Introduction

COX inhibitors are a class of drugs that are commonly used for the treatment of pain, fever, and inflammation. They have been used for decades for a variety of medical conditions and have become one of the most commonly used groups of drugs in the world (Toda 2021). The history of COX inhibitors dates back to the late nineteenth century when salicylates (such as aspirin) were first discovered to have pain-relieving and anti-inflammatory properties. Since then, many other COX inhibitors have been developed, including ibuprofen, naproxen, and celecoxib (Hacker and Satre 2021). The mechanism of action of COX inhibitors is related to their ability to inhibit the activity of enzymes called cyclooxygenases (COX), which are involved in the production of prostaglandins. Prostaglandins are chemical mediators that play a role in inflammation, pain, and fever. By inhibiting the activity of COX enzymes, COX inhibitors reduce the production of prostaglandins, thereby reducing pain, fever, and inflammation (Ngo and Addison 2018). Owing to their anti-inflammatory properties, COX inhibitors remain a popular and effective option for treating RA and tendinitis. They continue to be prescribed by healthcare providers and widely used by patients. There are currently at least 20 distinct allopathic COX inhibitors from six broad groups that are available for use in humans based on their chemical makeup (Chang 2015). Commonly used allopathic cox inhibitors include non-selective COX inhibitors like aspirin, a salicylate derivative that operates by blocking prostaglandin synthesis, inhibiting NF-kappa B, and inducing iNOS and COX inhibition (Kersley 2009). Diclofenac, an acetic acid derivative, functions by blocking VLA-4 activation (Berney 2007). Sulindac, also an acetic acid derivative, operates by inhibiting NF-kappa B (Horino et al. 2019). Ibuprofen, a propanoic acid derivative, operates through NF-kappa B inhibition (Weiser 2021). Naproxen, a propanoic acid derivative, functions through PI3/AKT inhibition (Hadi et al. 2016). Piroxicam and meloxicam are both enolic acid derivatives. They share the common mechanism of blocking β2 integrin activation (Samra et al. 2022; Ma et al. 2022). Oxaprozin, propanoic acid derivative, operates through PI3/AKT inhibition (Zhao et al. 2023). Meclofenamic acid, anthranilic acid derivative, functions by inducing L-shedding (Narsinghani and Chaturvedi 2006). Indomethacin, derived from acetic acid, operates through NF-kappa B inhibition (Janakiraman et al. 2018). Celecoxib (derived from sulfonamide) and etoricoxib (derived from carboxylic acid) are selective COX inhibitors that inhibit prostaglandin synthesis (Feng et al. 2018). Commonly used allopathic COX inhibitors include non-selective COX inhibitors like aspirin, a salicylate derivative that operates by blocking prostaglandin synthesis, inhibiting NF-Kappa B, and inducing iNOS and COX inhibition (Kersley 2009). Diclofenac, an acetic acid derivative, functions by blocking VLA-4 activation (Berney 2007). Sulindac, also an acetic acid derivative, operates by inhibiting NF-kappa B (Horino et al. 2019). Ibuprofen, a propanoic acid derivative, operates through NF-kappa B inhibition (Weiser 2021). Naproxen, a propanoic acid derivative, functions through PI3/AKT inhibition (Hadi et al. 2016). Piroxicam and meloxicam are both enolic acid derivatives. They share the common mechanism of blocking β2 integrin activation (Samra et al. 2022; Ma et al. 2022). Oxaprozin, propanoic acid derivative, operates through PI3/AKT inhibition (Zhao et al. 2023). Meclofenamic acid, an anthanilic acid derivative, functions by inducing L-shedding (Narsinghani and Chaturvedi 2006). Indomethacin, derived from acetic acid, operates through NF-kappa B inhibition (Janakiraman et al. 2018). Celecoxib (derived from sulfonamide) and etoricoxib (derived from carboxylic acid) are selective COX inhibitors that inhibit prostaglandin synthesis (Feng et al. 2018; Cheng et al. 2021).

Though COX inhibitors are effective in managing pain and inflammation, they also have numerous side effects. Common side effects of COX inhibitors include gastrointestinal symptoms such as nausea, vomiting, diarrhea, and abdominal pain. They can also cause damage to the gastrointestinal lining, leading to bleeding and ulceration, headache, dizziness, and an increased risk of heart attack or stroke (Singgih and Achmad 2020). Other side effects of COX inhibitors include renal adverse effects and hematologic side effects. Inhibition of both COX-1 and COX-2 can harm the kidneys. While this may not be a significant problem for patients with normal renal function, those with renal dysfunction are more susceptible to complications from reduced prostaglandin levels caused by COX inhibitors (Ansari 2016). Due to their antiplatelet activity, non-selective COX inhibitors are more likely to have hematologic side effects in patients with GI ulcers, von Willebrand disease, hemophilia, and thrombocytopenia and some perioperative situations (Gargya et al. 2017). Although COX inhibitors are effective in inflammation due to associated side effects in long-term use, there has been a surge in alternative therapies for managing pain and inflammation. Some of these alternatives include natural compounds (plant-derived COX inhibitors), such as ginger and turmeric, which have anti-inflammatory effects but may have fewer side effects (Sharma et al. 2021).

Methodology

This review assessed the role of inflammation and oxidative stress in rheumatoid arthritis and explored the role of phytochemicals on key signaling mechanisms involved in the disease. It provides an overview of in vitro, in vivo, and clinical studies that have investigated the underlined mechanisms and their critical targets in RA. The survey process for this study encompassed a comprehensive search across multiple esteemed scientific databases. These databases included NCBI, Springer, BioMed Central, ResearchGate, Google Scholar, Nature, Wiley Online Library, Frontiers, and ScienceDirect. The terms used during the search of the database include COX inhibitors, phytochemicals, rheumatoid arthritis, signaling pathways, oxidative stress, factors affecting inflammation, and targeting molecules of COX inhibitors. These terms were chosen based on their relevance to the topics under study. Initially, we found 310 articles that seemed to be relevant. After going through their titles and abstracts, we selected 218 papers that aligned with the objectives of our review, thereby establishing the credible scientific literature for the article.

Role of inflammation in rheumatoid arthritis and tendinitis

Inflammation is a complex biological response of the body against harmful stimuli, such as pathogens, damaged cells, or irritants. It is characterized by redness, heat, swelling, and pain in the affected area which is the body’s way of signaling the immune system to eradicate the source of injury or infection. Post pathogenic attack or infection, the body reacts by generating an inflammatory response through the release of inflammatory markers such as C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), prostaglandin E2 (PGE2), and nitric oxide (NO) (Yang et al. 2019). Recent studies confirmed the role of these inflammatory markers in RA, but there are limited reports about the involvement of pro-inflammatory markers like IL-1β in the case of tendinitis (Jomaa et al. 2020).

Rheumatoid arthritis and inflammation

The term arthritis encompasses over 100 different disorders that affect joints with symptoms like pain, stiffness, fatigue, and deformity. This condition can also affect surrounding tissues, connective tissue in muscles, skin, and bones (Sur et al. 2021). The underlying causes can range from inflammation, degeneration, metabolism, and viral illness. Rheumatoid arthritis (RA) is the most common form of chronic inflammatory arthritis. This disease is characterized by synovial inflammation and associated tissue damage and swelling of soft tissues surrounding synovial joints (McInnes and Schett 2017). RA is considered an autoimmune disease and is associated with risk factors such as smoking, older age, positive family history, and female gender (Alieva 2016). There is evidence that patients with RA, particularly those with more severe illnesses, have a shorter life expectancy compared to the general population. The exact cause of RA remains unknown, but numerous studies suggest that a combination of genetic, environmental, and hormonal factors may play a role in its development (Mateen et al. 2016). The advancement of knowledge about the molecular and immunological processes contributing to rheumatoid arthritis (RA) has greatly improved in recent years. Elevated levels of pro-inflammatory cytokines such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) in both synovial tissue and plasma of RA patients have been identified as indicators of inflammation (Yang et al. 2019). The imbalance between pro-inflammatory and anti-inflammatory cytokines is a hallmark of autoimmune disorders, including RA (Uttra et al. 2019). Their concentration in blood corresponds to the severity of the inflammation. The synovial tissue is considered to be the primary site of inflammation in RA (Takeuchi 2022). The diagnosis of RA can be a challenging task due to the absence of a single diagnostic test and the variable symptoms among individuals. Symptoms may not appear until several months after the onset of joint discomfort. Furthermore, the results of hematologic and X-ray screening may still be normal even after several months of joint discomfort (Ziegelasch et al. 2017). The diagnostic criteria for definite rheumatoid arthritis (RA) were updated by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR); according to the criteria given, there must be the presence of synovitis in at least one joint and a total score of 6 or higher from scores in four categories: the number and location of involved joints, serologic abnormality, elevated acute-phase response, and the level of rheumatoid factor (Aletaha and Smolen 2018). These updated classification criteria provide a new method for identifying individuals with early symptoms of RA and may benefit from early treatment.

Several studies have reported that IL-1 and TNF-α (tumor necrosis factor-α) are key players in the development of RA (Vasanthi et al. 2007; Unal et al. 2008). IL-1 is a major contributor to the synovial inflammation and pannus formation in RA through stimulating a variety of cells such as monocytes, macrophages, T and B lymphocytes, fibroblast-like synoviocytes, chondrocytes, and osteoclasts to contribute to the inflammatory processes (Dam and Buckner 2016). This further leads to the production of more pro-inflammatory mediators and destructive enzymes. It also increases the production of cell-adhesion molecules, cytokines, chemokines, angiogenic factors, and small inflammatory agents (prostaglandin E2 and nitric oxide) leading to inflammation (Kong et al. 2020). Several studies have reported the effectiveness of TNF-α inhibitors in treating of RA clinical trials. However, the use of TNF-α inhibitors in RA treatment can be associated with side effects such as infections and the development of malignancies. Also, the antibodies used to suppress TNF-α have been reported to decrease the production of other pro-inflammatory cytokines in synovial cells from RA patients (Amber et al. 2015). Also, interleukin-17 (IL-17) leads to activation of transcription factors like nuclear factor-kappa B and mitogen-activated protein kinase. This leads to the release of other pro-inflammatory cytokines such as IL-1, TNF-α, IL-6, IL-8, and prostaglandin-E2. IL-17 has a dual effect on cartilage, causing proteoglycan breakdown and inhibiting chondrocyte metabolism in healthy cartilage and promoting the production of metalloproteinases in chondrocytes and synoviocytes (Krueger and Brunner 2017). Interleukin-23 (IL-23) is a member of the IL-12 family. IL-23 is produced by activated dendritic cells and macrophages and triggers memory T cells, natural killer cells, macrophages, and dendritic cells. IL-23 is essential for the survival and growth of Th17 (T helper 17) cells, which secrete IL-17, IL-17F, IL-6, and TNF-α. These secreted cytokines cause inflammation in RA patients (Zaky and El-Nahrery 2016). Overproduction of these cytokines due to mutations in the TNF-α and IL-1 promoter leads to joint damage in RA patients (Voirin et al. 2020).

Tendinitis and inflammation

Tendinitis or tendonitis refers to the inflammation and pain of a tendon (a fibrous connective tissue that connects muscle to bone and enables movement). Tendons and their surrounding tissues can be damaged due to overuse and misuse, particularly in athletes and manual labor workers (Loiacono et al. 2019). Symptoms include pain and tenderness along a tendon, typically near a joint, and pain that worsens with activity. Tendonitis can also result from small tears in surrounding tissue or the slow degeneration of a tendon where it attaches to the bone. Commonly affected areas include the shoulders, elbows, hips, knees, heels, wrists, and fingers causing Tennis elbow, golfer’s elbow, and Achilles tendinitis (Mandot 2020). Treatment for tendonitis aims to relieve pain and reduce inflammation. This may involve rest and immobilization of the affected tendon, as well as non-steroidal anti-inflammatory medications. In some cases, surgical or non-surgical treatments may be necessary. Effective treatments for tendonitis may include rest, medication, and in some cases, surgery (Vaishya et al. 2021).

Scientific studies suggest that inflammation is a key factor in the development of tendinitis as in RA. Inflammatory cells, such as macrophages and neutrophils, are typically present in the affected tendons of individuals with tendinitis. These cells secrete pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which contribute to the inflammatory process in tendinitis. The release of pro-inflammatory cytokines leads to an increase in the expression of matrix metalloproteinases (MMPs), which are enzymes that degrade the extracellular matrix (ECM) of tendons (Connizzo and Grodzinsky 2018) leading to decreased mechanical strength of the tendons and ultimately tendinitis. Additionally, the release of pro-inflammatory cytokines also leads to increased production of proteoglycans, which are large macromolecules that can disrupt the normal organization of tendon fibers and contribute to tendinitis (Brauer 2011). Another mechanism by which inflammation contributes to tendinitis is through the recruitment of additional inflammatory cells to the affected area. These cells further contribute to the inflammatory process by releasing additional pro-inflammatory cytokines and enzymes (Dean et al 2015). This results in a vicious cycle of inflammation, ECM degradation, and further recruitment of inflammatory cells, which exacerbates the severity of tendinitis (Dakin et al. 2015). The role of inflammation in tendinitis has important implications for its treatment. Anti-inflammatory drugs, such as COX inhibitors and corticosteroids, are commonly used to reduce the inflammation associated with tendinitis (Heinemeier et al. 2017). Physical therapy and rehabilitation exercises can also be used to improve the strength and function of affected tendons, reducing the risk of further episodes of tendinitis (Hak et al. 2010; Capogna et al. 2017).

Oxidative stress in inflammation: a key role

Numerous biological mechanisms are controlled by chemical reactions that involve the exchange of electrons among molecules. This alters the redox state of the molecules involved (Schafer and Buettner 2001). When the level of oxidants surpasses the cell’s antioxidant defenses, the redox balance is disrupted, resulting in either oxidative stress (a more positive redox potential) or reductive stress (a more negative redox potential). Oxidative stress is a frequent type of stress that occurs in living systems (Shao et al. 2012). Therefore, oxidative stress arises due to the overproduction of oxidizing molecules compared to the cell’s reducing abilities. The reactive oxygen species (ROS) and the reactive nitrogen species (RNS) are the common oxidants that cause oxidative stress in living systems (Pacher et al. 2007). Scientific studies suggest that ROS is positively associated with the severity of RA. Innate immune cells like macrophages and neutrophils produce ROS in the form of O2- and H2O2 (Crowley 2014). Scientific reports suggest that an increase in ROS production due to redox reactions is related to the pathophysiology of inflammation in RA (Nathan and Cunningham-Bussel 2013; Blaser et al. 2016). ROS can also modify NF-kB signaling and nuclear translocation of NF-kB can be induced by H2O2 (Kabe et al. 2005). Other components of the signaling cascade that lead to inflammation like AP-1 inducible hypoxia factor (HIF-1), and gamma-activated peroxisome proliferator receptor (PPARγ) are also induced by ROS (Espinosa-Diez et al. 2015). Scientific studies suggest that mitochondria continuously produce O2- because of the discharge of electrons from the electron transport chain (Drose and Brandt 2012). Mitochondrial ROS help in the production of inflammatory cytokines like IL-1, IL-6, and TNF-α (Bulua et al. 2011). OS is considered a pathogenic signature in RA given the fivefold increase in mitochondrial ROS production in whole blood and monocytes of RA patients compared to healthy persons (Ponist et al. 2020; García-Sánchez et al. 2020).

Other factors affecting inflammation

Heredity

There is strong evidence to suggest that genetics play a major role in the development of RA. MacGregor et al. (2000) reported the estimated heritability of RA to be ~ 60%. Different genetic loci have been identified that are associated with increased risk of RA as shown in Table 1. One of the strongest genetic risk factors for RA is associated with a set of alleles within the major histocompatibility complex (MHC) region. The MHC genes encode human leukocyte antigens (HLAs); within the MHC region, there are specific amino acid sequences in the HLA peptide binding groove that are associated with the risk of development of RA (Bang et al. 2010; Raychaudhuri et al. 2012). These are collectively referred to as shared epitope (SE). Some studies suggest SE alleles contribute ~ 40% of the genetic risk of RA (Plenge 2009; Kronzer and Davis 2021). Other genetic factors have shown a strong association with RA; as per genome-wide studies, more than 100 loci are associated with RA (Okada 2014; Messemaker et al. 2015a, b). A significant genetic association with RA has been identified in the PTPN22 gene; specifically, the polymorphism that affects its function is believed to be a major factor for RA development. However, the precise mechanism by which this polymorphism leads to RA is not fully known. Recent studies suggest that PTPN22 polymorphism may also influence the process of citrullination, which involves the conversion of arginine to citrulline. This is catalyzed by PAD (peptidylarginine deiminases) enzyme. Altered interactions between PAD and PTPN22 may lead to increased citrullination. This hypercitrullination may contribute to inflammation in RA (Chang et al. 2015). Some other genes or their products have been reported to be associated with RA including CTL4A (Plenge et al. 2005), STAT4 (Remmers et al. 2007), IL-6(Ferreira et al. 2013), and NF-kB (Spurlock et al. 2015). In addition, non-coding regions within the TRAF-C5 region have also been identified as being associated with RA. TRAF genes are involved in immune signaling pathways, and variations within TRAF-C5 region may affect the immune response and contribute to RA development (Messemaker et al. 2015a, b).

Table 1 Genetic factors and their role in inflammation in RA
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High glucose levels

Elevated glucose concentrations above the physiological normal of 22mmol/L have been found to induce a rise in the release of TNF-α and IL-6 from normal human mononuclear cells in in vitro experiments (Weyand and Goronzy 2017). There is also evidence that a 24-h incubation in a high-glucose medium increases the production of IL-6 by human monocytes separated from healthy individuals (Morohoshi et al. 2006). The chance of tendinopathy development is increased by the possibility of chronic inflammation caused by these cytokines (Ruscitti et al. 2015). Moreover, the development of RA is also significantly influenced by inflammatory cytokines like TNF-α, IL-6, and IL-1 (Movahedi et al. 2015). Therefore, high glucose levels have a significant impact on the development of inflammation in rheumatoid arthritis and tendinitis patients.

Sedentary lifestyle

A sedentary lifestyle refers to activities that involve remaining seated or reclining and require minimal energy expenditure. Examples include watching television, playing games, and spending prolonged periods being seated. A sedentary lifestyle in RA patients may be associated with increased inflammation. This could result in a vicious loop whereby the decreased physical function, increased fatigue, and increased local disease may result in sedentariness which may further increase inflammation and contribute to the severity of RA-related health outcomes (Thomsen et al. 2015). The majority of experimental conditions that cause a drop in mechanical stress result in a loss of tendon elastic characteristics in both humans and animals, except Botox-induced muscle paralysis (Fenton et al. 2017; Steultjens et al. 2022) (Fig. 1).

Fig. 1
figure 1

Hypothesized mechanism of sedentary lifestyle on rheumatoid arthritis

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Gender

Women make up about two-thirds of RA patients. In the adult population, the cumulative risk of having RA is estimated to be 3.6% for women and 1.7% for males (Maranini et al. 2022). Although the contribution of hormones to the onset of RA is still debatable, estrogen’s immune system-stimulating properties may explain why RA affects women more frequently than males. Early menopause, polycystic ovarian syndrome, and pre-eclampsia are among the factors that have been connected to an elevated risk for the manifestation of RA (Alpízar-Rodríguez et al. 2016). Breastfeeding, oral contraception, and hormone replacement treatment are the things that can postpone the start of RA (Ghamarzad et al. 2016). First-degree relatives (FDRs) of RA patients with lower rates of rheumatoid factor (RF) positivity have been linked to oral contraceptive use, indicating that hormones may have an early “pre-clinical” impact on the etiology of RA (Orellana et al. 2017). Although exogenous hormone use is associated with a lowered risk for RA and may reduce endogenous hormone synthesis, the exact processes behind this link are yet unknown (Makol and Krause 2016).

Why plant-derived COX inhibitors?

The utilization of natural compounds derived from medicinal plants for the treatment of various diseases has gained substantial popularity in clinical research. Of particular interest are polyphenolic compounds, which have garnered significant attention for their ability to modulate inflammasomes (Ambriz-Pérez et al. 2016). Medicinal plants are being utilized as an alternative to allopathic COX inhibitors due to the undesirable side effects associated with their or usage, particularly on the gastrointestinal tract and renal system. The use of potent synthetic drugs is accompanied by concerns regarding their toxicity and the recurrence of symptoms upon discontinuation. As a result, there is a growing need to develop anti-inflammatory drugs derived from medicinal plants. Extensive efforts are being made to explore the potential of medicinal plants in the search for effective and safer anti-inflammatory treatments (Asenso et al. 2016). Acheflan® is an example of a phytotherapeutic agent used for the local treatment of inflammatory conditions; another phytotherapeutic agent, Daflon 500 mg®, is composed of a purified flavonoid fraction and is known for its venotonic and vasoprotective effects (Nunes et al. 2020). Consequently, the immunopharmacological properties of various plant species have revealed various extracts, fractions, and chemical classes that exhibit significant therapeutic potential. This not only offers a promising alternative for treating inflammatory processes and associated diseases but also validates their traditional use in ethnobotanical practices. Furthermore, scientific literature highlights the significant anti-inflammatory activities displayed by plant-derived molecules, with many of their mechanisms involving the inhibition of cytokines, chemokines, and adhesion molecules, as well as pathways involving arachidonic acid and nitric oxide (Hughes et al. 2017; Akbari et al. 2022) (Tables 2 and 3).

Table 2 Plant-derived COX inhibitors (pre-clinical studies)
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Table 3 Plant-derived COX inhibitors (clinical studies)
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Associated target in inflammation by plant-derived COX inhibitors

Plant-derived COX inhibitors target various pathways and molecules involved in inflammation. These main targeted pathways and molecules include inducible nitric oxide synthase (iNOS), MAP kinase signaling pathway, oxidative stress, and inflammatory cytokines (Fig. 2) (Table 4).

Fig. 2
figure 2

Mechanism of action of various phytochemicals in inhibition of iNOS activation (ACA = 1-acetoxychavicol acetate (ACA), LPS = lipopolysaccharide, TLR = Toll-like receptor 4, MAPK = mitogen-activated protein kinase, NF-KB = nuclear factor-kappa B)

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Table 4 Mode of action of various phytochemicals targeting multiple molecular targets of arthritis
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Inducible nitric oxide synthase

Inducible nitric oxide synthase (iNOS) is an enzyme that is involved in the production of NO (nitric oxide), a key mediator of inflammation. iNOS is one of the three isoforms of nitric oxide synthase (NOS) (Vannini et al. 2015; Kashfi et al. 2021). Unlike other forms, it produces significantly higher amounts of NO, reaching levels in the micromolecular range, and it can sustain NO production for longer periods ranging from hours to even days (Vannini et al. 2015). The interplay of pro- and anti-inflammatory cytokonins in the affected tissues of RA patients leads to the activation of iNOS (McInnes and Schett 2007). A study by Grabowski et al. (1997) suggested that CD68 + macrophages in the synovial lining and fibroblasts are the source of iNOS expression in the synovium of RA patients. In the case of tendonitis, all three isoforms of iNOS synthesize NO after tendon injury. The expression of all three isoforms was seen during shoulder surgery in tendon-injured patients (Millar et al. 2017). In the activation of iNOS gene transcription, the process involves the binding of LPS (lipopolysaccharide) to TLR4, which triggers the activation of its adaptor protein MyD88. This activation leads to the recruitment of downstream proteins like IRAK and TRAF6. Subsequently, multiple protein kinases including IkB, IKK, and MAPKs (such as p38, MAPK, JNK1/2, ERK 1/2) are activated. The activation of these protein kinases plays an important role in the activation of central transcription factors involved in iNOS gene expression, namely, NF-kB and activator protein-1 (AP-1) (Murakami and Ohigashi 2007; Wu et al. 2019). Studies by Lee et al. suggested that the iNOS promoter gene contains binding sites for NF-kB and AP-1 and these binding sites are important for the expression of iNOS induction (Lee et al. 2003; Tsai et al. 1999).

Various studies showed the therapeutic potential of phytochemicals in suppressing iNOS expression. For instance, resveratrol, a phytochemical extracted from red grapes, suppresses LPS-induced iNOS mRNA expression. This suppression results due to inhibition of IKB degradation by resveratrol thus blocking the activation of NF-KB in macrophages (Youn et al. 2009). Curcumin, a phytochemical extracted from turmeric plants, has also been reported to suppress iNOS activity (Nakatake et al. 2017). While the exact target of this agent in macrophages is not known, studies suggest that curcumin may act on several signaling pathways upstream of iNOS transcription and post transcription; these pathways include MAPK and JAK/STAT (Murakami 2009). Also, several novel phytochemicals have been isolated such as 1-acetoxychavicol acetate (ACA)—derived from Alpinia galangal (Zingiberaceae), zerumbone extracted from Zingiber zerumbet (zingiberaceae) and Auraptene and Nobiletin found in citrus fruits. These can attenuate iNOS induction in macrophages, which may help in combating the inflammation in RA as well as tendonitis (Giang et al. 2009; Murakami 2009; Murakami 2009; Kobayashi 2010).

Mitogen-activated protein kinase

Mitogen-activated protein kinase (MAPK) regulates various cellular functions in eukaryotes including cell proliferation, cell differentiation, and cell death. It consists of a series of protein kinases, MAPKKKs, MAPKKs, and MAPKs, which sequentially phosphorylate each other, finally activating several transcription factors. In mammals, MAPKs can be classified into three main classes—extracellular signal-regulated kinase (ERK), stress-activated protein kinases (SAPK), and p38 MAPK (Korb et al. 2006; (Liang and Yang 2019) (Fig. 3).

Fig. 3
figure 3

Interaction of various phytochemicals with their target molecules in MAPK pathways.(RAS = rat sarcoma protein, TRAF = tumor necrosis factor receptor-associated dactor, ASK1 = apoptosis signal-regulating kinase 1, MLK3 = mixed-lineage kinase 3, TAK1 = transforming growth factor-beta-activated kinase 1, MEKK = mitogen-activated protein kinase kinase kinase, ERK = extracellular signal-regulated kinase, JNK = Jun N-terminal kinase, AP1 = activator protein 1, SMAD = mothers against decapentaplegic homolog, MSK = mitogen- and stress-activated protein kinase, ELK = ETS-like gene, E-ts = E twenty-six, C-MYC = cellular myelocytomatosis viral oncogene)

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In the synovial tissues of RA patients, all three types of MAPKs have been reported but the significant one is p38 MAPK (Thalhamer et al. 2007; Li et al. 2017). The p38 MAPK is a crucial member of the MAPK family that plays an important role in the regulation of inflammatory cytokines like- IL-1 and TNF-α. Different isoforms of p38 have been reported to play a significant role in the pathogenesis of RA by regulating various processes like migration of inflammatory cells and mediators and cytokine production. The activation of p38 MAPK cascade is initiated by various stimuli like LPS, TNF-α and IL-1 (Li et al. 2016). These ligands bind to cell surface receptors and cause conformational changes in receptors which ultimately leads to the recruitment and activation of downstream signaling proteins like TRAF. These proteins then activate the MAPKKKs (mitogen-activated protein kinase kinase kinase) like MEKK1-4, MLK, TAK-1, and ASK-1. These kinases are activated by interaction with small GTPases. Activated MAPKKKs then phosphorylate the next components in a cascade like MAPK or MAPKK (mitogen-activated protein kinase kinase). Important MAPKKs in p38 cascade are MKK-3 and MKK-6. These MAPKKs primarily activate p38 by phosphorylation of serine and tyrosine residues on p38 MAPK. Once activated, p38 MAPK phosphorylates downstream targets like ATF-2, MSK-1, Max/Myc, and ELK-1 (Li et al. 2002; Bassi et al. 2008).

The stress-activated protein kinase (SAPK) also known as the c-Jun N-terminal kinase (JNK) cascade is another member of the MAPK family. It plays an important role in various cellular and inflammatory responses. The external stimuli in the case of the JNK pathway can be stress. The MAPKKK in the case of JNK is MEKK-1 (MAPK/ERK kinase kinase-1) which can be activated by various upstream signals. Activated MAPKKK phosphorylate MAPKK which in the case of JNK are MKK4 and MKK7 (Kitanaka et al. 2017). These MAPKKs then directly activate JNK by phosphorylating serine threonine residues in its activation loop. Activated JNK translocates to the nucleus and phosphorylates transcription factors like c-Jun, smad-4, AP-1, and ELK-1 (Namba et al. 2017; Hu et al. 2018).

ERK (extracellular signal-regulated kinase) is another member of MAPK family. The extracellular signals activate surface receptors which stimulate ERK–GTPases (RAS, RAF). The activated GTPases phosphorylated MAPKKKs of ERK cascade–MEKK-1/4 which then activate MAPKKs of ERK-MEK-1/2. These MEKs are dual-specificity kinases that phosphorylate ERK. Phosphorylated ERK then translocates into the nucleus and activates transcription factors like ELK-1, Ets-1, and c-Myc (Lu and Malemud 2019; (Shang et al. 2016).

FMAPKs are considered the most promising therapeutic targets for RA. Some phytochemicals directly suppress phosphorylated MAPK complex hence stopping them from activating transcription factors leading to inflammation. These include allylpyrocatechol (APC) a phenolic compound derived from the leaves of Piper betle belonging to Piperaceae family. It has been found to suppress p38 complex and thus stop it from activating transcription factors inside the nucleus. It also has been found to inhibit the production of pro-inflammatory cytokines like TNF-α. Therefore, it helps to modulate inflammatory response in RA (De et al. 2016). Berberine (BBR) is an isoquinoline alkaloid that is extracted from various plant species belonging to the genera Berberis, Coptis, and Phellodendron of the Ranunculaceae family. It has been extensively used in RA patients for its anti-inflammatory properties. Studies suggest the suppressive effects of berberine on p-ERK, p-p38, and p-JNK (Wang et al. 2014). Cryptotanshinone (CTS) is a quinoid triterpene that is extracted from the roots of Salvia miltiorhiza of the Lamiaceae family. It has been found to possess significant anti-inflammatory and anticancer activities. It has been found that CTS suppresses ERK-1/2, JNK, and p38 and hence prevents the activation of transcription factors (Tang et al. 2010). Andrographolide (AD) is a triterpenoid compound extracted from the plant Andrographis paniculata, of the Acanthaceae family. Chemically it is [1-naphthalenyl] ethylidene} dihydroxy-4–2(3H)-furanone. AD has extensively shown anti-inflammatory and antioxidant activity. Studies have suggested that AD completely suppressed ERK signaling while it did not have any impact on p38 and JNK signaling (Li et al. 2017). Curcumin (CUR) is extracted from the roots of Curcuma longa, of the Zingiberaceae family. Studies have suggested that CUR inhibited p-p38, p-ERK, and p-JNK by preventing their translocation to the nucleus (Shang et al. 2016). Epigallocatechin-3-gallate (ECGC) is a polyphenol that is found in green tea. It has anticancerous, anti-inflammatory, and cardioprotective properties. Scientific studies suggest that ECGC inhibits the phosphorylation of MAPKs including p38, JNK, and ERK in response to TNF-α stimulation. It also inhibits the activation of transcription factors—c-Jun, AP-1, and smad-4 in JUN-k cascade. MAPKK- TAK-1 is also inhibited by ECGC (Singh et al. 2003).

NF-κB

NF-κB is the most important regulator in RA. It controls inflammation, cell survival, and cell proliferation. It is generally present in immune cells and regulates the transcription of cytokines. NF-κB activation is initiated by various stimuli including TNF-α, IL-1, and oxidative stress (Hutami et al. 2019). Mammalian NF-kB has five regulators—p105, p100, ReIA, REI-B, and C-ReI. In the active state, these regulators dimerize and activate the signaling cascade. In the inactivate state, IkB, an inhibitor, prevents the dimerization of NF-kB complex and its subsequent translocation into nucleus. NF-kB can be activated by two distinct pathways—canonical and non-canonical. But the most significant pathway in RA is canonical pathway (Fig. 4). It progresses by the dimerization of IKK proteins consisting of IKK-α, IKKβ, and IKK-γ/NEMO. NEMO (NF-kappa-B essential modulator) is a crucial regulator of NF-κB (Chakraborty et al. 2021). Scientific studies have shown that canonical pathway activation requires NEMO for phosphorylation of IkB. IkB is the inhibitor that controls regulatory unit of NF-kB. The pathway is primarily dependent on degradation of IkB that allows translocation of NF-kB complex into the nucleus and stimulate transcription. NF-kB complex in the nucleus predominantly includes p65/p50 dimers (Sarmiento Salinas et al. 2017; Choi et al. 2019).

Fig. 4
figure 4

Canonical activation of NF-kB and its targets in RA (TCR = T cell receptor, TNFR = tumor necrosis factor receptor, NF-kB = nuclear factor kappa B, IKK = inhibitor of nuclear factor kappa-B kinase, EGCG = epigallocatechin-3-gallate, GN = genistein)

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Various molecules in NF-kB can be targeted to suppress RA, and numerous phytochemicals have shown the ability to effectively to inhibit activity of molecules within this pathway without causing side effects (Bacher and Schmitz 2004). These include the following: andrographolide (AD) is a triterpenoid extracted from Andrographis paniculata, of the Acanthaceae family. It has shown anti-inflammatory and antioxidant properties. Scientific studies have shown that AD prevents NF-kB signaling by inhibiting the IkB degradation and by suppressing the nuclear translocation of p65 subunit of NF-Kb (Zhai et al. 2014). Berberine (BBR) is an isoquinoline alkaloid that is extracted from various plant species belonging to the genera Berberis, Coptis, and Phellodendron, of the Ranunculaceae family. It inhibits the upregulation of AMPK (5′ AMP-activated protein kinase) and phosphorylation of p65 and IkB resulting in a negative effect on NF-kB signaling (Zhou et al. 2019). Apigenin (APG) is a flavone and is most commonly found in vegetables and fruits. It is known for its anti-inflammatory properties. It inhibits NF-kB activation inhibiting IkB degradation and phosphorylation (Xu et al. 2008). Cafeic acid (CA) is a phenol and is naturally found in various plants. It strongly inhibits the phosphorylation of P-IKKα/β and P-IκBα (Wang et al. 2017b). Celastrol (CEL) is a triterpenoid extracted from Tripterygium wilfordii, of the family Cealstraceae. It has been shown to possess anti-inflammatory activity. It suppresses the phosphorylation of IKK and IKBα and therefore inhibits the nuclear translocation of p65 (Cascão et al. 2017). CTS also inhibited the nuclear translocation of p65 (Wang et al. 2015). EGCG inhibits activation of the NF-kB pathway by inhibiting the NF-kB p65 subunit transcriptional activity without affecting IkB degradation (Lee et al. 2009). Genistein (GN) (4,5,7-trihydroxy isoflavone) is a phytoestrogen and a tyrosine kinase inhibitor. It is extracted from soybeans and has been shown to have anticancer and anti-inflammatory properties. Scientific studies have shown complete suppression of TNF-α-induced phosphorylation of p65 subunit; it also suppresses the expression levels of IKK and p65 (Li et al. 2014).

JAK-STAT pathway

The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is an important signaling cascade involved in the pathogenesis of RA. The cytokines that activate JAK-STAT cascade in RA include IL-6, IFN-γ, and TNF-α (Kato 2020). The JAK family consists of 4 cytoplasmic non-receptor tyrosine kinases—JAK-1, JAK-2, JAK-3, and TYK2. These kinases phosphorylate STAT proteins. The STAT proteins are transcription factors that cause the activation of target genes. STAT-3 is one of the STATs that gets activated continuously in RA. After the binding of the ligand to the receptor on the cell surface, the activation of JAK proteins is triggered. This activation leads to the autophosphorylation of JAK. The activated JAK then phosphorylates the STAT-3 proteins. Phosphorylated STAT-3 proteins undergo dimerization and translocate into the nucleus, where it binds to specific nuclear sequences and promote gene expression. One important regulator of this pathway is a family of proteins known as SOCS (suppressor of cytokine signaling). There are 8 members of the SOCS protein family and each plays a distinct role in regulating the JAK-STAT cascade. Specifically, SOCS-1 and SOCS-3 inhibit the cascade by binding to phosphorylated STAT proteins and activated proteins (Malemud 2018). Targeting this pathway has emerged as a potential therapeutic approach for managing RA. Various phytochemicals have been shown to possess the property of inhibiting this cascade by targeting the key molecules of the cascade (Malemud and Pearlman 2009; Böhmer and Friedrich 2014).

Scientific studies have shown CTS downregulated the p300-mediated acetylation of STAT-3, which is necessary for its activation, and suppressed the JAK-2-independent STAT-3 activation (Wang et al. 2017c). Curcumin suppresses the production of IFN-γ and IL-6, the key pro-inflammatory cytokines of the cascade. It also inhibited the expression of IFN-γ at the transcription level, thereby suppressing IFN-γ-stimulated STAT-1 phosphorylation and its subsequent translocation to the nucleus (Huang et al. 2012). ECGC also suppressed the nuclear translocation of p-STAT-3 proteins (Lee et al. 2016). Resveratrol (RVL) is a polyphenol that is extracted from grapes, cranberries, and peanuts. It has anticancer and anti-inflammatory properties. It inhibits the mRNA expression levels of STAT-3 (Fig. 5).

Fig. 5
figure 5

Depiction of the overview of JAK-STAT pathway and its phytochemical target in RA. (JAK-STAT = Janus kinase-signal transducers and activators of transcription, RVL = resveratrol)

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Conclusion

Although COX inhibitors’ anti-inflammatory, antipyretic, and analgesic effects have been thoroughly studied, a variety of other molecular and cellular mechanisms that are still poorly understood are crucial in the etiology of inflammation. This review covers the role of various molecules in inflammation and their pathways. The role of inflammation in the etiology of rheumatoid arthritis and tendinitis has also been thoroughly covered. COX inhibitors are the widely prescribed drugs worldwide. These drugs should be provided for the shortest amount of time at the lowest dosage while being closely monitored for GI, renal, and cardiovascular damage. Many plant-derived substances are now being researched as possible anti-inflammatory drugs with the least side effects. This review also assists present and future researchers in identifying anti-inflammatory plants whose active components can be separated through a variety of separation techniques. Such a kind of research could result in the identification of novel compounds of natural origin that can be used to treat inflammatory diseases. However, more thorough research could be done to determine the real mechanism(s) of action of these phytochemical agents.