, and PG2 expression of rheumatoid arthritis synovial Malik S, Suchal K, Bhatia J, Khan S I, Vasisth S, Tomar A, Goyal S, Kumar R, fibroblasts from patients. J. Mater. Med. LiShiZhen Med. Mater. Med. Res. Arya D S, Ojha SK (2016). Therapeutic potential and molecular editorial department mailbox. 2015: 01. mechanisms of emblica officinalis gaertn in countering nephrotoxicity in Joseph RM, Hunter AL, Ray WD, Dixon WG (2016). Systemic glucocorticoid rats induced by the chemotherapeutic agent cisplatin. Front. Pharmacol. therapy and adrenal insufficiency in adults: A systemic review. Semin. 7: 350. Arthritis Rheum. 46(1): 133-43. Manjula N, Gayathri B, Vinaykumar KS, Shankernarayanan NP, Joshi BC, Mukhija M, Kalia AN (2014). Pharmacognostical review of Urtica Vishwakarma RA, Balakrishnan A (2006). Inhibition of MAP Kinases by dioica L. Int. J. of Green Pharm. 8(4): 201-209 Crude Extract and Pure Compound Isolated from Commiphora Mukul Jung HW, Yoon CH, Park KM, Han HS, Park YK (2009). Hexane fraction of Leads to down Regulation of TNF‑alpha, IL‑1beta and IL‑2. Int. Zingiberis rhizoma crudus extract inhibits the production of nitric oxide Immunopharmacol. 6(2): 122‑32. and proinflammatory cytokines in lps-stimulated BV2 microglial cells via Mechanisms and Therapeutic Applications. Chapter 15: 291-298. the NF-KappaB pathway. Food Chem. Toxicol. 47(6): 1190-7. Mikaili P, Maadirad S, Moloudizargari M, Aghajanshakeri S, Sarahroodi S Kahlenberg J, Fox D (2011). Advances in the Medical Treatment of (2013). Therapeutic uses and pharmacological properties of garlic, Rheumatoid Arthritis. Hand Clin. 27(1): 11-20. shallot, and their biologically active compounds. Iran J. Basic Med. Sci. Khan KH (2009). Roles of Emblica officinalis in Medicine - A Review. Bot. 16(10): 1031-1048. Res. Int. 2(4): 218-228. Ming-jin H, Chun-li L, Gang G, De-wen Q, Wen-quan W (2011). Effects and Kim HM, Kim YM, Huh JH, Lee ES, Kwon MH, Lee BR, Ko HJ, Chung CH molecular mechanism of Periploca Forrestii against rheumatoid (2017). α-Mangostin Ameliorates Hepatic Steatosis and Insulin arthritis. Chinese J. Exp. Tradit. Med. Formulae. Resistance by Inhibition C-C Chemokine Receptor 2. PLoS One. 12(6): Moosavian SP, Paknahad Z, Habibagahi Z, Maracy M (2020). The effects of e0179204. garlic (Allium sativum) supplementation on inflammatory biomarkers, Kim SY, Solomon DH (2010). Tumor necrosis factor blockade and the risk fatigue, and clinical symptoms in patients with active rheumatoid of viral infection. Nat. Rev. Rheumatol. 6(3): 165-174 arthritis: a randomized, double‐blind, placebo‐controlled trial. Kumar V, Verma A, Ahmed D, Sachan NK, Anwar F, Mujeeb M (2013). Phytother. Res. DOI: 10.1002/ptr.6723. Fostered antiarthritic upshot of Moringa oleifera Lam. stem bark extract Moutia M, Seghrouchni F, Abouelazz O, Elouaddari A, Al Jahid A, Elhou A, Academia Journal of Medicinal Plants; Kaloni et al. 190

Nadifi S, Eddine JJ, Habti N, Badou A (2016). Allium sativum L. Regulates Tao XL, Ying S, Dong Y, et al (1989). A prospective, controlled, in Vitro IL-17 Gene Expression in Human Peripheral Blood Mononuclear double‐blind, cross‐over study of Tripterygium wilfodii Hook F in Cells. BMC Complement. Altern. Med. 16(1): 377. treatment of rheumatoid arthritis. Chin. Med. J. (Engl). 102(5): 327-32. Mushtaq S, Goodman SM, Scanzello CR (2010). Perioperative Tao XL, Younger J, Fan FZ, Wang B, Lipsky PE (2002). Benefit of an extract management of biologic agents used in treatment of rheumatoid of Tripterygium wilfordii hook F in patients with rheumatoid arthritis: a arthritis. Am. J. Ther.18(5): 426-34. double-blind, placebo-controlled study. Arthritis Rheum. 46(7): 1735- Naderi Z, Mozaffari‑Khosravi H, Dehghan A, Nadjarzadeh A, Huseini HF 1743. (2015). Effect of ginger powder supplementation on nitric oxide and C - Ting Liu, Xia Wang, Yan-Ling He, Yang Wang, Li Dong, Xue Ma, et al (2018). reactive protein in elderly knee osteoarthritis patients: A 12-week In vivo and in vitro anti-arthritic effects of cardenolide-rich and double-blind randomized placebo-controlled clinical trial. J. Tradit. caffeoylquinic acid-rich fractions of Periploca forrestii. Molecules 23(8): Complement. Med. 6(3): 199-203. 1988 Nair V, Singh S, Gupta YK (2012). Evaluation of disease modifying activity Tsou HK, Chen HT, Chang CH, Yang WY, Tang CH (2012). Apoptosis signal- of Coriandrum sativum in experimental models. Indian J. Med. Res. regulating kinase 1 is mediated in tnf-α-induced CCL2 expression in 135(2): 240-245. human synovial fibroblasts. J. Cell Biochem. 113(11): 3509-3519. Nanjundaiah SM, Venkatesha SH, Yu H, Tong L, Stains JP, Moudgil KD Venkatesha SH, Dudics S, Astry B, Moudgil KD (2016). Control of (2012). Celastrus and its bioactive celastrol protect against bone autoimmune inflammation by celastrol, a natural triterpenoid. Pathog. damage in autoimmune arthritis by modulating osteoimmune cross- Dis. 74(6): ftw059. talk. J. Biol. Chem. 287: 22216–22226. Wang J, Chen N, Fang L, Feng Z, et al (2018). A Systematic Review about Oliveira T, Figueiredo CA, Brito C, Stavroullakis A, Prakki A, da Silva Velozo the Efficacy and Safety of Tripterygium Wilfordii Hook.f. Preparations E (2014). Effect of Allium cepa L. on lipopolysaccharide-stimulated Used for the Management of Rheumatoid Arthritis. Evid. Based osteoclast precursor cell viability, count, and morphology using 4′, Complement. Alternat. Med. doi: 10.1155/2018/1567463 6‑diamidino‑2‑phenylindole‑staining. Int. J. Cell Biol. 7 pp. Wang YT, Zhu L, Zeng D, Long W, Zhu SM (2016). Chemical composition Ong CK, Lirk P, Tan CH, Seymour RA (2007). An evidence-based update on and anti-inflammatory activities of essential oil from Trachydium roylei. nonsteroidal anti-inflammatory drugs. Clin. Med. Res. 5(1): 19-34. J. Food Drug Anal. 24(3): 602‑9. Pan MH, Hsieh MC, Kuo JM, Lai CS, Wu H, Sang S, Ho CT (2008). 6-Shogaol Widowati W, Darsono L, Suherman J, Fauziah N, Maesaroh M, Erawijantari induces apoptosis in human colorectal carcinoma cells via ros PP (2016). Anti-Inflammatory Effect of mangosteen (Garcinia production, caspase activation, and GADD 153 expression. Mol. Nutr. mangostana L.) Peel extract and its compounds in LPS-Induced Food Res. 52(5): 527-37. RAW264.7 cells. Nat. Prod. Sci. 22(3): 147-153. Pandey M, Debnath M, Gupta S, Chikara S (2011). Phytomedicine: An Wu TT, Tsai CW, Yao HT, Lii CK, Chen HW, Wu YL, Chen PY, Liu KL (2010). ancient approach turning into future potential source of therapeutics. J. Suppressive Effects of Extracts from the Aerial Part of Coriandrum Pharmacogn. Phytother. 3(2): 27-37 sativum L. on LPS-induced inflammatory responses in murine RAW Park C, Moon D, Choi I, Choi B, Nam T, Rhu C, et al (2007). Curcumin 264.7 Macrophages. J. Sci. Food Agric. 90(11): 1846-54. induces apoptosis and inhibits prostaglandin E2 production in synovial Xia X, May BH, Zhang AL, Guo X, et al (2020). Chinese Herbal Medicines for fibroblasts of patients with rheumatoid arthritis. Int. J. Mol. Med. Rheumatoid Arthritis: Text-Mining the Classical Literature for https://doi.org/doi: 10.3892/ijmm.20.3.365. Potentially Effective Natural Products. Evid. Based Complement. Penolazzi L, LamprontiI, Borgatti M, Khan MT, et al (2008). Induction of Alternat. Med. doi: 10.1155/2020/7531967. apoptosis of human primary osteoclasts treated with extracts from the Yadav KN, Kadam PV, Patel JA, Patil MJ (2014). Strychnos Potatorum: medicinal plant Emblica officinalis. BMC Complement. Altern. Med 8: 59. Phytochemical and Pharmacological Review. Pharmacogn. Rev. 8(15): Prakash D, Katiyar NS, Singh AP, Gangwar AK (2016). Evaluation of anti- 61-66. arthritic potential of Zingiber officinale in experimental rats. Eur. J. Ye S, Shao Q, Zhang A (2017). Anoectochilus roxburghii: A review of its Pharm. Med. Res. 3(4): 305-308. phytochemistry, pharmacology, and clinical applications. J. Ren J, Chung SH (2007). Anti-Inflammatory Effect of alpha-linolenic acid Ethnopharmacol. 209: 184-202. and its mode of action through the inhibition of nitric oxide production Zuo J, Yin Q, Wang L, Zhang W, et al (2018). mangosteen ethanol extract and inducible nitric oxide synthase gene expression via NF-KappaB and alleviated the severity of collagen-induced arthritis in rats and mitogen-activated protein kinase pathways. J Agric. Food Chem. 55(13): produced synergistic effects with methotrexate. Pharm. Biol. 56(1): 5073-80. 455-464. Riehmaan K, Behnke B, Schulze-Ostho K (1999). Plant extracts from Stinging Nettle (Urtica dioica), an anti rheumatic remedy, inhibit the proinfammatory transcription factor NF-UB. FEBS Lett. 442(1): 89-94. Roux CH, Brocq O, Breuil V, et al (2006). Safety of anti-TNF-{alpha} therapy in rheumatoid arthritis and spondylarthropathies with concurrent B or C chronic hepatitis. Rheumatology (Oxford). 45(10): 1294-7. Sanmuga Priya E, Venkataraman S (2007). Anti-Inflammatory effect of Strychnos potatorum. Seeds on acute and subacute inflammation in experimental rat models. Pharm. Biol. 45(6): 435-439. Shakibaei M, John T, Schulze-Tanzil G, Lehmann I, Mobasheri A (2007). Suppression of NF‑kappaB activation by curcumin leads to inhibition of expression of cyclooxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis. Biochem. Pharmacol. 73(9): 1434‑45. Cite this article as: Sharma H, Chauhan P, Singh S (2018). Evaluation of the anti-arthritic

activity of Cinnamomum cassia bark extract in experimental models. Kaloni D, Chakraborty D, Biswas S (2020). A review on the efficacy Integr. Med. Res 7(4): 366-373. of phytomedicines for Rheumatoid arthritis. Acad. J. Med. Plants. Shiel WC (2017). Rheumatoid Arthritis. (accessed 2017 May 12). Available 8(12): 179-190. from: http://www.medicinenet.com/rheumatoid_arthri-tis/article.htm

Smolen JS, Steiner G (2003). Therapeutic strategies for rheumatoid Submit your manuscript at: arthritis. Nat. Rev. Drug Discov. 2(6): 473-88. https://www.academiapublishing.org/journals/ajmp/ Tao XL, Cush JJ, Garret M, Lipsky PE (2001). A phase I study of ethyl

acetate extract of the chinese antirheumatic herb Tripterygium wilfordii hook F in rheumatoid arthritis. J. Rheumatol. 28(10): 2160-2167.