Chronic diseases, inflammation, and spices: how are they linked?

Chronic diseases, also called as non-communicable diseases that include Alzheimer’s disease, arthritis, cancer, cardiovascular disease (CVD), diabetes and Parkinson’s disease, remain the primary root cause of death and disability worldwide [1‐3]. The major risk factors associated with these diseases are unhealthy lifestyle including lack of physical activity, poor diet, stress, excessive tobacco and alcohol consumption, exposure to radiation, and infection with pathogenic microorganisms. It is now well established that these agents induce inflammation and dysregulate inflammatory pathways, which lead to the development of chronic diseases [1‐3].

Inflammation, which means, “to set on fire” is a body’s natural response against harmful pathogen and stimuli that occurs in two stages namely, acute and chronic inflammation [4]. Acute inflammation is a part of innate immunity initiated by the immune cells that persists only for a short time. However, if the inflammation continues, the second stage of inflammation called chronic inflammation commences which instigates various kinds of chronic diseases, including arthritis, cancer, cardiovascular diseases, diabetes, and neurological diseases via dysregulation of various signaling pathways such as nuclear factor kappa-B (NF-κB), signal transducer and activator of transcription 3 (STAT3) etc. [5]. Hence, targeting the inflammatory pathways has high potential in preventing and eradicating these deadly diseases [1]. However, most of the drugs developed till today for the treatment of chronic diseases are highly expensive and associated with adverse side effects [1]. Therefore, there is an urgent need to develop novel, safe, affordable, and highly efficacious agents for the management of these diseases.

Congregate evidence suggests that a diet rich in plant-based agents including spices has the ability to prevent most of the chronic diseases. The earliest evidence of the use of spices by humans dates back to 5000 B.C., and till today their biological activities have been extensively studied [6]. “Spice” originates from the Latin word, “species”, which means a commodity of special distinction or value [7]. Spices have been extensively used since ancient times as means of remedy, coloring agent, flavoring agent, and preservative. Subsequently, tremendous studies have shown that nutraceuticals derived from spices such as clove, coriander, garlic, ginger, onion, pepper, turmeric, etc., remarkably prevent and cure various chronic diseases by targeting inflammatory pathways [8]. This review emphasizes the association between inflammation and chronic diseases and the benefits of spices in warding off these global major health issues.

Aforementioned, inflammation is essentially an immune response to infection or injury in the body that helps to maintain tissue homeostasis under stressful conditions [9]. Eventually, it was discovered that transcription factors such as NF-κB and STAT3, inflammatory enzymes such as cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), and inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (IL) such as IL-1, -6, -8, and chemokines are the main molecular mediators of this response. Amongst these mediators, ubiquitous transcription factor NF-κB is the key mediator of inflammation as it regulates large arrays of genes encoding cytokines, cytokine receptors, and cell adhesion molecules that are involved in triggering inflammation [10, 11]. In normal condition, NF-κB exists in the cytoplasm in the form of a heterotrimer that comprises of the subunit p50, p65, and inhibitory subunit IκBα. Upon activation by certain inflammatory stimuli, cytokines, carcinogens, free radicals, tumor promoters, UV-light, γ-rays, and x-rays, the subunits p50 and p65 translocate into the nucleus, bind to the promoters region of various genes, and activate more than 400 genes that are involved in inflammation and other chronic diseases [12] (Fig. 1). Activation of NF-κB is also known to instigate cancer cell proliferation, survival, invasion, angiogenesis, metastasis, chemoresistance, and radiation resistance.

NF-κB regulates the expression of inflammatory mediators such as COX-2, inducible nitric oxide synthase (iNOS), TNF-α, and interleukins [11]. Overexpression of the cytokine, TNF-α, the most potent pro-inflammatory cytokine so far discovered, can lead to various chronic diseases, including cancer, via the activation of NF-κB. Therefore, the blockers of TNF-α have high potential for the prevention and management of chronic diseases and the global market for TNF-α blockers is approximately $20 billion. However, most of these blockers that have been approved for the treatment of chronic diseases are very expensive and have numerous adverse side effects. Interleukins are a group of cytokines that are released by macrophages. Interleukins such as IL-1β, IL-6 and IL-8 also play pivotal roles in inducing inflammatory response [10]. Upregulation of COX-2, iNOS, and aberrant expression of TNF-α and IL-1, IL-6 and IL-8 have been reported to play important roles in oxidative stress that leads to inflammation [5].

IL-6 is a key NF-κB-dependent cytokine that induces the activation of STAT3. STAT3 is a cytoplasmic protein that acts as a transcriptional factor and induces several types of immune and inflammatory responses. The activation of STAT3 involves tyrosine phosphorylation, homodimerization, nuclear translocation where it binds to the DNA and regulates gene transcription [6, 13] (Fig. 1). Protein kinases such as Janus-activated kinase (JAK) 1, 2, and 3 were found to phosphorylate STAT3 and induce its nuclear translocation [6].

Besides these, other transcription factors such as activator protein-1 (AP-1), hypoxia-inducible factor-1α (HIF-1α), nuclear factor of activated T cells (NFAT) and nuclear factor erythroid 2–related factor 2 (Nrf2) are also modulated by inflammatory cytokines and play crucial function for mediating cellular stress responses [5]. The mitogen-activated protein kinase (MAPK) family consisting of three different stress-activated protein kinase pathways namely p38, JNK and ERK, has been found to modulate the level of IL-5 and other cytokines during inflammation. Therefore, MAPK pathway can also be used as a potential molecular target for the treatment of chronic inflammatory diseases [14] (Fig. 1).

Chronic diseases are the leading cause of mortality in the world accounting for approximately 60% of all deaths. Aforementioned, various inflammatory biomarkers are altered in chronic diseases such as transcription factors (NF-κB, STAT3) and their downstream products such as inflammatory cytokines (TNF-α, IL-1, IL-6, IL-8) and pro-inflammatory enzymes such as COX-2, MMP-9, cell adhesion molecules (CAM), vascular endothelial growth factor (VEGF) etc. [1, 15].

Amongst the chronic diseases, cancer is one of the major diseases caused by chronic inflammation. In 2009, Colotta et al. proposed inflammation as the seventh hallmark of cancer [16]. Both inflammation and cancer are linked through intrinsic and extrinsic pathways i.e. oncogenes regulate the inflammatory microenvironment intrinsically, whilst the inflammatory microenvironment facilitates the development and progression of cancer extrinsically [17]. Specifically, the inflammatory response positively aids in tumor development and increases the risk of malignancy [18]. Approximately 15% of the cancer cases are caused by persistent infection and chronic inflammation [19]. It has been well established that NF-κB is constitutively activated in various cancers such as cancers of the breast, colon, liver, lung, pancreas etc. in response to carcinogens such as tobacco, alcohol, and exposure to radiation etc. Upregulation of NF-κB subsequently activates hundreds of pro-inflammatory gene products including TNF-α, IL-1, IL-6, chemokines, MMP-9, 5-LOX, VEGF, and COX-2 [20]. These pro-inflammatory cytokines play a vital role in inflammation-induced cancer cell proliferation, angiogenesis, invasion, metastasis, and suppression of apoptosis. In addition, even in cancers that are not instigated by inflammation, inflammatory cells enter the tumor stroma and consequently induce cancer development [21]. More importantly, an in vivo study has illustrated that NF-κB activation via the IκB kinase (IKK) complex acts as a molecular link between inflammation and cancer [22]. Moreover, NF-κB activation also leads to radioresistance and chemoresistance. These observations suggest that NF-κB plays an important role in inflammation and cancer. Therefore, anti-inflammatory agents that target NF-κB and its regulated products may have high efficacy in both the prevention and treatment of cancers.

Inflammatory cytokines IL-1 and IL-6 also modulate pro-oncogenic transcription factor STAT3, thereby increasing survival, proliferation, angiogenesis, invasion, and metastasis of cancer cells [23]. STAT3 was also known to be upregulated in many cancer patients, and the level of STAT3 was directly correlated with poor prognosis [1]. In case of oral cancer, oral submucous fibrosis or oral lichen planus are precancerous conditions implicated with immuno-inflammatory processes that may transform to cancer [24]. Besides, chronic inflammation in various organs or tissues leads to different types of cancers. For example, chronic obstructive pulmonary disease (COPD) leads to lung cancer, colitis leads to colon cancer, gastritis leads to stomach cancer, pancreatitis leads to pancreatic cancer, prostatitis leads to prostate cancer, etc. [25‐28].

Aforesaid, unresolved inflammation of the pancreas, pancreatitis leads to pancreatic cancer. It has been demonstrated that O-GlcNAc transferase (OGT)—mediated O-GlcNAcylation activated NF-κB signaling pathway and inflammation in pancreatic acinar cells, ultimately leading to the progression of acute pancreatitis [29]. T helper cell-mediated inflammation also has been found to be associated with pancreatic β-cell dysfunction and leads to chronic pancreatitis [30]. COPD is an epidemic chronic inflammatory disease of the lung [31, 32]. Interleukin-33 enhances the production of the inflammatory cytokine such as IL-6 and IL-8 in chronic airway inflammation, thus contributing to COPD development [33]. It has also been reported that inflammatory responses in COPD promote lung tumor initiation and progression [34]. Another inflammation induced chronic disease is rheumatoid arthritis (RA) which is an autoimmune disease characterized by the production of the pro-inflammatory cytokine IL-17 [35]. Studies suggested that pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α also play pathological roles in the development of RA [36]. In addition, it has been demonstrated that STAT3 also caused chronic inflammation and joint destruction in RA [36]. Hence, targeting inflammatory pathways can be used for the prevention and treatment of RA.

In Alzheimer’s disease (AD), which is the prevalent chronic neurodegenerative disease, inflammation has an essential role in the disease pathogenesis. Studies have indicated that microRNAs, astrocytes, microglia, and infiltrating immune cells from the peripheral region might affect the development of neuroinflammation and neurodegeneration in AD patients [37]. Accumulated evidence has depicted that deposition of extracellular amyloid beta (Aβ) in AD leads to upregulation of pro-inflammatory mediators IL-1β, IL-6 and TNF-α, by the activated immune cells, which promote additional inflammatory pathways via instigation of COX-2 and NF-κB [37].

Inflammatory bowel disease (IBD) is a group of inflammatory disorders of the digestive tract, which mainly includes Crohn’s disease and ulcerative colitis. Studies have shown that IBD patients have high susceptibility to develop colorectal cancer. Inflammatory mediators including cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-21), eicosanoids, and reactive oxygen metabolites play a vital role in causing the chronic inflammatory condition in IBD [13, 38]. In addition, activation of STAT3 signaling pathway is associated with colitis and colorectal cancer [39].

Allergic asthma is an airway inflammatory disease caused due to exposure to allergens causing bronchoconstriction. Asthma is characterized by an imbalance between the T helper type 1 (Th1) and T helper type 2 (Th2) responses and excessive production of reactive oxygen species (ROS) [40]. Th2 cells release several cytokines such as IL-4 and IL-13 that in turn produces immunoglobulin, IgE resulting in allergic response [41]. Numerous studies also indicate that attenuation of the Type 2 inflammatory pathway caused a clinically substantial reduction in asthma exacerbations. Thus, it is now evident that type 2 inflammation is an imperative mechanism of susceptibility to asthma exacerbation [42].

Diabetes mellitus (DM) is a predominant metabolic chronic disease that affects more than 170 million people globally. Type 1 DM is induced by the chronic inflammation of pancreatic islets, while type 2 DM is associated with insulin resistance resulting in elevated production of inflammatory markers such as C-reactive protein (CRP), IL-6, and TNF-α [43]. Patients with type 2 diabetes have a higher chance of developing atherosclerosis, which is a disease wherein plaque accumulates in arteries. Arachidonic acid derived eicosanoids such as prostaglandin E₂ (PGE₂) and leukotriene B4 (LTB4) are the potential pro-inflammatory mediators in atherosclerosis and are regulated by NF-κB [43].

Collectively, it is apparent that dysregulation of inflammatory pathways is the underlying mechanism of various chronic diseases. Therefore, many drugs have been developed that target inflammatory pathways for the management of these diseases. However, most of these drugs developed so far are highly expensive and are not devoid of adverse side effects. Hence, there is an urgent need to develop safe, affordable, and efficacious drugs for the prevention and treatment of these chronic diseases. It has been well established that the population who consume spices are less susceptible to the development of chronic diseases. The components present in these spices have the ability to inhibit inflammatory pathways that lead to chronic inflammation, which contributes to the biological properties of these spices.

Mother nature has bestowed us with a profuse source of remedies to treat various kinds of ailments. Since time immemorial, phytochemicals, both in their natural as well as synthetic forms have been used for the treatment of various chronic diseases [12]. The root, leaf, bud, seed, bark, berry, stigma of a plant or flower used for the culinary purpose are generally called as spices. Spices not only add flavor and taste to food, but also exhibit tremendous health benefits [44]. Numerous results from preclinical and clinical studies over the past several decades have ascertained the efficacious role of spices and their active components in preventing and combating various diseases including arthritis, asthma, cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases [45]. The most commonly used spices for culinary purpose that shows biological activities are black pepper, cardamom, cinnamon, clove, cumin, fenugreek, fennel, garlic, ginger, onion, rosemary, turmeric etc.

Turmeric (Curcuma longa) is the most commonly used spice in the world. Curcumin, the main component of turmeric (2–5%), obtained from rhizomes of this plant, is a yellow colored compound, which gives the golden color to turmeric, was first isolated by Vogel in 1842. In 1910, the structure of curcumin was determined as diferuloylmethane and later synthesized and cocrystallized with 5-LOX in 2003 [46]. This ‘golden spice’ is recognized for its anti-inflammatory, antimicrobial, insecticidal, antimutagenic, radioprotective, and anticancer properties. Over ten thousand studies have been reported in the literature about the biological activities of this compound including more than 120 clinical trials. Besides curcumin, the other active components of turmeric include demethoxycurcumin, bisdemethoxycurcumin, sesquiterpenes, diterpenes, triterpenoids, [47, 48]. Black pepper (Piper nigrum), another commonly used spice is widely known for its immunomodulatory, anti-oxidant, anti-asthmatic, anti-carcinogenic, anti-inflammatory and anti-ulcer properties [49]. Other than its main component piperine, black pepper also contains β-caryophyllene, limonene, δ-3-carene, α-pinene, β-pinene, α-phellandrene, myrcene, terpinolene, etc. [50]. Another extensively used spice, ginger (Zingiber officinale) is reported to have different biological properties such as antioxidant, anti-inflammatory and antiproliferative properties. 6-gingerol is the main component of this spice, which is responsible for its biological properties [51]. Other than gingerol, ginger also contains 6-paradol, 6-gingerdiol, gingerdione, shogoal, zingiberene, citral (neral and geranial), bisabolene, cineol, α-farnesene, β-phellandrene, zingerone etc. [52]. The most commonly used spice for cardiovascular diseases in the ancient system of medicine is garlic (Allium sativum). It also possesses anti-inflammatory, gastroprotective and anti-cancer properties due to the presence of phytochemicals such as diallyl sulfides, diallyl disulfides, ajoene, allicin, alliin, diallyl trisulfide, S-allylcysteine, methiin, isoalliin, cycloalliin, S-allylmercaptocysteine [53, 54]. Another spice that is widely used all over the world to enhance the spice level of dishes is red pepper (Capsicum). Apart from capsaicin, red pepper also contains β-carotene, zeaxanthin, lutein, caffeic acid and capsanthin [55]. The other commonly used spices and their active components include cardamom (1,8-cineole, α-terpinyl acetate, limonene, linalool, linalyl acetate, terpinolene and myrcene) [4, 56]; cinnamon (cinnamaldehyde, cinnamyl acetate, cineole, coumarin, ethyl cinnamate, linalool, humulene, β-caryophyllene, τ-cadinol) [57, 58]; clove (eugenol) [4]; fenugreek (diosgenin, yamogenin, choline, resins, trigonelline) [59]; black cumin (thymoquinone, cuminaldehyde, γ-terpinene, β-pinene, p-mentha-1, 3-diene-7-al, p-mentha-1, 4-dien-7-al, p-cymene) [60]; kokum (garcinol, xanthochymol, isoxanthochymol, 1,2-dihydroxypropane-1,2,3-tricarboxylic acid) [61]; rosemary [bornyl acetate, rosmarinic acid, carnosol, carnosic acid, camphor, limonene, camphene, borneol, cineole, α-pinene, (Z)-linalool oxide] [62]; saffron (crocetin and crocin) [63]; star anise (estragole, trans-anethole, limonene) etc. [64]. Hence, it is evident that spices contain a diverse range of active components that provide tremendous health benefits. Table 1 shows a list of spices, their common names, scientific names, and their active components. Figure 2 depicts the structures of active components of spices.

Increasing lines of evidence have established the efficacy of the principal components of spices in preventing as well as alleviating different types of chronic diseases. The main components of spices and their curative potentials are discussed below:

Overall, it is evident from these studies that the allure of spices is attributed not only to their aroma, but also more importantly, to their wellness power. The spice-derived compounds can interact with multiple targets and alter the dysregulated inflammatory pathways and mediators associated with chronic diseases. Hence, with the fatal side effects and inflating cost of modern therapeutics, spices and their active components hold a huge guarantee for the development of affordable, novel and safe drugs against chronic diseases. However, in-depth scientific investigations are required to completely determine the potential of the spice-derived nutraceuticals and open new avenues for the better management of patients with chronic diseases.