Chronic diseases, inflammation, and spices: how are they linked?
Journal of Translational Medicinevolume 16, Article number: 14 (2018)
Extensive research within the last several decades has revealed that the major risk factors for most chronic diseases are infections, obesity, alcohol, tobacco, radiation, environmental pollutants, and diet. It is now well established that these factors induce chronic diseases through induction of inflammation. However, inflammation could be either acute or chronic. Acute inflammation persists for a short duration and is the host defense against infections and allergens, whereas the chronic inflammation persists for a long time and leads to many chronic diseases including cancer, cardiovascular diseases, neurodegenerative diseases, respiratory diseases, etc. Numerous lines of evidence suggest that the aforementioned risk factors induced cancer through chronic inflammation. First, transcription factors NF-κB and STAT3 that regulate expression of inflammatory gene products, have been found to be constitutively active in most cancers; second, chronic inflammation such as pancreatitis, prostatitis, hepatitis etc. leads to cancers; third, activation of NF-κB and STAT3 leads to cancer cell proliferation, survival, invasion, angiogenesis and metastasis; fourth, activation of NF-κB and STAT3 leads to resistance to chemotherapy and radiation, and hypoxia and acidic conditions activate these transcription factors. Therefore, targeting these pathways may provide opportunities for both prevention and treatment of cancer and other chronic diseases. We will discuss in this review the potential of various dietary agents such as spices and its components in the suppression of inflammatory pathways and their roles in the prevention and therapy of cancer and other chronic diseases. In fact, epidemiological studies do indicate that cancer incidence in countries such as India where spices are consumed daily is much lower (94/100,000) than those where spices are not consumed such as United States (318/100,000), suggesting the potential role of spices in cancer prevention.
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 [1,2,3]. 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 [1,2,3].
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 . 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. . Hence, targeting the inflammatory pathways has high potential in preventing and eradicating these deadly diseases . However, most of the drugs developed till today for the treatment of chronic diseases are highly expensive and associated with adverse side effects . 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 . “Spice” originates from the Latin word, “species”, which means a commodity of special distinction or value . 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 . This review emphasizes the association between inflammation and chronic diseases and the benefits of spices in warding off these global major health issues.
Molecular pathways linked to inflammation
Aforementioned, inflammation is essentially an immune response to infection or injury in the body that helps to maintain tissue homeostasis under stressful conditions . 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  (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 . 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 . 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 .
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 .
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 . 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  (Fig. 1).
Chronic diseases and inflammation
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 . 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 . Specifically, the inflammatory response positively aids in tumor development and increases the risk of malignancy . Approximately 15% of the cancer cases are caused by persistent infection and chronic inflammation . 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 . 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 . 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 . 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 . STAT3 was also known to be upregulated in many cancer patients, and the level of STAT3 was directly correlated with poor prognosis . 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 . 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. [25,26,27,28].
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 . T helper cell-mediated inflammation also has been found to be associated with pancreatic β-cell dysfunction and leads to chronic pancreatitis . 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 . It has also been reported that inflammatory responses in COPD promote lung tumor initiation and progression . 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 . Studies suggested that pro-inflammatory cytokines such as IL-1β, IL-6 and TNF-α also play pathological roles in the development of RA . In addition, it has been demonstrated that STAT3 also caused chronic inflammation and joint destruction in RA . 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 . 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 .
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 .
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) . Th2 cells release several cytokines such as IL-4 and IL-13 that in turn produces immunoglobulin, IgE resulting in allergic response . 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 .
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 . 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 .
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.
Spices and their active components
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 . 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 . 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 . 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 . 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 . 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. . 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 . 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. . 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 . 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) ; fenugreek (diosgenin, yamogenin, choline, resins, trigonelline) ; black cumin (thymoquinone, cuminaldehyde, γ-terpinene, β-pinene, p-mentha-1, 3-diene-7-al, p-mentha-1, 4-dien-7-al, p-cymene) ; kokum (garcinol, xanthochymol, isoxanthochymol, 1,2-dihydroxypropane-1,2,3-tricarboxylic acid) ; rosemary [bornyl acetate, rosmarinic acid, carnosol, carnosic acid, camphor, limonene, camphene, borneol, cineole, α-pinene, (Z)-linalool oxide] ; saffron (crocetin and crocin) ; star anise (estragole, trans-anethole, limonene) etc. . 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.
Active components of spices, inflammatory pathways, and chronic diseases
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:
1,8-Cineole (Cin) is a monoterpene oxide found in variety of spices such as basil, cardamom, and sage . Cin has been used to treat multiple inflammatory disorders such as bronchitis, sinusitis, chronic rhinitis, and asthma (Table 2). Cin has been shown to downregulate NOS-2, COX-2, and NF-κB, hence showing its potential as an anti-inflammatory agent . Moreover, Cin also attenuated the colonic damage in trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats; decreased acute pulmonary inflammation in vivo; ameliorated acute pancreatitis in vivo via downregulation of cytokines, oxidative stress and NF-κB [38, 65, 66]. In AD, insoluble amyloid β deposits induced inflammation. However, it has been found that 1,8-cineole significantly lowered the expression of proinflammatory cytokines TNF-α, IL-1β and IL-6 in amyloid β toxicated PC12 cells . In addition, numerous studies also showed its potential in preventing different chronic diseases such as asthma, colitis, COPD, pancreatitis, etc. by modulation of inflammatory pathways including TNF-α, COX-2, NF-κB, IL-1β, etc. [66,67,68,69] (Table 2) (Fig. 3).
6-Gingerol, the main active component of ginger, is shown to possess different biological activities such as anti-oxidative, anti-inflammatory and anti-proliferative properties . Its therapeutic effect was observed against various chronic diseases such as AD, colorectal cancer and diabetes [70,71,72] (Table 2) (Fig. 3). For example, 6-Gingerol can induce downregulation of inflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1), TNF-α, and IL-6, and NF-κB thereby, ameliorating steatohepatitis in vivo . 6-gingerol also has a protective role against colitis in vivo through the activation of adenosine monophosphate-activated protein kinase (AMPK) pathway . Studies have shown that this nutraceutical is a potential candidate for the treatment of diabetes. Diabetic rat treated with a ginger extract containing 5% of 6-gingerol significantly attenuated the expression of NF-κB and inhibited the activity of TNF-α and VEGF . Moreover, 6-gingerol possesses anti-tumorigenic and pro-apoptotic properties. For instance, 6-gingerol promoted cell apoptosis in human colorectal cancer cells via the upregulation of nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1 (NAG-1) . Another study also demonstrated that 6-gingerol suppressed cytokine production for T cell activation and proliferation, hindering B cell and mast cell activation, thereby alleviating symptoms of allergic rhinitis (AR) .
α-Pinene is a monoterpene, found mainly in eucalyptus oils and oils of aromatic plants such as rosemary. It is known to possess antimicrobial, apoptotic, antimetastatic, and antibiotic properties . α-pinene is one promising agent for treatment of various inflammatory diseases as it has been found to suppress MAPKs and NF-κB pathway  (Fig. 3). The inflammation associated with acute pancreatitis is considerably reduced by treatment with α-pinene in vivo via the downregulation of TNF-α, IL-1β, and IL-6 . Furthermore, treatment of AR mouse model with α-pinene significantly inhibited receptor-interacting protein 2 (RIP2), IκB kinase (IKK)-β, NF-κB, and caspase-1, thereby making α-pinene an anti-allergic agent against AR .
Diallyl sulphide (DAS)
Diallyl sulphide (DAS) is the major organo sulphur compound of garlic. It is a potential agent for treatment of airway inflammation such as asthma through its ability to regulate nuclear factor-E2-related factor 2/haemoxygenase-1 (Nrf2/HO-1) and NF-κB pathway . Likewise, in vivo studies have also shown that DAS alleviated ovalbumin (OVA)-induced allergic asthma by inhibiting inflammatory factors such as ROS, NF-κB and 8-hydroxy-2′-deoxyguanosine, 8-iso-prostaglandin F2α, and increasing the activation of Nrf2 . In case of osteoarthritis, DAS was reported to inhibit the expression of COX-2 potentially via NF-κB pathway . In vivo study confirmed that DAS protected the cartilage in the development of osteoarthritis by inhibiting the expression of MMP-1, MMP-3, MMP-13, and IL-1β as well as enhancing the production of collagen II . DAS has also been demonstrated to have anticancer properties against different cancers such as colon cancer, prostate cancer, skin cancer, etc. via modulation of inflammatory pathways [82,83,84].
Curcumin, an active component of turmeric, is the most widely studied nutraceutical. It is known to possess anti-antioxidant, anti-bacterial, anti-cancer, , anti-fungal, anti-inflammatory and anti-viral activities. Thus, it is a potential agent against various chronic illnesses. It has been shown to modulate various inflammatory mediators including IL-6, TNF-α, PI3K/Akt, STAT3, IL-27, NF-κB, MAPK, etc. in various preclinical and clinical studies (Table 2) (Fig. 3). For example, inflammation of microglia cells prompts central nervous system (CNS) disorders. Interestingly, curcumin attenuates PI3K/Akt phosphorylation, NF-κB activation, and iNOS in lipopolysaccharide (LPS)-induced inflammatory responses in microglial cells . This nutraceutical also effectively reduced the inflammatory responses in mastitis mice model via suppression of TLR4-mediated NF-κB signaling pathway . Furthermore, curcumin was shown to ameliorate the insulin signaling in the brain of AD in vivo, thus showing its feasibility for treatment of AD . Additionally, curcumin also alleviated chronic nonbacterial prostatitis by downregulating TNF-α, IL-6, and IL-8 in vivo . Furthermore, it has been demonstrated that curcumin reduced asthmatic airway inflammation by activating Nrf2/HO-1 signaling pathway . In case of human non-small cell lung cancer, this potent compound induced apoptosis via the upregulation of micro RNA, miR-192-5p and downregulation of PI3K/Akt signaling pathway . Also, this compound was reported as a protectant against severe acute pancreatitis via attenuation of NF-κB in vivo . This compound is known to inhibit cancer cell proliferation, survival, invasion, angiogenesis, metastases, chemoresistance, and radiation resistance in different types of cancers via modulation of different signaling pathways including NF-κB. Approximately, over 120 clinical trials have proven its potential to treat different chronic diseases without showing any adverse side effects. Curcumin has been shown to inhibit IBD, colitis, rhinitis, oral lichen planus, psoriasis, and prostatitis in various clinical trials. It has also been shown to inhibit cancer alone or in combination with standard chemotherapeutic agents in many clinical trials. So far, curcumin is the most extensively studied spice derived component for the treatment of different chronic diseases in both preclinical and clinical settings.
Diosgenin is a bioactive compound obtained from the spice Trigonella foenum-graecum L. (fenugreek). Over the years, this spice has been known for its anti-carcinogenic, anti-diabetic, anti-oxidant, hypocholesterolemic and immunological properties. Because of its anti-inflammatory activities, diosgenin is a potential agent for various chronic diseases including AD, breast cancer, chronic myeloid leukemia, and osteoarthritis [92,93,94,95] (Table 2) (Fig. 3). For instance, it has been shown to inhibit the expression of MMP-3, MMP-13, iNOS, and COX-2 on human osteoarthritis (OA) in vivo, thus, making diosgenin a suitable agent for OA therapy . Additionally, diosgenin was found to exhibit anti-viral activity against hepatitis C in vitro; induce apoptosis in hepatocellular carcinoma and prostate cancer and inhibit migration of human breast cancer in vitro [93, 96,97,98]. Diosgenin also enhanced ROS-dependent autophagy and cytotoxicity in chronic myeloid leukemia cells via inhibition of mammalian target of rapamycin (mTOR) signaling pathway . This compound was also reported to prevent bone loss on retinoic acid-induced osteoporosis in vivo .
Aforementioned, capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a principal component of the spice red pepper (Capsicum) [100, 101]. It is highly efficacious in ameliorating several chronic diseases such as asthma, diabetes, cancers of breast, cervical, stomach, etc. via the inhibition of STAT3, NF-κB, PGE2, IL-6, TNF-α, etc. [102,103,104,105,106,107] (Table 2) (Fig. 3). Additionally, capsaicin also exhibits anticancer activity against cancer of the colon, lung, prostate, skin and tongue . Studies revealed that capsaicin inhibits inflammatory cytokines such as IL-1β, IL-6, and TNF-α by upregulating Liver X receptor α (LXRα) . Capsaicin can also reduce inflammation in salivary glands via inhibition of NF-κB pathway . This efficient compound also effectively induced cell cycle arrest in bladder cancer cells via forehead box O3a (FOXO3a)-mediated pathway . In vitro and in vivo studies also revealed that capsaicin ameliorated chronic diseases such as AD, skin inflammation, small cell lung cancer, etc. [111,112,113,114].
Eugenol, the active principle from clove extract, is well known for its anti-inflammatory properties via modulation of inflammatory biomarkers such as TNF-α, IL-1, IL-6, COX-2, PGE2, NF-κB, etc.  (Table 2) (Fig. 3). In addition, it has been shown to inhibit various chronic diseases in preclinical studies (Table 2). For instance, eugenol was shown to restrict the progression of asthma in vivo by inhibition of NF-κB pathway . This compound also inhibited cell proliferation in gastric cancer in vivo by suppressing NF-κB pathway . Eugenol was found to enhance the efficacy of anti-cancer drug, gemcitabine and exert anti-inflammatory activity in human cervical cancer cells . In addition, eugenol was shown to inhibit skin cancer via attenuation of c-Myc, H-ras and induction of p53 dependent apoptosis and induction of apoptosis in breast cancer cells via E2F1/survivin downregulation [103, 116]. Numerous investigations further revealed that eugenol exhibits anti-depressant as well as anti-diabetic activities [100, 117].
Cinnamaldehyde (CM) is the active component of the spice cinnamon (Cinnamomum zeylanicum). This component is widely known for its anti-inflammatory, anti-microbial, anti-oxidant, anti-tumor, cholesterol lowering and immunomodulatory properties . CM exerted its anti-inflammatory effect in gastric inflammation by inhibiting NF-κB activation . Cinnamon can also reduce allergic encephalomyelitis in vivo via regulatory T cells . Cinnamon bark has a prominent action in reducing inflammation in arthritis model in vivo via inhibiting cytokines such as IL-2, IL-4, and interferon γ (IFNγ), hence may be regarded as a potent anti-rheumatic agent . Moreover, cinnamon is also effective for the treatment of neurodegenerative diseases such as AD [121, 122] (Table 2).
Garcinol is a polyisoprenylated benzophenone isolated from the plant Garcinia indica (Kokum) . A functional investigation has revealed the anti-carcinogenic, anti-inflammatory and anti-oxidative properties of garcinol . Studies showed that garcinol inhibited the proliferation of breast cancer cells in vitro . Additionally, it also sensitized breast cancer cells to a chemotherapeutic agent, taxol via downregulation of NF-κB/Twist1 and caspase-3/iPLA(2) signaling pathways in a mouse 4T1 breast tumor model . This active component also inhibited inflammation-associated colon carcinogenesis in vivo . Furthermore, garcinol also mediated anti-tumor effect by inhibiting the constitutive activation of STAT3 and NF-κB in squamous cell carcinoma of the head and neck . It has also been reported that garcinol exerted its anti-cancer activity by inducing downregulation of p38-MAPK signaling in lung cancer; NF-κB inhibition in oral cancer; modulation of epithelial–mesenchymal transition (EMT) and Wnt signaling in breast cancer [105, 127, 128].
Thymoquinone is isolated from black cumin (Nigella sativa). It has been shown to possess anti-inflammatory, anti-oxidant, and chemopreventive activities . A recent report has depicted that this bioactive component inhibited IL-1β-induced inflammation via downregulating NF-κB and MAPKs signaling in human osteoarthritis chondrocytes . It also prevented inflammation, neoangiogenesis, and vascular remodeling in asthma in vivo . Thymoquinone also inhibited TNF-α-induced inflammation and cell adhesion in RA, thus making it a promising anti-inflammatory agent . Studies also reported the ameliorative activity of thymoquinone against ovalbumin-induced allergic conjunctivitis in vivo . Additionally, it was also found to be effective against cancer of the bladder, lung, ovarian, gastric, etc. Thymoquinone portrayed its anti-tumor function via inactivation of PI3K/Akt, ERK, NF-κB and STAT3 pathways [134,135,136,137] (Table 2) (Fig. 3).
Quercetin is a dietary flavonoid obtained from onions. The anti-cancer, anti-inflammatory, and anti-oxidant properties of this phytochemical are demonstrated by numerous studies. Quercetin is effective against various chronic diseases including arthritis, breast cancer, dermatitis, diabetes, IBD, hepatitis, psoriasis, etc. due to its ability to inhibit the dysregulated inflammatory pathways involved in these chronic diseases (Table 2) [138,139,140,141,142,143,144]. The anti-inflammatory properties of quercetin is attributed to its ability to downregulate NF-κB and MAPK pathways and enhance PI3K/Akt and Nrf2 pathways [145,146,147] (Table 2) (Fig. 3).
Piperine is the principal plant alkaloid isolated from black pepper (Piper nigrum) and long pepper (Piper longum). Piperine has several biological properties including analgesic, anti-convulsant, anti-tumor and anti-inflammatory activities . Several studies have shown that piperine could attenuate the inflammatory response associated with chronic diseases such as AD, asthma, arthritis, chronic gastritis, endometritis, Parkinson’s disease, etc. [149,150,151] (Table 2). The anti-inflammatory activity of piperine in these chronic diseases is achieved via downregulation of inflammatory pathways such as NF-κB, MAPK, AP-1, COX-2, NOS-2, IL-1β, TNF-α, PGE2, STAT3, etc. [148, 149, 151,152,153,154] (Table 2) (Fig. 3).
Sulforaphane is an isothiocyanate (sulphur containing compounds) distributed amongst cruciferous vegetables including mustard. Studies have shown that sulphoraphane possesses anti-cancer and cardioprotective activities . It elicits protection against cardiovascular diseases via activation of Nrf2 . Studies also reported that sulforaphane represents a promising agent for treatment of chronic diseases such as AD, bladder cancer, colorectal cancer, diabetes, and lung cancer [156,157,158] (Table 2). Another study has also suggested that sulforaphane inhibit pro-inflammatory signaling through inhibition of NF-κB pathway  (Fig. 3).
Besides these active components, other compounds found in spices includes allicin (garlic), anethole (fennel), carnosol (rosemary); linalool (coriander), crocin (saffron), sesamin (sesame seed), ursolic acid (basil), carvone (mint), myristicin (nutmeg), etc. These potent ingredients of diverse spices have been found to aid in preventing and alleviating various chronic diseases (Fig. 4), mostly by downregulating signaling pathways such as NF-κB, STAT3 and ERK/MAPK pathways [129, 146, 148, 159,160,161,162,163].
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.
1,25D3-membrane-associated, rapid response steroid-binding protein
activator protein 1
apoptosis signal-regulating kinase 1
brain-derived neurotrophic factor
cell adhesion molecule-1
chemokine (C–C motif) ligand 20
fasting blood sugar
intercellular cell adhesion molecule-1
insulin-like growth factor 1
inducible nitric oxide synthase
- IκB kinase β:
I kappa B kinase beta
inhibitory factor kappa B alpha
Janus kinase 2
c-JUN N-terminal kinase
mitogen-activated protein kinases
monocyte chemoattractant protein-1
macrophage inflammatory protein
nonsteroidal anti-inflammatory drug (NSAID)-activated gene-1
nuclear factor kappa B
nuclear factor of activated T-cells
nuclear factor of activated T cells cytoplasmic 1
nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing-3
nitric oxide synthases
nuclear factor erythroid 2–related factor 2
proliferating cell nuclear antigen
peroxisome proliferator-activated receptor gamma coactivator 1-alpha
peroxisome proliferator-activated receptor
postsynaptic density protein 93
phosphatase and tensin homolog
receptor for advanced glycation end products
receptor activator of nuclear factor kappa-B ligand
rho-associated protein kinase
sterol regulatory element-binding protein-1
signal transducer and activator of transcription
thiobarbituric acid reactive substance
transforming growth factor beta
Toll-like receptor 4
tumor necrosis factor-alpha
regulatory T cells
transient receptor potential cation channel, subfamily A, member 1
transient receptor potential cation channel subfamily M member 8
transient receptor potential vanilloid type 1
vascular cell adhesion molecule
alpha-smooth muscle actin
Prasad S, Sung B, Aggarwal BB. Age-associated chronic diseases require age-old medicine: role of chronic inflammation. Prev Med. 2012;54(Suppl):S29–37.
Pawelec G, Goldeck D, Derhovanessian E. Inflammation, ageing and chronic disease. Curr Opin Immunol. 2014;29:23–8.
Nasef NA, Mehta S, Ferguson LR. Susceptibility to chronic inflammation: an update. Arch Toxicol. 2017;91(3):1131–41.
Aggarwal BB, Van Kuiken ME, Iyer LH, Harikumar KB, Sung B. Molecular targets of nutraceuticals derived from dietary spices: potential role in suppression of inflammation and tumorigenesis. Exp Biol Med (Maywood). 2009;234(8):825–49.
Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med. 2010;49(11):1603–16.
Sung B, Prasad S, Yadav VR, Aggarwal BB. Cancer cell signaling pathwaystargeted by spice-derived nutraceuticals. Nutr Cancer. 2012;64(2):173–97.
Van der Veen M, Morales J. The Roman and Islamic spice trade: newarchaeological evidence. J Ethnopharmacol. 2015;167:54–63.
Kannappan R, Gupta SC, Kim JH, Reuter S, Aggarwal BB. Neuroprotection by spice-derived nutraceuticals: you are what you eat! Mol Neurobiol. 2011;44(2):142–59.
Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell. 2010;140(6):771–6.
Aggarwal BB. Inflammation, a silent killer in cancer is not so silent! Curr Opin Pharmacol. 2009;9(4):347–50.
Kawabata K, Tung NH, Shoyama Y, Sugie S, Mori T, Tanaka T. Dietary Crocin Inhibits Colitis and Colitis-Associated Colorectal Carcinogenesis in Male ICR Mice. Evid Based Complement Alternat Med. 2012;2012:820415.
Yadav VR, Prasad S, Sung B, Kannappan R, Aggarwal BB. Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer. Toxins (Basel). 2010;2(10):2428–66.
Pandurangan AK, Ismail S, Saadatdoust Z, Esa NM. Allicin alleviates dextran sodium sulfate− (DSS−) induced ulcerative colitis in BALB/c mice. Oxid Med Cell Longev. 2015;2015:605208.
Liang Z, Xu Y, Wen X, Nie H, Hu T, Yang X, Chu X, Yang J, Deng X, He J. Rosmarinic acid attenuates airway inflammation and hyperresponsiveness in a murine model of asthma. Molecules. 2016;21(6):769.
Laveti D, Kumar M, Hemalatha R, Sistla R, Naidu VG, Talla V, Verma V, Kaur N, Nagpal R. Anti-inflammatory treatments for chronic diseases: a review. Inflamm Allergy Drug Targets. 2013;12(5):349–61.
Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073–81.
Raposo TP, Beirão BC, Pang LY, Queiroga FL, Argyle DJ. Inflammation and cancer: till death tears them apart. Vet J. 2015;205(2):161–74.
Rakoff-Nahoum S. Why cancer and inflammation? Yale J Biol Med. 2006;79(3–4):123–30.
Mangino G, Chiantore MV, Iuliano M, Fiorucci G, Romeo G. Inflammatory microenvironment and human papillomavirus-induced carcinogenesis. Cytokine Growth Factor Rev. 2016;30:103–11.
Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006;72(11):1605–21.
Wang K, Karin M. Tumor-elicited inflammation and colorectal cancer. Adv Cancer Res. 2015;128:173–96.
Karin M. The IkappaB kinase—a bridge between inflammation and cancer. Cell Res. 2008;18(3):334–42.
Dmitrieva OS, Shilovskiy IP, Khaitov MR, Grivennikov SI. Interleukins 1 and 6 as main mediators of inflammation and cancer. Biochemistry (Mosc). 2016;81(2):80–90.
Feller L, Altini M, Lemmer J. Inflammation in the context of oral cancer. Oral Oncol. 2013;49(9):887–92.
Watari J, Chen N, Amenta PS, Fukui H, Oshima T, Tomita T, Miwa H, Lim KJ, Das KM. Helicobacter pylori associated chronic gastritis, clinical syndromes, precancerous lesions, and pathogenesis of gastric cancer development. World J Gastroenterol. 2014;20(18):5461–73.
Iwanaga K, Nakamura T, Maeda S, Aritake K, Hori M, Urade Y, Ozaki H, Murata T. Mast cell-derived prostaglandin D2 inhibits colitis and colitis-associated colon cancer in mice. Cancer Res. 2014;74(11):3011–9.
Hung SC, Lai SW, Tsai PY, Chen PC, Wu HC, Lin WH, Sung FC. Synergistic interaction of benign prostatic hyperplasia and prostatitis on prostate cancer risk. Br J Cancer. 2013;108(9):1778–83.
Houghton AM. Mechanistic links between COPD and lung cancer. Nat Rev Cancer. 2013;13(4):233–45.
Zhang D, Cai Y, Chen M, Gao L, Shen Y, Huang Z. OGT-mediated O-GlcNAcylation promotes NF-κB activation and inflammation in acute pancreatitis. Inflamm Res. 2015;64(12):943–52.
Talukdar R, Sasikala M, Pavan Kumar P, Rao GV, Pradeep R, Reddy DN. T-helper cell-mediated islet inflammation contributes to β-Cell dysfunction in chronic pancreatitis. Pancreas. 2016;45(3):434–42.
Mahtaj LG, Feizpour A, Kianmehr M, Soukhtanloo M, Boskabady MH. The effect of carvacrol on systemic inflammation in guinea pigs model of COPD induced by cigarette smoke exposure. Pharmacol Rep. 2015;67(1):140–5.
Barbu C, Iordache M, Man MG. Inflammation in COPD: pathogenesis, local and systemic effects. Rom J Morphol Embryol. 2011;52(1):21–7.
Shang J, Zhao J, Wu X, Xu Y, Xie J, Zhao J. Interleukin-33 promotes inflammatory cytokine production in chronic airway inflammation. Biochem Cell Biol. 2015;93(4):359–66.
Bozinovski S, Vlahos R, Anthony D, McQualter J, Anderson G, Irving L, Steinfort D. COPD and squamous cell lung cancer: aberrant inflammation andimmunity is the common link. Br J Pharmacol. 2016;173(4):635–48.
Roeleveld DM, van Nieuwenhuijze AE, van den Berg WB, Koenders MI. The Th17 pathway as a therapeutic target in rheumatoid arthritis and other autoimmune and inflammatory disorders. BioDrugs. 2013;27(5):439–52.
Mori T, Miyamoto T, Yoshida H, Asakawa M, Kawasumi M, Kobayashi T, Morioka H, Chiba K, Toyama Y, Yoshimura A. IL-1β and TNFα-initiated IL-6-STAT3 pathway iscritical in mediating inflammatory cytokines and RANKL expression in inflammatoryarthritis. Int Immunol. 2011;23(11):701–12.
Shadfar S, Hwang CJ, Lim MS, Choi DY, Hong JT. Involvement of inflammation in Alzheimer’s disease pathogenesis and therapeutic potential of anti-inflammatory agents. Arch Pharm Res. 2015;38(12):2106–19.
Santos FA, Silva RM, Campos AR, De Araújo RP, Lima Júnior RC. Rao VS.1,8-cineole (eucalyptol), a monoterpene oxide attenuates the colonic damage in rats on acute TNBS-colitis. Food Chem Toxicol. 2004;42(4):579–84.
He Z, Ke J, He X, Lian L, Sun L, Chen Z, Wu X, Lan P. Inflammation promotes the development of colitis-associated colorectal cancer. Zhonghua Wei Chang Wai Ke Za Zhi. 2014;17(7):706–10.
Shin IS, Hong J, Jeon CM, Shin NR, Kwon OK, Kim HS, Kim JC, Oh SR, Ahn KS. Diallyl-disulfide, an organosulfur compound of garlic, attenuates airway inflammation via activation of the Nrf-2/HO-1 pathway and NF-kappaB suppression. Food Chem Toxicol. 2013;62:506–13.
Liu J, Cheng Y, Zhang X, Zhang X, Chen S, Hu Z, Zhou C, Zhang E, Ma S. Astragalin attenuates allergic inflammation in a murine asthma model. Inflammation. 2015;38(5):2007–16.
Dunican EM, Fahy JV. The role of type 2 inflammation in the pathogenesis of asthma exacerbations. Ann Am Thorac Soc. 2015;12(Suppl 2):S144–9.
Pedicino D, Liuzzo G, Trotta F, Giglio AF, Giubilato S, Martini F, Zaccardi F, Scavone G, Previtero M, Massaro G, Cialdella P, Cardillo MT, Pitocco D, Ghirlanda G, Crea F. Adaptive immunity, inflammation, and cardiovascular complications in type 1 and type 2 diabetes mellitus. J Diabetes Res. 2013;2013:184258.
Nilius B, Appendino G. Spices: the savory and beneficial science of pungency. Rev Physiol Biochem Pharmacol. 2013;164:1–76.
Opara EI, Chohan M. Culinary herbs and spices: their bioactive properties, the contribution of polyphenols and the challenges in deducing their true health benefits. Int J Mol Sci. 2014;15(10):19183–202.
Aggarwal BB, Kunnumakkara AB, Harikumar KB, Tharakan ST, Sung B, Anand P. Potential of spice-derived phytochemicals for cancer prevention. Planta Med. 2008;74(13):1560–9.
Gupta SC, Patchva S, Aggarwal BB. Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J. 2013;15(1):195–218.
Lin JK, Shiau SYL. Turmeric (Curcumin). In: Aggarwal BB, Kunnumakkara AB, editors. Molecular targets and therapeutic uses of spices. Singapore: World scientific publishing; 2009. p. 403–24.
Meghwal M, Goswami TK. Piper nigrum and piperine: an update. Phytother Res. 2013;27(8):1121–30.
Musenga A, Mandrioli R, Ferranti A, D’Orazio G, Fanali S, Raggi MA. Analysis of aromatic and terpenic constituents of pepper extracts by capillary electrochromatography. J Sep Sci. 2007;30:612–9.
Surh Y. Molecular mechanisms of chemopreventive effects of selected dietary and medicinal phenolic substances. Mutat Res. 1999;428(1–2):305–27.
Jolad SD, Lantz RC, Chen GJ, Bates RB, Timmermann BN. Commercially processed dry ginger (Zingiber officinale): composition and effects on LPS-stimulated PGE2 production. Phytochemistry. 2005;66(13):1614–35.
Kimbaris AC, Siatis NG, Daferera DJ, Tarantilis PA, Pappas CS, Polissiou MG. Comparison of distillation and ultrasound-assisted extraction methods for the isolation of sensitive aroma compounds from garlic (Allium sativum). Ultrason Sonochem. 2006;13:54–60.
Srinivasan K. Antioxidant potential of spices and their active constituents. Crit Rev Food Sci Nutr. 2014;54(3):352–72.
Howard LR, Talcott ST, Brenes CH, Villalon B. Changes in phytochemical and antioxidant activity of selected pepper cultivars (Capsicum species) as influenced by maturity. J Agric Food Chem. 2000;48:1713–20.
Marongiu B, Piras A, Porcedda S. Comparative analysis of the oil and supercritical CO2 extract of Elettaria cardamomum (L.) Maton. J Agric Food Chem. 2004;52:6278–82.
Gruenwald J, Freder J, Armbruester N. Cinnamon and health. Crit Rev Food Sci Nutr. 2010;50:822–34.
Jayaprakasha GK, Jagan Mohan Rao L, Sakariah KK. Volatile constituents from Cinnamomum zeylanicum fruit stalks and their antioxidant activities. J Agric Food Chem. 2003;51:4344–8.
Mullaicharam AR, Deori G, Maheswari RU. Medicinal values of fenugreek—a review. Res J Pharm Biol Chem Sci. 2013;4(1):1304.
Iacobellis NS, Lo Cantore P, Capasso F, Senatore F. Antibacterial activity of Cuminum cyminum L. and Carum carvi L. essential oils. J Agric Food Chem. 2005;53:57–61.
Pandey MK, Kunnumakkara AB, Aggarwal BB. Kokum (Garcinol). In: Aggarwal BB, Kunnumakkara AB, editors. Molecular targets and therapeutic uses of spices. Singapore: World scientific publishing; 2009. p. 281–304.
Bozin B, Mimica-Dukic N, Samojlik I, Jovin E. Antimicrobial and antioxidant properties of rosemary and sage (Rosmarinus officinalis L. and Salvia officinalis L., Lamiaceae) essential oils. J Agric Food Chem. 2007;55:7879–85.
Gohari AR, Saeidnia S, Mahmoodabadi MK. An overview on saffron, phytochemicals, and medicinal properties. Pharmacogn Rev. 2013;7(13):61.
Butt MS, Naz A, Sultan MT, Qayyum MM. Anti-oncogenic perspectives of spices/herbs: a comprehensive review. EXCLI J. 2013;12:1043–65.
Zhao C, Sun J, Fang C, Tang F. 1,8-cineol attenuates LPS-induced acute pulmonary inflammation in mice. Inflammation. 2014;37(2):566–72.
Lima PR, de Melo TS, Carvalho KM, de Oliveira ÍB, Arruda BR, de Castro Brito GA, Rao VS, Santos FA. 1,8-cineole (eucalyptol) ameliorates cerulein-induced acute pancreatitis via modulation of cytokines, oxidative stress and NF-κB activity in mice. Life Sci. 2013;92(24–26):1195–201.
Khan A, Vaibhav K, Javed H, Tabassum R, Ahmed ME, Khan MM, Khan MB, Shrivastava P, Islam F, Siddiqui MS, Safhi MM, Islam F. 1,8-cineole (eucalyptol) mitigates inflammation in amyloid Beta toxicated PC12 cells: relevance to Alzheimer’s disease. Neurochem Res. 2014;39(2):344–52.
Santos FA, Silva RM, Tomé AR, Rao VS, Pompeu MM, Teixeira MJ, De Freitas LA, De Souza VL. 1,8-cineole protects against liver failure in an in vivo murine model of endotoxemic shock. J Pharm Pharmacol. 2001;53(4):505–11.
Juergens UR. Anti-inflammatory properties of the monoterpene 1.8-cineole: current evidence for co-medication in inflammatory airway diseases. Drug Res (Stuttg). 2014;64(12):638–46.
Lee SH, Cekanova M, Baek SJ. Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells. Mol Carcinog. 2008;47(3):197–208.
Dongare S, Gupta SK, Mathur R, Saxena R, Mathur S, Agarwal R, Nag TC, Srivastava S, Kumar P. Zingiber officinale attenuates retinal microvascular changes in diabetic rats via anti-inflammatory and antiangiogenic mechanisms. Mol Vis. 2016;22:599–609.
Lee C, Park GH, Kim CY, Jang JH. -Gingerol attenuates β-amyloid-induced oxidative cell death via fortifying cellular antioxidant defense system. Food Chem Toxicol. 2011;49(6):1261–9.
Tzeng TF, Liou SS, Chang CJ, Liu IM. 6-gingerol protects against nutritional steatohepatitis by regulating key genes related to inflammation and lipid metabolism. Nutrients. 2015;7(2):999–1020.
Chang KW, Kuo CY. 6-Gingerol modulates proinflammatory responses in dextran sodium sulfate (DSS)-treated Caco-2 cells and experimental colitis in mice through adenosine monophosphate-activated protein kinase (AMPK) activation. Food Funct. 2015;6(10):3334–41.
Kawamoto Y, Ueno Y, Nakahashi E, Obayashi M, Sugihara K, Qiao S, Iida M, Kumasaka MY, Yajima I, Goto Y, Ohgami N, Kato M, Takeda K. Prevention of allergic rhinitis by ginger and the molecular basis of immunosuppression by 6-gingerol through T cell inactivation. J Nutr Biochem. 2016;27:112–22.
Nam SY, Chung CK, Seo JH, Rah SY, Kim HM, Jeong HJ. The therapeutic efficacy of α-pinene in an experimental mouse model of allergic rhinitis. Int Immunopharmacol. 2014;23(1):273–82.
Kim DS, Lee HJ, Jeon YD, Han YH, Kee JY, Kim HJ, Shin HJ, Kang J, Lee BS, Kim SH, Kim SJ, Park SH, Choi BM, Park SJ, Um JY, Hong SH. Alpha-pinene exhibits anti-inflammatory activity through the suppression of MAPKs and the NF-κB pathway in mouse peritoneal macrophages. Am J Chin Med. 2015;43(4):731–42.
Bae GS, Park KC, Choi SB, Jo IJ, Choi MO, Hong SH, Song K, Song HJ, Park SJ. Protective effects of alpha-pinene in mice with cerulein-induced acute pancreatitis. Life Sci. 2012;91(17–18):866–71.
Ho CY, Lu CC, Weng CJ, Yen GC. Protective effects of diallyl sulfide on ovalbumin-induced pulmonary inflammation of allergic asthma mice by microRNA-144,-34a, and -34b/c-modulated Nrf2 activation. J Agric Food Chem. 2016;64(1):151–60.
Lee HS, Lee CH, Tsai HC, Salter DM. Inhibition of cyclooxygenase 2 expression by diallyl sulfide on joint inflammation induced by urate crystal and IL-1beta. Osteoarthr Cartil. 2009;17(1):91–9.
Chen WP, Tang JL, Bao JP, Hu PF, Yu C, Shi ZL, Wu LD. Effects of diallyl sulphide in chondrocyte and cartilage in experimental osteoarthritis in rabbit. Phytother Res. 2011;25(3):351–6.
Kang JS, Kim TM, Shim TJ, Salim EI, Han BS, Kim DJ. Modifying effect of diallyl sulfide on colon carcinogenesis in C57BL/6 J-ApcMin/+ mice. Asian Pac J Cancer Prev. 2012;13(4):1115–8.
Arora A, Shukla Y. Induction of apoptosis by diallyl sulfide in DMBA-induced mouse skin tumors. Nutr Cancer. 2002;44(1):89–94.
Gayathri R, Gunadharini DN, Arunkumar A, SenthilkumarKrishnamoorthy G, Banudevi S, Vignesh RC, Arunakaran J. Effects of diallyl disulfide (DADS) on expression of apoptosis associated proteins in androgen independent human prostate cancer cells (PC-3). Mol Cell Biochem. 2009;320(1–2):197–203.
Cianciulli A, Calvello R, Porro C, Trotta T, Salvatore R, Panaro MA. PI3k/Akt signalling pathway plays a crucial role in the anti-inflammatory effects of curcumin in LPS-activated microglia. Int Immunopharmacol. 2016;36:282–90.
Fu Y, Gao R, Cao Y, Guo M, Wei Z, Zhou E, Li Y, Yao M, Yang Z, Zhang N. Curcumin attenuates inflammatory responses by suppressing TLR4-mediated NF-κB signaling pathway in lipopolysaccharide-induced mastitis in mice. Int Immunopharmacol. 2014;20(1):54–8.
Feng HL, Dang HZ, Fan H, Chen XP, Rao YX, Ren Y, Yang JD, Shi J, Wang PW, Tian JZ. Curcumin ameliorates insulin signalling pathway in brain of Alzheimer’s disease transgenic mice. Int J Immunopathol Pharmacol. 2016;29(4):734–41.
Zhang QY, Mo ZN, Liu XD. Reducing effect of curcumin on expressions of TNF-alpha, IL-6 and IL-8 in rats with chronic nonbacterial prostatitis. Zhonghua Nan Ke Xue. 2010;16(1):84–8.
Liu L, Shang Y, Li M, Han X, Wang J, Wang J. Curcumin ameliorates asthmatic airway inflammation by activating nuclear factor-E2-related factor 2/haem oxygenase (HO)-1 signalling pathway. Clin Exp Pharmacol Physiol. 2015;42(5):520–9.
Jin H, Qiao F, Wang Y, Xu Y, Shang Y. Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192-5p and suppression of PI3K/Akt signaling pathway. Oncol Rep. 2015;34(5):2782–9.
Zhong K. Curcumin mediates a protective effect via TLR-4/NF-κB signaling pathway in rat model of severe acute pancreatitis. Cell Biochem Biophys. 2015;73(1):175–80.
Chojnacki JE, Liu K, Saathoff JM, Zhang S. Bivalent ligands incorporating curcumin and diosgenin as multifunctional compounds against Alzheimer’s disease. Bioorg Med Chem. 2015;23(22):7324–31.
He Z, Chen H, Li G, Zhu H, Gao Y, Zhang L, Sun J. Diosgenin inhibits the migration of human breast cancer MDA-MB-231 cells by suppressing Vav2 activity. Phytomedicine. 2014;21(6):871–6.
Jiang S, Fan J, Wang Q, Ju D, Feng M, Li J, Guan ZB, An D, Wang X, Ye L. Diosgenin induces ROS-dependent autophagy and cytotoxicity via mTOR signaling pathway in chronic myeloid leukemia cells. Phytomedicine. 2016;23(3):243–52.
Wang L, Ma T, Zheng Y, Lv S, Li Y, Liu S. Diosgenin inhibits IL-1β-induced expression of inflammatory mediators in human osteoarthritis chondrocytes. Int J Clin Exp Pathol. 2015;8(5):4830–6.
Wang YJ, Pan KL, Hsieh TC, Chang TY, Lin WH, Hsu JT. Diosgenin, a plant-derived sapogenin, exhibits antiviral activity in vitro against hepatitis C virus. J Nat Prod. 2011;74(4):580–4.
Li Y, Wang X, Cheng S, Du J, Deng Z, Zhang Y, Liu Q, Gao J, Cheng B, Ling C. Diosgenin induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma cells. Oncol Rep. 2015;33(2):693–8.
Nie C, Zhou J, Qin X, Shi X, Zeng Q, Liu J, Yan S, Zhang L. Diosgenin-induced autophagy and apoptosis in a human prostate cancer cell line. Mol Med Rep. 2016;14(5):4349–59.
Zhao S, Niu F, Xu CY, Liu Y, Ye L, Bi GB, Chen L, Tian G, Nie TH. Diosgenin prevents bone loss on retinoic acid-induced osteoporosis in rats. Ir J Med Sci. 2016;185(3):581–7.
Mnafgui K, Kaanich F, Derbali A, Hamden K, Derbali F, Slama S, Allouche N, Elfeki A. Inhibition of key enzymes related to diabetes and hypertension by Eugenol in vitro and in alloxan-induced diabetic rats. Arch Physiol Biochem. 2013;119(5):225–33.
Pan C, Dong Z. Antiasthmatic effects of eugenol in a mouse model of allergic asthma by regulation of vitamin D3 upregulated protein 1/NF-κB pathway. Inflammation. 2015;38(4):1385–93.
Hussain A, Brahmbhatt K, Priyani A, Ahmed M, Rizvi TA, Sharma C. Eugenol enhances the chemotherapeutic potential of gemcitabine and induces anticarcinogenic and anti-inflammatory activity in human cervical cancer cells. Cancer Biother Radiopharm. 2011;26(5):519–27.
Al-Sharif I, Remmal A, Aboussekhra A. Eugenol triggers apoptosis in breast cancer cells through E2F1/survivin down-regulation. BMC Cancer. 2013;13(13):600.
Manikandan P, Vinothini G, Vidya Priyadarsini R, Prathiba D, Nagini S. Eugenol inhibits cell proliferation via NF-κB suppression in a rat model of gastric carcinogenesis induced by MNNG. Invest New Drugs. 2011;29(1):110–7.
Aggarwal S, Das SN. Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-κB inhibition in oral cancer. Tumour Biol. 2016;37(6):7175–84.
Behera AK, Swamy MM, Natesh N, Kundu TK. Garcinol and its role in chronic diseases. Adv Exp Med Biol. 2016;928:435–52.
Wang B, Lin L, Ai Q, Zeng T, Ge P, Zhang L. HAT inhibitor, garcinol, exacerbates lipopolysaccharide-induced inflammation in vitro and in vivo. Mol Med Rep. 2016;13(6):5290–6.
Tang J, Luo K, Li Y, Chen Q, Tang D, Wang D, Xiao J. Capsaicin attenuates LPS-induced inflammatory cytokine production by upregulation of LXRα. Int Immunopharmacol. 2015;28(1):264–9.
Shin YH, Namkoong E, Choi S, Bae JS, Jin M, Hwang SM, Arote R, Choi SY, Park K. Capsaicin regulates the NF-κB pathway in salivary gland inflammation. J Dent Res. 2013;92(6):547–52.
Qian K, Wang G, Cao R, Liu T, Qian G, Guan X, Guo Z, Xiao Y, Wang X. capsaicinsuppresses cell proliferation, induces cell cycle arrest and ROS production in bladder cancer cells through FOXO3a-mediated pathways. Molecules. 2016;21(10):1406.
Desai PR, Marepally S, Patel AR, Voshavar C, Chaudhuri A, Singh M. Topical delivery of anti-TNFα siRNA and capsaicin via novel lipid-polymer hybrid nanoparticles efficiently inhibits skin inflammation in vivo. J Control Release. 2013;170(1):51–63.
Jiang X, Jia LW, Li XH, Cheng XS, Xie JZ, Ma ZW, Xu WJ, Liu Y, Yao Y, Du LL, Zhou XW. Capsaicin ameliorates stress-induced Alzheimer’s disease-like pathological and cognitive impairments in rats. J Alzheimers Dis. 2013;35(1):91–105.
Venier NA, Yamamoto T, Sugar LM, Adomat H, Fleshner NE, Klotz LH, Venkateswaran V. Capsaicin reduces the metastatic burden in the transgenic adenocarcinoma of the mouse prostate model. Prostate. 2015;75(12):1300–11.
Brown KC, Witte TR, Hardman WE, Luo H, Chen YC, Carpenter AB, Lau JK, Dasgupta P. Capsaicin displays anti-proliferative activity against human small cell lung cancer in cell culture and nude mice models via the E2F pathway. PLoS ONE. 2010;5(4):e10243.
Bachiega TF, de Sousa JP, Bastos JK, Sforcin JM. Clove and eugenol in noncytotoxic concentrations exert immunomodulatory/anti-inflammatory action on cytokine production by murine macrophages. J Pharm Pharmacol. 2012;64(4):610–6.
Pal D, Banerjee S, Mukherjee S, Roy A, Panda CK, Das S. Eugenol restricts DMBA croton oil induced skin carcinogenesis in mice: downregulation of c-Myc and H-ras, and activation of p53 dependent apoptotic pathway. J Dermatol Sci. 2010;59(1):31–9.
Yeh JL, Hsu JH, Hong YS, Wu JR, Liang JC, Wu BN, Chen IJ, Liou SF. Eugenolol and glyceryl-isoeugenol suppress LPS-induced iNOS expression by down-regulating NF-kappaB AND AP-1 through inhibition of MAPKS and AKT/IkappaBalpha signaling pathways in macrophages. Int J Immunopathol Pharmacol. 2011;24(2):345–56.
Muhammad JS, Zaidi SF, Shaharyar S, Refaat A, Usmanghani K, Saiki I, Sugiyama T. Anti-inflammatory effect of cinnamaldehyde in Helicobacter pylori induced gastric inflammation. Biol Pharm Bull. 2015;38(1):109–15.
Mondal S, Pahan K. Cinnamon ameliorates experimental allergic encephalomyelitis in mice via regulatory T cells: implications for multiple sclerosis therapy. PLoS ONE. 2015;10(1):e0116566.
Rathi B, Bodhankar S, Mohan V, Thakurdesai P. Ameliorative effects of a polyphenolic fraction of Cinnamomum zeylanicum L. bark in animal models of inflammation and arthritis. Sci Pharm. 2013;81(2):567–89.
Modi KK, Roy A, Brahmachari S, Rangasamy SB, Pahan K. Cinnamon and its metabolite sodium benzoate attenuate the activation of p21rac and protect memory and learning in an animal model of Alzheimer’s disease. PLoS ONE. 2015;10(6):e0130398.
Shaltiel-Karyo R, Davidi D, Frenkel-Pinter M, Ovadia M, Segal D, Gazit E. Differential inhibition of α-synuclein oligomeric and fibrillar assembly in parkinson’s disease model by cinnamon extract. Biochim Biophys Acta. 2012;1820(10):1628–35.
Tsai ML, Chiou YS, Chiou LY, Ho CT, Pan MH. Garcinol suppresses inflammation-associated colon carcinogenesis in mice. Mol Nutr Food Res. 2014;58(9):1820–9.
Ye X, Yuan L, Zhang L, Zhao J, Zhang CM, Deng HY. Garcinol, an acetyltransferase inhibitor, suppresses proliferation of breast cancer cell line MCF-7 promoted by 17β-estradiol. Asian Pac J Cancer Prev. 2014;15(12):5001–7.
Tu SH, Chiou YS, Kalyanam N, Ho CT, Chen LC, Pan MH. Garcinol sensitizes breast cancer cells to Taxol through the suppression of caspase-3/iPLA(2) and NF-κB/Twist1 signaling pathways in a mouse 4T1 breast tumor model. Food Funct. 2017;8(3):1067–79.
Li F, Shanmugam MK, Chen L, Chatterjee S, Basha J, Kumar AP, Kundu TK, Sethi G. Garcinol, a polyisoprenylated benzophenone modulates multiple proinflammatory signaling cascades leading to the suppression of growth and survival of head and neck carcinoma. Cancer Prev Res (Phila). 2013;6(8):843–54.
Yu SY, Liao CH, Chien MH, Tsai TY, Lin JK, Weng MS. Induction of p21(Waf1/Cip1) by garcinol via downregulation of p38-MAPK signaling in p53-independent H1299 lung cancer. J Agric Food Chem. 2014;62(9):2085–95.
Ahmad A, Sarkar SH, Bitar B, Ali S, Aboukameel A, Sethi S, Li Y, Bao B, Kong D, Banerjee S, Padhye SB, Sarkar FH. Garcinol regulates EMT and Wnt signaling pathways in vitro and in vivo, leading to anticancer activity against breast cancer cells. Mol Cancer Ther. 2012;11(10):2193–201.
Thummuri D, Jeengar MK, Shrivastava S, Nemani H, Ramavat RN, Chaudhari P, Naidu VG. Thymoquinone prevents RANKL-induced osteoclastogenesis activation and osteolysis in an in vivo model of inflammation by suppressing NF-KB and MAPK Signalling. Pharmacol Res. 2015;99:63–73.
Wang D, Qiao J, Zhao X, Chen T, Guan D. Thymoquinone Inhibits IL-1β-Induced Inflammation in Human Osteoarthritis Chondrocytes by Suppressing NF-κB and MAPKs Signaling Pathway. Inflammation. 2015;38(6):2235–41.
Su X, Ren Y, Yu N, Kong L, Kang J. Thymoquinone inhibits inflammation, neoangiogenesis and vascular remodeling in asthma mice. Int Immunopharmacol. 2016;38:70–80.
Umar S, Hedaya O, Singh AK, Ahmed S. Thymoquinone inhibits TNF-α-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation. Toxicol Appl Pharmacol. 2015;287(3):299–305.
Hayat K, Asim MB, Nawaz M, Li M, Zhang L, Sun N. Ameliorative effect of thymoquinone on ovalbumin-induced allergic conjunctivitis in Balb/c mice. Curr Eye Res. 2011;36(7):591–8.
Mu HQ, Yang S, Wang YJ, Chen YH. Role of NF-κB in the anti-tumor effect of thymoquinone on bladder cancer. Zhonghua Yi Xue Za Zhi. 2012;92(6):392–6.
Yang J, Kuang XR, Lv PT, Yan XX. Thymoquinone inhibits proliferation and invasion of human nonsmall-cell lung cancer cells via ERK pathway. Tumour Biol. 2015;36(1):259–69.
Wilson AJ, Saskowski J, Barham W, Yull F, Khabele D. Thymoquinone enhances cisplatin-response through direct tumor effects in a syngeneic mouse model of ovarian cancer. J Ovarian Res. 2015;8:46.
Zhu WQ, Wang J, Guo XF, Liu Z, Dong WG. Thymoquinone inhibits proliferation in gastric cancer via the STAT3 pathway in vivo and in vitro. World J Gastroenterol. 2016;22(16):4149–59.
Li X, Liu HC, Yao QY, Xu BL, Zhang SC, Tu CT. Quercetin protects mice from ConA-induced hepatitis by inhibiting HMGB1-TLR expression and down-regulating the nuclear factor kappa B pathway. Inflammation. 2016;39(1):96–106.
Gardi C, Bauerova K, Stringa B, Kuncirova V, Slovak L, Ponist S, Drafi F, Bezakova L, Tedesco I, Acquaviva A, Bilotto S, Russo GL. Quercetin reducedinflammation and increased antioxidant defense in rat adjuvant arthritis. ArchBiochem Biophys. 2015;583:150–7.
Ranganathan S, Halagowder D, Sivasithambaram ND. Quercetin suppresses twist to induce apoptosis in MCF-7 breast cancer cells. PLoS ONE. 2015;10(10):e0141370.
Dodda D, Chhajed R, Mishra J. Protective effect of quercetin against acetic acid induced inflammatory bowel disease (IBD) like symptoms in rats: possible morphological and biochemical alterations. Pharmacol Rep. 2014;66(1):169–73.
Karuppagounder V, Arumugam S, Thandavarayan RA, Sreedhar R, Giridharan VV, Watanabe K. Molecular targets of quercetin with anti-inflammatory properties in atopic dermatitis. Drug Discov Today. 2016;21(4):632–9.
Maciel RM, Costa MM, Martins DB, França RT, Schmatz R, Graça DL, Duarte MM, Danesi CC, Mazzanti CM, Schetinger MR, Paim FC, Palma HE, Abdala FH, Stefanello N, Zimpel CK, Felin DV, Lopes ST. Antioxidant and anti-inflammatory effects ofquercetin in functional and morphological alterations in streptozotocin-induced diabetic rats. Res Vet Sci. 2013;95(2):389–97.
Vijayalakshmi A, Ravichandiran V, Malarkodi V, Nirmala S, Jayakumari S. Screening of flavonoid “quercetin” from the rhizome of Smilax china Linn. For anti-psoriatic activity. Asian Pac. J Trop Biomed. 2012;2(4):269–75.
Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, Simonyi A. Quercetinattenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS ONE. 2015;10(10):e0141509.
Cho YH, Kim NH, Khan I, Yu JM, Jung HG, Kim HH, Jang JY, Kim HJ, Kim DI, Kwak JH, Kang SC, An BJ. Anti-inflammatory potential of quercetin-3-O-β-d-(“2″-galloyl)-glucopyranoside and Quercetin Isolated from Diospyros kaki calyx via suppression of MAP signaling molecules in LPS-induced RAW 264.7 macrophages. J Food Sci. 2016;81(10):C2447–56.
Lu XL, Zhao CH, Yao XL, Zhang H. Quercetin attenuates high fructose feeding-induced atherosclerosis by suppressing inflammation and apoptosis via ROS-regulated PI3K/AKT signaling pathway. Biomed Pharmacother. 2017;85:658–71.
Zhai WJ, Zhang ZB, Xu NN, Guo YF, Qiu C, Li CY, Deng GZ, Guo MY. Piperine plays an anti-inflammatory role in Staphylococcus aureus endometritis by inhibiting activation of NF-κB and MAPK pathways in mice. Evid Based Complement Alternat Med. 2016;2016:8597208.
Hou XF, Pan H, Xu LH, Zha QB, He XH, Ouyang DY. Piperine suppresses the expression of CXCL8 in lipopolysaccharide-activated SW480 and HT-29 cells via downregulating the mitogen-activated protein kinase pathways. Inflammation. 2015;38(3):1093–102.
Kim SH, Lee YC. Piperine inhibits eosinophil infiltration and airway hyperresponsiveness by suppressing T cell activity and Th2 cytokine production in the ovalbumin-induced asthma model. J Pharm Pharmacol. 2009;61(3):353–9.
Umar S, Golam Sarwar AH, Umar K, Ahmad N, Sajad M, Ahmad S, Katiyar CK, Khan HA. Piperine ameliorates oxidative stress, inflammation and histological outcome in collagen induced arthritis. Cell Immunol. 2013;284(1–2):51–9.
Kim HG, Han EH, Jang WS, Choi JH, Khanal T, Park BH, Tran TP, Chung YC, Jeong HG. Piperine inhibits PMA-induced cyclooxygenase-2 expression through downregulating NF-κB, C/EBP and AP-1 signaling pathways in murine macrophages. Food Chem Toxicol. 2012;50(7):2342–8.
Vaibhav K, Shrivastava P, Javed H, Khan A, Ahmed ME, Tabassum R, Khan MM, Khuwaja G, Islam F, Siddiqui MS, Safhi MM, Islam F. Piperine suppresses cerebral ischemia-reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-κB in middle cerebral artery occlusion rat model. Mol Cell Biochem. 2012;367(1–2):73–84.
Xia Y, Khoi PN, Yoon HJ, Lian S, Joo YE, Chay KO, Kim KK, Jung YD. Piperine inhibits IL-1β-induced IL-6 expression by suppressing p38 MAPK and STAT3 activation in gastric cancer cells. Mol Cell Biochem. 2015;398(1–2):147–56.
Bai Y, Wang X, Zhao S, Ma C, Cui J, Zheng Y. Sulforaphane protects against cardiovascular disease via Nrf2 activation. Oxid Med Cell Longev. 2015;2015:407580.
Leone A, Diorio G, Sexton W, Schell M, Alexandrow M, Fahey JW, Kumar NB. Sulforaphane for the chemoprevention of bladder cancer: molecular mechanism targeted approach. Oncotarget. 2017;8(21):35412–24.
Yamagishi S, Matsui T. Protective role of sulphoraphane against vascularcomplications in diabetes. Pharm Biol. 2016;54(10):2329–39.
Tortorella SM, Royce SG, Licciardi PV, Karagiannis TC. Dietary sulforaphane incancer chemoprevention: the role of epigenetic regulation and HDAC inhibition. Antioxid Redox Signal. 2015;22(16):1382–424.
Schmitz K, Barthelmes J, Stolz L, Beyer S, Diehl O, Tegeder I. “Diseasemodifying nutricals” for multiple sclerosis. Pharmacol Ther. 2015;148:85–113.
Kunnumakkara AB, Bordoloi D, Padmavathi G, Monisha J, Roy NK, Prasad S, Aggarwal BB. Curcumin, the golden nutraceutical: multitargeting for multiple chronic diseases. Br J Pharmacol. 2017;174(11):1325–48.
Bordoloi D, Roy NK, Monisha J, Padmavathi G, Kunnumakkara AB. Multi targeted agents in cancer cell chemosensitization: what we learnt from curcumin thus far. Recent Pat Anticancer Drug Discov. 2016;11(1):67–97.
Li LC, Piao HM, Zheng MY, Lin ZH, Li G, Yan GH. Sesamin attenuates mast cell-mediated allergic responses by suppressing the activation of p38 and nuclear factor-κB. Mol Med Rep. 2016;13(1):536–42.
Rocha J, Eduardo-Figueira M, Barateiro A, Fernandes A, Brites D, Bronze R, Duarte CM, Serra AT, Pinto R, Freitas M, Fernandes E, Silva-Lima B, Mota-Filipe H, Sepodes B. Anti-inflammatory effect of rosmarinic acid and an extract of Rosmarinus officinalis in rat models of local and systemic inflammation. BasicClin Pharmacol Toxicol. 2015;116(5):398–413.
Shojaii A, Abdollahi Fard M. Review of pharmacological properties and chemical constituents of Pimpinella anisum. ISRN Pharm. 2012;2012:510795.
Mahendra P, Bisht S. Ferula asafoetida: traditional uses and pharmacological activity. Pharmacogn Rev. 2012;6(12):141–6.
El-Soud NH, Deabes M, El-Kassem LA, Khalil M. Chemical composition and antifungal activity of Ocimum basilicum L. essential oil. Maced. J Med Sci. 2015;3(3):374–9.
Sahin Basak S, Candan F. Effect of Laurus nobilis L. Essential oil and its main components on α-glucosidase and reactive oxygen species scavenging activity. Iran. J Pharm Res. 2013;12(2):367–79.
Yalçin H, Anik M, Sanda MA, Cakir A. Gas chromatography/mass spectrometry analysis of Laurus nobilis essential oil composition of northern Cyprus. J Med Food. 2007;10(4):715–9.
Beis SJ, Goshman LM, Newkirk GL. Risk factors for metformin-associated lactic acidosis. WMJ. 1999;98:56–7.
Khan R, Adil M, Danishuddin M, Verma PK, Khan AU. In vitro and in vivo inhibition of Streptococcus mutans biofilm by Trachyspermum ammi seeds: an approach of alternative medicine. Phytomedicine. 2012;19(8–9):747–55.
Jirovetz L, Buchbauer G, Stoilova I, Stoyanova A, Krastanov A, Schmidt E. Chemical composition and antioxidant properties of clove leaf essential oil. J Agric Food Chem. 2006;54(17):6303–7.
Shukla S, Gupta S. Coriander. In: Aggarwal BB, Kunnumakkara AB, editors. Molecular targets and therapeutic uses of spices. Singapore: World scientific publishing; 2009. p. 149–71.
Kazemi M. Phenolic profile, antioxidant capacity and anti-inflammatory activity of Anethum graveolens L. essential oil. Nat Prod Res. 2015;29(6):551–3.
Barazani O, Fait A, Cohen Y, Diminshtein S, Ravid U, Putievsky E, Lewinsohn E, Friedman J. Chemical variation among indigenous populations of Foeniculum vulgare var. vulgare in Israel. Planta Med. 1999;65(5):486–9.
Jolad SD, Lantz RC, Solyom AM, Chen GJ, Bates RB, Timmermann BN. Fresh organically grown ginger (Zingiber officinale): composition and effects on LPS-induced PGE2 production. Phytochemistry. 2004;65:1937–54.
Kunnumakkara AB, Chung JG, Koca C, Dey S. Mint and its constituents. In: Aggarwal BB, Kunnumakkara AB, editors. Molecular targets and therapeutic uses of spices. Singapore: World scientific publishing; 2009. p. 373–401.
Peng C, Zhao SQ, Zhang J, Huang GY, Chen LY, Zhao FY. Chemical composition, antimicrobial property and microencapsulation of Mustard (Sinapis alba) seed essential oil by complex coacervation. Food Chem. 2014;165:560–8.
Du SS, Yang K, Wang CF, You CX, Geng ZF, Guo SS, Deng ZW, Liu ZL. Chemical constituents and activities of the essential oil from Myristica fragrans against cigarette beetle Lasioderma serricorne. Chem Biodivers. 2014;11(9):1449–56.
Ly TN, Hazama C, Shimoyamada M, Ando H, Kato K, Yamauchi R. Antioxidative compounds from the outer scales of onion. J Agric Food Chem. 2005;53:8183–9.
Lopez MG, Sanchez-Mendoza IR, Ochoa-Alejo N. Comparative study of volatile components and fatty acids of plants and in vitro cultures of parsley (Petroselinum crispum (Mill) nym ex hill). J Agric Food Chem. 1999;47:3292–6.
Ríos JL, Recio MC, Giner RM, Máňez S. An update review of saffron and its active constituents. Phytother Res. 1996;10:189–93.
Raal A, Orav A, Arak E. Composition of the essential oil of Salvia officinalis L. from various European countries. Nat Prod Res. 2007;21(5):406–11.
Pathak N, Rai AK, Kumari R, Bhat KV. Value addition in sesame: a perspective on bioactive components for enhancing utility and profitability. Pharmacogn Rev. 2014;8(16):147–55.
Hudaib M, Speroni E, Di Pietra AM, Cavrini V. GC/MS evaluation of thyme (Thymus vulgaris L.) oil composition and variations during the vegetative cycle. J Pharm Biomed Anal. 2002;29(4):691–700.
Sinha AK, Verma SC, Sharma UK. Development and validation of an RP-HPLC method for quantitative determination of vanillin and related phenolic compounds in Vanilla planifolia. J Sep Sci. 2007;30(1):15–20.
Juergens UR, Stöber M, Schmidt-Schilling L, Kleuver T, Vetter H. Antiinflammatory effects of euclyptol (1.8-cineole) in bronchial asthma: inhibition of arachidonic acid metabolism in human blood monocytes ex vivo. Eur J Med Res. 1998;3(9):407–12.
Fan JZ, Yang X, Bi ZG. The effects of 6-gingerol on proliferation, differentiation, and maturation of osteoblast-like MG-63 cells. Braz J Med Biol Res. 2015;48(7):637–43.
Rufino AT, Ribeiro M, Judas F, Salgueiro L, Lopes MC, Cavaleiro C, Mendes AF. Anti-inflammatory and chondroprotective activity of (+)-α-pinene: structural and enantiomeric selectivity. J Nat Prod. 2014;77(2):264–9.
Gu X, Wu H, Fu P. Allicin attenuates inflammation and suppresses HLA-B27 protein expression in ankylosing spondylitis mice. Biomed Res Int. 2013;2013:171573.
Li XH, Li CY, Lu JM, Tian RB, Wei J. Allicin ameliorates cognitive deficits ageing-induced learning and memory deficits through enhancing of Nrf2 antioxidant signaling pathways. Neurosci Lett. 2012;514(1):46–50.
García-Trejo EM, Arellano-Buendía AS, Argüello-García R, Loredo-Mendoza ML, García-Arroyo FE, Arellano-Mendoza MG, Castillo-Hernández MC, Guevara-Balcázar G, Tapia E, Sánchez-Lozada LG, Osorio-Alonso H. Effects of allicin on hypertensionand cardiac function in chronic kidney disease. Oxid Med Cell Longev. 2016;2016:3850402.
Luo R, Fang D, Hang H, Tang Z. The mechanism in gastric cancer chemoprevention by allicin. Anticancer Agents Med Chem. 2016;16(7):802–9.
Cha JH, Choi YJ, Cha SH, Choi CH, Cho WH. Allicin inhibits cell growth and induces apoptosis in U87MG human glioblastoma cells through an ERK-dependent pathway. Oncol Rep. 2012;28(1):41–8.
El-Sheakh AR, Ghoneim HA, Suddek GM, Ammar ES. Attenuation of oxidative stress, inflammation, and endothelial dysfunction in hypercholesterolemic rabbits by allicin. Can J Physiol Pharmacol. 2015;94:216–49.
Jiang XW, Hu J, Mian FI. A new therapeutic candidate for oral aphthous ulcer: allicin. Med Hypotheses. 2008;71(6):897–9.
Osman M, Adnan A, Salmah Bakar N, Alashkham F. Allicin has significant effect on autoimmune anti-islet cell antibodies in type 1 diabetic rats. Pol J Pathol. 2012;63(4):248–54.
Chen CH, deGraffenried LA. Anethole suppressed cell survival and inducedapoptosis in human breast cancer cells independent of estrogen receptor status. Phytomedicine. 2012;19(8–9):763–7.
Lam S, MacAulay C, Le Riche JC, Dyachkova Y, Coldman A, Guillaud M, Hawk E, Christen MO, Gazdar AF. A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia. J Natl Cancer Inst. 2002;94(13):1001–9.
Wang Q, Ma S, Li D, Zhang Y, Tang B, Qiu C, Yang Y, Yang D. Dietary capsaicin ameliorates pressure overload-induced cardiac hypertrophy anfibrosis through the transient receptor potential vanilloid type 1. Am J Hypertens. 2014;27(12):1521–9.
Hong ZF, Zhao WX, Yin ZY, Xie CR, Xu YP, Chi XQ, Zhang S, Wang XM. Capsaicin enhances the drug sensitivity of cholangiocarcinoma through the inhibition of chemotherapeutic-induced autophagy. PLoS ONE. 2015;10(5):e0121538.
Lu HF, Chen YL, Yang JS, Yang YY, Liu JY, Hsu SC, Lai KC, Chung JG. Antitumor activity of capsaicin on human colon cancer cells in vitro and colo 205 tumorxenografts in vivo. J Agric Food Chem. 2010;58(24):12999–3005.
Fernandes ES, Cerqueira AR, Soares AG, Costa SK. Capsaicin and its role in chronic diseases. Adv Exp Med Biol. 2016;929:91–125.
Bai H, Li H, Zhang W, Matkowskyj KA, Liao J, Srivastava SK, Yang GY. Inhibition of chronic pancreatitis and pancreatic intraepithelial neoplasia (PanIN) by capsaicin in LSL-KrasG12D/Pdx1-Cre mice. Carcinogenesis. 2011;32(11):1689–96.
Banji OJ, Banji D, Soumya N, Chilipi KK, Kalpana CH, Kranthi Kumar CH, Annamalai AR. Combination of carvacrol with methotrexate suppresses Complete Freund’s Adjuvant induced synovial inflammation with reduced hepatotoxicity in rats. Eur J Pharmacol. 2014;723:91–8.
Kianmehr M, Rezaei A, Boskabady MH. Effect of carvacrol on various cytokines genes expression in splenocytes of asthmatic mice. Iran J Basic Med Sci. 2016;19(4):402–10.
Lee KP, Sudjarwo GW, Jung SH, Lee D, Lee DY, Lee GB, Baek S, Kim DY, Lee HM, Kim B, Kwon SC, Won KJ. Carvacrol inhibits atherosclerotic neointima formation by downregulating reactive oxygen species production in vascular smooth muscle cells. Atherosclerosis. 2015;240(2):367–73.
Arigesavan K, Sudhandiran G. Carvacrol exhibits anti-oxidant and anti-inflammatory effects against 1, 2-dimethyl hydrazine plus dextran sodium sulfate induced inflammation associated carcinogenicity in the colon of Fischer 344 rats. Biochem Biophys Res Commun. 2015;461(2):314–20.
Silva FV, Guimarães AG, Silva ER, Sousa-Neto BP, Machado FD, Quintans-Júnior LJ, Arcanjo DD, Oliveira FA, Oliveira RC. Anti-inflammatory and anti-ulcer activities of carvacrol, a monoterpene present in the essential oil of oregano. J Med Food. 2012;15(11):984–91.
Alvarenga EM, Souza LK, Araújo TS, Nogueira KM, Sousa FB, Araújo AR, Martins CS, Pacífico DM, de Brito GA, Souza EP, Sousa DP, Medeiros JV. Carvacrolreduces irinotecan-induced intestinal mucositis through inhibition of inflammation and oxidative damage via TRPA1 receptor activation. Chem Biol Interact. 2016;260:129–40.
Bakır M, Geyikoglu F, Colak S, Turkez H, Bakır TO, Hosseinigouzdagani M. The carvacrol ameliorates acute pancreatitis-induced liver injury via antioxidant response. Cytotechnology. 2016;68(4):1131–46.
Botelho MA, Rao VS, Montenegro D, Bandeira MA, Fonseca SG, Nogueira NA, Ribeiro RA, Brito GA. Effects of a herbal gel containing carvacrol and chalcones on alveolar bone resorption in rats on experimental periodontitis. Phytother Res. 2008;22(4):442–9.
Sengupta A, Ghosh S, Bhattacharjee S. Dietary cardamom inhibits the formation of azoxymethane-induced aberrant crypt foci in mice and reduces COX-2 and iNOS expression in the colon. Asian Pac J Cancer Prev. 2005;6(2):118–22.
Qiblawi S, Dhanarasu S, Faris MA. Chemopreventive effect of cardamom (Elettaria cardamomum L.) against benzo(α)pyrene-induced forestomach papillomagenesis in swiss albino mice. J Environ Pathol Toxicol Oncol. 2015;34(2):95–104.
Samarghandian S, Azimi-Nezhad M, Borji A, Samini M, Farkhondeh T. Protective effects of carnosol against oxidative stress induced brain damage by chronicmstress in rats. BMC Complement Altern Med. 2017;17(1):249.
Amar Y, Meddah B, Bonacorsi I, Costa G, Pezzino G, Saija A, Cristani M, Boussahel S, Ferlazzo G, Meddah AT. Phytochemicals, antioxidant and antiproliferative properties of Rosmarinus officinalis L on U937 and CaCo-2Cells. Iran J Pharm Res. 2017;16(1):315–27.
Kwon HK, Hwang JS, Lee CG, So JS, Sahoo A, Im CR, Jeon WK, Ko BS, Lee SH, Park ZY, Im SH. Cinnamon extract suppresses experimental colitis through modulation of antigen-presenting cells. World J Gastroenterol. 2011;17(8):976–86.
Kwon HK, Hwang JS, So JS, Lee CG, Sahoo A, Ryu JH, Jeon WK, Ko BS, Im CR, Lee SH, Park ZY, Im SH. Cinnamon extract induces tumor cell death through inhibition of NFkappaB and AP1. BMC Cancer. 2010;10:392.
Hosni AA, Abdel-Moneim AA, Abdel-Reheim ES, Mohamed SM, Helmy H. Cinnamaldehyde potentially attenuates gestational hyperglycemia in rats through modulation of PPARγ, proinflammatory cytokines and oxidative stress. Biomed Pharmacother. 2017;88:52–60.
Lee BJ, Kim YJ, Cho DH, Sohn NW, Kang H. Immunomodulatory effect of water extract of cinnamon on anti-CD3-induced cytokine responses and p38, JNK, ERK1/2, and STAT4 activation. Immunopharmacol Immunotoxicol. 2011;33(4):714–22.
Cioanca O, Hritcu L, Mihasan M, Hancianu M. Cognitive-enhancing and antioxidant activities of inhaled coriander volatile oil in amyloid β(1-42) rat model of Alzheimer’s disease. Physiol Behav. 2013;120:193–202.
Liu QF, Jeong H, Lee JH, Hong YK, Oh Y, Kim YM, Suh YS, Bang S, Yun HS, Lee K, Cho SM, Lee SB, Jeon S, Chin YW, Koo BS, Cho KS. Coriandrum sativum suppresses Aβ42-induced ROS increases, glial cell proliferation, and ERK activation. Am J Chin Med. 2016;44(7):1325–47.
Patel D, Desai S, Gajaria T, Devkar R, Ramachandran AV. Coriandrum sativum L. seed extract mitigates lipotoxicity in RAW 264.7 cells and prevents atherogenic changes in rats. EXCLI J. 2013;12:313–34.
Heidari B, Sajjadi SE, Minaiyan M. Effect of Coriandrum sativum hydroalcoholic extract and its essential oil on acetic acid- induced acute colitis in rats. Avicenna J Phytomed. 2016;6(2):205–14.
Park G, Kim HG, Lim S, Lee W, Sim Y, Oh MS. Coriander alleviates 2,4-dinitrochlorobenzene-induced contact dermatitis-like skin lesions in mice. J Med Food. 2014;17(8):862–8.
Eidi M, Eidi A, Saeidi A, Molanaei S, Sadeghipour A, Bahar M, Bahar K. Effect of coriander seed (Coriandrum sativum L.) ethanol extract on insulin release from pancreatic beta cells in streptozotocin-induced diabetic rats. Phytother Res. 2009;23(3):404–6.
Hosseinzadeh S, Ghalesefidi MJ, Azami M, Mohaghegh MA, Hejazi SH, Ghomashlooyan M. In vitro and in vivo anthelmintic activity of seed extract of Coriandrum sativum compared to Niclosamid against Hymenolepis nana infection. J Parasit Dis. 2016;40(4):1307–10.
Finley JW, Gao S. Perspective on Crocus sativus L. (Saffron) constituen crocin: a potent water-soluble antioxidant and potential therapy for Alzheimer’s disease. J Agric Food Chem. 2017;65(5):1005–20.
Xiong Y, Wang J, Yu H, Zhang X, Miao C. Anti-asthma potential of crocin and its effect on MAPK signaling pathway in a murine model of allergic airway disease. Immunopharmacol Immunotoxicol. 2015;37(3):236–43.
Hazman Ö, Aksoy L, Büyükben A. Effects of crocin on experimental obesity and type-2 diabetes. Turk J Med Sci. 2016;46(5):1593–602.
Yang L, Dong X. Inhibition of inflammatory response by crocin attenuates hemorrhagic shock-induced organ damages in rats. J Interferon Cytokine Res. 2017. https://doi.org/10.1089/jir.2016.0137.
Li X, Jiang C, Zhu W. Crocin reduces the inflammation response in rheumatoid arthritis. Biosci Biotechnol Biochem. 2017;81(5):891–8.
Chen FY, Zhou J, Guo N, Ma WG, Huang X, Wang H, Yuan ZY. Curcumin retunes cholesterol transport homeostasis and inflammation response in M1 macrophage to prevent atherosclerosis. Biochem Biophys Res Commun. 2015;467(4):872–8.
Hernández M, Wicz S, Corral RS. Cardioprotective actions of curcumin on the pathogenic NFAT/COX-2/prostaglandin E(2) pathway induced during Trypanosoma cruzi infection. Phytomedicine. 2016;23(12):1392–400.
Zhang M, Xie Y, Yan R, Shan H, Tang J, Cai Y, Yin J, Chen M, Zhang J, Yang X, Zhang Q, Li Y. Curcumin ameliorates alveolar epithelial injury in a rat model of chronic obstructive pulmonary disease. Life Sci. 2016;164:1–8.
Liu L, Liu YL, Liu GX, Chen X, Yang K, Yang YX, Xie Q, Gan HK, Huang XL. GanHT. Curcumin ameliorates dextran sulfate sodium-induced experimental colitis by blocking STAT3 signaling pathway. Int Immunopharmacol. 2013;17(2):314–20.
Castro CN, Barcala Tabarrozzi AE, Winnewisser J, Gimeno ML, Antunica Noguerol M, Liberman AC, Paz DA, Dewey RA, Perone MJ. Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes. Clin Exp Immunol. 2014;177(1):149–60.
Kaur H, Patro I, Tikoo K, Sandhir R. Curcumin attenuates inflammatory response and cognitive deficits in experimental model of chronic epilepsy. Neurochem Int. 2015;89:40–50.
He P, Zhou R, Hu G, Liu Z, Jin Y, Yang G, Li M, Lin Q. Curcumin-induced histone acetylation inhibition improves stress-induced gastric ulcer disease in rats. Mol Med Rep. 2015;11(3):1911–6.
Rechtman MM, Har-Noy O, Bar-Yishay I, Fishman S, Adamovich Y, Shaul Y, Halpern Z, Shlomai A. Curcumin inhibits hepatitis B virus via down-regulation of the metabolic coactivator PGC-1alpha. FEBS Lett. 2010;584(11):2485–90.
Gupta SC, Sung B, Kim JH, Prasad S, Li S, Aggarwal BB. Multitargeting by turmeric, the golden spice: from kitchen to clinic. Mol Nutr Food Res. 2013;57(9):1510–28.
Lee H, Kim H, Lee G, Chung HS, Bae H. Curcumin attenuates lupus nephritis upon interaction with regulatory T cells in New Zealand Black/White mice. Br J Nutr. 2013;110(1):69–76.
Kang D, Li B, Luo L, Jiang W, Lu Q, Rong M, Lai R. Curcumin shows excellent therapeutic effect on psoriasis in mouse model. Biochimie. 2016;123:73–80.
Tohda C, Urano T, Umezaki M, Nemere I, Kuboyama T. Diosgenin is an exogenous activator of 1,25D3-MARRS/Pdia3/ERp57 and improves Alzheimer’s disease pathologies in 5XFAD mice. Sci Rep. 2012;2:535.
Kalailingam P, Kannaian B, Tamilmani E, Kaliaperumal R. Efficacy of natural diosgenin on cardiovascular risk, insulin secretion, and beta cells in streptozotocin (STZ)-induced diabetic rats. Phytomedicine. 2014;21(10):1154–61.
Naidu PB, Ponmurugan P, Begum MS, Mohan K, Meriga B, RavindarNaik R, Saravanan G. Diosgenin reorganises hyperglycaemia and distorted tissue lipid profile in high-fat diet-streptozotocin-induced diabetic rats. J Sci Food Agric. 2015;95(15):3177–82.
Cai H, Wang Z, Zhang HQ, Wang FR, Yu CX, Zhang FX, Gao L, Zhang J, Zhao JJ. Diosgenin relieves goiter via the inhibition of thyrocyte proliferation in a mouse model of Graves’ disease. Acta Pharmacol Sin. 2014;35(1):65–73.
Zhang Z, Song C, Fu X, Liu M, Li Y, Pan J, Liu H, Wang S, Xiang L, Xiao GG, Ju D. High-dose diosgenin reduces bone loss in ovariectomized rats via attenuation of the RANKL/OPG ratio. Int J Mol Sci. 2014;15(9):17130–47.
Venkadeswaran K, Thomas PA, Geraldine P. An experimental evaluation of the anti-atherogenic potential of the plant, Piper betle, and its active constitutent, eugenol, in rats fed an atherogenic diet. Biomed Pharmacother. 2016;80:276–88.
Irie Y, Itokazu N, Anjiki N, Ishige A, Watanabe K, Keung WM. Eugenol exhibits antidepressant-like activity in mice and induces expression of metallothionein-III in the hippocampus. Brain Res. 2004;1011(2):243–6.
Jo HK, Kim GW, Jeong KJ, Kim DY, Chung SH. Eugenol ameliorates hepatic steatosis and fibrosis by down-regulating SREBP1 gene expression via AMPK-mTOR-p70S6K signaling pathway. Biol Pharm Bull. 2014;37(8):1341–51.
Sanae F, Kamiyama O, Ikeda-Obatake K, Higashi Y, Asano N, Adachi I, Kato A. Effects of eugenol-reduced clove extract on glycogen phosphorylase b and the development of diabetes in db/db mice. Food Funct. 2014;5(2):214–9.
Kaur G, Athar M, Alam MS. Eugenol precludes cutaneous chemical carcinogenesis in mouse by preventing oxidative stress and inflammation and by inducing apoptosis. Mol Carcinog. 2010;49(3):290–301.
Wang Y, Tsai ML, Chiou LY, Ho CT, Pan MH. antitumor activity of garcinol in human prostate cancer cells and xenograft mice. J Agric Food Chem. 2015;63(41):9047–52.
Hirota R, Nakamura H, Bhatti SA, Ngatu NR, Muzembo BA, Dumavibhat N, Eitoku M, Sawamura M, Suganuma N. Limonene inhalation reduces allergic airway inflammation in Dermatophagoides farinae-treated mice. Inhal Toxicol. 2012;24(6):373–81.
Sun J. d-Limonene: safety and clinical applications. Altern Med Rev. 2007;12(3):259–64.
d’Alessio PA, Ostan R, Bisson JF, Schulzke JD, Ursini MV, Béné MC. Oral administration of d-limonene controls inflammation in rat colitis and display anti-inflammatory properties as diet supplementation in humans. Life Sci. 2013;92(24–26):1151–6.
Chaudhary SC, Siddiqui MS, Athar M, Alam MS. d-Limonene modulate inflammation, oxidative stress and Ras-ERK pathway to inhibit murine skin tumorigenesis. Hum Exp Toxicol. 2012;31(8):798–811.
Deepa B, Venkatraman Anuradha C. Effects of linalool on inflammation, matrix accumulation and podocyte loss in kidney of streptozotocin-induced diabetic rats. Toxicol Mech Methods. 2013;23(4):223–34.
Gunaseelan S, Balupillai A, Govindasamy K, Muthusamy G, Ramasamy K, Shanmugam M, Prasad NR. The preventive effect of linalool on acute and chronic UVB-mediated skin carcinogenesis in Swiss albino mice. Photochem Photobiol Sci. 2016;15(7):851–60.
Chang MY, Shieh DE, Chen CC, Yeh CS, Dong HP. Linalool induces cell cycle arrest and apoptosis in leukemia cells and cervical cancer cells through CDKIs. Int J Mol Sci. 2015;16(12):28169–79.
Iwasaki K, Zheng YW, Murata S, Ito H, Nakayama K, Kurokawa T, Sano N, Nowatari T, Villareal MO, Nagano YN, Isoda H, Matsui H, Ohkohchi N. Anticancer effect of linalool via cancer-specific hydroxyl radical generation in human colon cancer. World J Gastroenterol. 2016;22(44):9765–74.
Wang Y, Wang X, Yang Z, Zhu G, Chen D, Meng Z. Menthol inhibits the proliferation and motility of prostate cancer DU145 cells. Pathol Oncol Res. 2012;18(4):903–10.
Xue J, Li H, Deng X, Ma Z, Fu Q, Ma S. l-Menthone confers antidepressant-like effects in an unpredictable chronic mild stress mouse model via NLRP3 inflammasome-mediated inflammatory cytokines and central neurotransmitters. Pharmacol Biochem Behav. 2015;134:42–8.
Liu Z, Shen C, Tao Y, Wang S, Wei Z, Cao Y, Wu H, Fan F, Lin C, Shan Y, Zhu P, Sun L, Chen C, Wang A, Zheng S, Lu Y. Chemopreventive efficacy of menthol on carcinogen-induced cutaneous carcinoma through inhibition of inflammation and oxidative stress in mice. Food Chem Toxicol. 2015;82:12–8.
Sabzghabaee AM, Nili F, Ghannadi A, Eizadi-Mood N, Anvari M. Role of menthol in treatment of candidial napkin dermatitis. World J Pediatr. 2011;7(2):167–70.
Fallon MT, Storey DJ, Krishan A, Weir CJ, Mitchell R, Fleetwood-Walker SM, Scott AC, Colvin LA. Cancer treatment-related neuropathic pain: proof of concept study with menthol–a TRPM8 agonist. Support Care Cancer. 2015;23(9):2769–77.
Paul S, Hwang JK, Kim HY, Jeon WK, Chung C, Han JS. Multiple biological properties of macelignan and its pharmacological implications. Arch Pharm Res. 2013;36(3):264–72.
Shin K, Chung HC, Kim DU, Hwang JK, Lee SH. Macelignan attenuated allergic lung inflammation and airway hyper-responsiveness in murine experimental asthma. Life Sci. 2013;92(22):1093–9.
Han YS, Kim MS, Hwang JK. Macelignan inhibits histamine release and inflammatory mediator production in activated rat basophilic leukemia mast cells. Inflammation. 2012;35(5):1723–31.
Elnaggar YS, Etman SM, Abdelmonsif DA, Abdallah OY. Intranasal piperine-loadedchitosan nanoparticles as brain-targeted therapy in Alzheimer’s disease: optimization, biological efficacy, and potential toxicity. J Pharm Sci. 2015;104(10):3544–56.
Deng Y, Sriwiriyajan S, Tedasen A, Hiransai P, Graidist P. Anti-cancer effects of Piper nigrum via inducing multiple molecular signaling in vivo and in vitro. J Ethnopharmacol. 2016;188:87–95.
Toyoda T, Shi L, Takasu S, Cho YM, Kiriyama Y, Nishikawa A, Ogawa K, Tatematsu M, Tsukamoto T. Anti-inflammatory effects of capsaicin and piperine on helicobacter pylori-induced chronic gastritis in mongolian gerbils. Helicobacter. 2016;21(2):131–42.
Prashant A, Rangaswamy C, Yadav AK, Reddy V, Sowmya MN, Madhunapantula S. In vitro anticancer activity of ethanolic extracts of Piper nigrum against colorectal carcinoma cell lines. Int J Appl Basic Med Res. 2017;7(1):67–72.
Mao QQ, Huang Z, Zhong XM, Xian YF, Ip SP. Brain-derived neurotrophic factor signalling mediates the antidepressant-like effect of piperine in chronically stressed mice. Behav Brain Res. 2014;261:140–5.
Hwang YP, Yun HJ, Kim HG, Han EH, Choi JH, Chung YC, Jeong HG. Suppression of phorbol-12-myristate-13-acetate-induced tumor cell invasion by piperine via the inhibition of PKCα/ERK1/2-dependent matrix metalloproteinase-9 expression. Toxicol Lett. 2011;203(1):9–19.
Yang W, Chen YH, Liu H, Qu HD. Neuroprotective effects of piperine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease mouse model. Int J Mol Med. 2015;36(5):1369–76.
Abdelhamed S, Yokoyama S, Refaat A, Ogura K, Yagita H, Awale S, Saiki I. Piperine enhances the efficacy of TRAIL-based therapy for triple-negative breast cancer cells. Anticancer Res. 2014;34(4):1893–9.
Li Q, Zhai W, Jiang Q, Huang R, Liu L, Dai J, Gong W, Du S, Wu Q. Curcumin-piperine mixtures in self-microemulsifying drug delivery system for ulcerative colitis therapy. Int J Pharm. 2015;490(1–2):22–31.
Napimoga MH, Clemente-Napimoga JT, Macedo CG, Freitas FF, Stipp RN, Pinho-Ribeiro FA, Casagrande R, Verri WA Jr. Quercetin inhibits inflammatory bone resorption in a mouse periodontitis model. J Nat Prod. 2013;76(12):2316–21.
Seo JS, Choi J, Leem YH, Han PL. Rosmarinic acid alleviates neurological symptoms in the G93A-SOD1 transgenic mouse model of amyotrophic lateral sclerosis. Exp Neurobiol. 2015;24(4):341–50.
Jin BR, Chung KS, Cheon SY, Lee M, Hwang S, Noh Hwang S, Rhee KJ, An HJ. Rosmarinic acid suppresses colonic inflammation in dextran sulphate sodium (DSS)-induced mice via dual inhibition of NF-κB and STAT3 activation. Sci Rep. 2017;7:46252.
Xu Y, Han S, Lei K, Chang X, Wang K, Li Z, Liu J. Anti-Warburg effect of rosmarinic acid via miR-155 in colorectal carcinoma cells. Eur J Cancer Prev. 2016;25(6):481–9.
Han S, Yang S, Cai Z, Pan D, Li Z, Huang Z, Zhang P, Zhu H, Lei L, Wang W. Anti-Warburg effect of rosmarinic acid via miR-155 in gastric cancer cells. Drug Des Devel Ther. 2015;9:2695–703.
Cao W, Hu C, Wu L, Xu L, Jiang W. Rosmarinic acid inhibits inflammation and angiogenesis of hepatocellular carcinoma by suppression of NF-κB signaling in H22 tumor-bearing mice. J Pharmacol Sci. 2016;132(2):131–7.
Heo SK, Noh EK, Yoon DJ, Jo JC, Koh S, Baek JH, Park JH, Min YJ, Kim H. Rosmarinic acid potentiates ATRA-induced macrophage differentiation in acute promyelocytic leukemia NB4 cells. Eur J Pharmacol. 2015;747:36–44.
Ghasemzadeh Rahbardar M, Amin B, Mehri S, Mirnajafi-Zadeh SJ, Hosseinzadeh H. Anti-inflammatory effects of ethanolic extract of Rosmarinus officinalis L. and rosmarinic acid in a rat model of neuropathic pain. Biomed Pharmacother. 2017;86:441–9.
Omori A, Yoshimura Y, Deyama Y, Suzuki K. Rosmarinic acid and arbutin suppress osteoclast differentiation by inhibiting superoxide and NFATc1 downregulation in RAW 264.7 cells. Biomed Rep. 2015;3(4):483–90.
Fan YT, Yin GJ, Xiao WQ, Qiu L, Yu G, Hu YL, Xing M, Wu DQ, Cang XF, Wan R, Wang XP, Hu GY. rosmarinic acid attenuates sodium taurocholate-induced acute pancreatitis in rats by inhibiting nuclear factor-κB activation. Am J Chin Med. 2015;43(6):1117–35.
Zhou MW, Jiang RH, Kim KD, Lee JH, Kim CD, Yin WT, Lee JH. Rosmarinic acid inhibits poly(I:C)-induced inflammatory reaction of epidermal keratinocytes. Life Sci. 2016;155:189–94.
Osakabe N, Takano H, Sanbongi C, Yasuda A, Yanagisawa R, Inoue K, Yoshikawa T. Anti-inflammatory and anti-allergic effect of rosmarinic acid (RA); inhibition of seasonal allergic rhinoconjunctivitis (SAR) and its mechanism. BioFactors. 2004;21(1–4):127–31.
Lin CH, Shen ML, Zhou N, Lee CC, Kao ST, Wu DC. Protective effects of the polyphenol sesamin on allergen-induced T(H)2 responses and airway inflammation in mice. PLoS ONE. 2014;9(4):e96091.
Narasimhulu CA, Selvarajan K, Litvinov D, Parthasarathy S. Anti-atherosclerotic and anti-inflammatory actions of sesame oil. J Med Food. 2015;18(1):11–20.
Lee CC, Liu KJ, Wu YC, Lin SJ, Chang CC, Huang TS. Sesamin inhibitsmacrophage-induced vascular endothelial growth factor and matrixmetalloproteinase-9 expression and proangiogenic activity in breast cancer cells. Inflammation. 2011;34(3):209–21.
Mohammad Shahi M, Zakerzadeh M, Zakerkish M, Zarei M, Saki A. Effect of sesamin supplementation on glycemic status, inflammatory markers, and adiponectin levels in patients with type 2 diabetes mellitus. J Diet Suppl. 2016; 1–12.
Kong X, Ma MZ, Zhang Y, Weng MZ, Gong W, Guo LQ, Zhang JX, Wang GD, Su Q, Quan ZW, Yang JR. Differentiation therapy: sesamin as an effective agent in targeting cancer stem-like side population cells of human gallbladder carcinoma. BMC Complement Altern Med. 2014;14:254. https://doi.org/10.1186/1472-6882-14-254.
Kong P, Chen G, Jiang A, Wang Y, Song C, Zhuang J, Xi C, Wang G, Ji Y, Yan J. Sesamin inhibits IL-1β-stimulated inflammatory response in human osteoarthritis chondrocytes by activating Nrf2 signaling pathway. Oncotarget. 2016;7(50):83720–6.
Xu P, Cai F, Liu X, Guo L. Sesamin inhibits lipopolysaccharide-induced proliferation and invasion through the p38-MAPK and NF-κB signaling pathways in prostate cancer cells. Oncol Rep. 2015;33(6):3117–23.
Pennisi M, Crupi R, Di Paola R, Ontario ML, Bella R, Calabrese EJ, Crea R, Cuzzocrea S, Calabrese V. Inflammasomes, hormesis, and antioxidants inneuroinflammation: role of NRLP3 in Alzheimer disease. J Neurosci Res. 2016;95(7):1360–72.
Byrne MM, Murphy RT, Ryan AW. Epigenetic modulation in the treatment of atherosclerotic disease. Front Genet. 2014;5:364.
Shing CM, Fassett RG, Peake JM, Coombes JS. Effect of tocopherol on atherosclerosis, vascular function, and inflammation in apolipoprotein E knockout mice with subtotal nephrectomy. Cardiovasc Ther. 2014;32(6):270–5.
Jiang Q, Jiang Z, Hall YJ, Jang Y, Snyder PW, Bain C, Huang J, Jannasch A, Cooper B, Wang Y, Moreland M. Gamma-tocopherol attenuates moderate but not severe colitis and suppresses moderate colitis-promoted colon tumorigenesis in mice. Free Radic Biol Med. 2013;65:1069–77.
Yang CS, Lu G, Ju J, Li GX. Inhibition of inflammation and carcinogenesis in the lung and colon by tocopherols. Ann NY Acad Sci. 2010;1203:29–34.
Smolarek AK, So JY, Thomas PE, Lee HJ, Paul S, Dombrowski A, Wang CX, Saw CL, Khor TO, Kong AN, Reuhl K, Lee MJ, Yang CS, Suh N. Dietary tocopherols inhibit cell proliferation, regulate expression of ERα, PPARγ, and Nrf2, and decrease serum inflammatory markers during the development of mammary hyperplasia. Mol Carcinog. 2013;52(7):514–25.
Zhou E, Fu Y, Wei Z, Yu Y, Zhang X, Yang Z. Thymol attenuates allergic airway inflammation in ovalbumin (OVA)-induced mouse asthma. Fitoterapia. 2014;96:131–7.
Wu H, Jiang K, Yin N, Ma X, Zhao G, Qiu C, Deng G. Thymol mitigates lipopolysaccharide-induced endometritis by regulating the TLR4- and ROS-mediated NF-κB signaling pathways. Oncotarget. 2017;8(12):20042–55.
Ribeiro AR, Diniz PB, Pinheiro MS, Albuquerque-Júnior RL, Thomazzi SM. Gastroprotective effects of thymol on acute and chronic ulcers in rats: the role of prostaglandins, ATP-sensitive K(+) channels, and gastric mucus secretion. ChemBiol Interact. 2016;244:121–8.
Liang D, Li F, Fu Y, Cao Y, Song X, Wang T, Wang W, Guo M, Zhou E, Li D, Yang Z, Zhang N. Thymol inhibits LPS-stimulated inflammatory response via down-regulation of NF-κB and MAPK signaling pathways in mouse mammary epithelial cells. Inflammation. 2014;37(1):214–22.
Xu D, Ma Y, Zhao B, Li S, Zhang Y, Pan S, Wu Y, Wang J, Wang D, Pan H, Liu L, Jiang H. Thymoquinone induces G2/M arrest, inactivates PI3K/Akt and nuclear factor-κB pathways in human cholangiocarcinomas both in vitro and in vivo. Oncol Rep. 2014;31(5):2063–70.
Aquib M, Najmi AK, Akhtar M. Antidepressant effect of thymoquinone in animal models of depression. Drug Res (Stuttg). 2015;65(9):490–4.
El-Mahmoudy A, Shimizu Y, Shiina T, Matsuyama H, El-Sayed M, Takewaki T. Successful abrogation by thymoquinone against induction of diabetes mellitus with streptozotocin via nitric oxide inhibitory mechanism. Int Immunopharmacol. 2005;5(1):195–207.
Siveen KS, Mustafa N, Li F, Kannaiyan R, Ahn KS, Kumar AP, Chng WJ, Sethi G. Thymoquinone overcomes chemoresistance and enhances the anticancer effects of bortezomib through abrogation of NF-κB regulated gene products in multiple myeloma xenograft mouse model. Oncotarget. 2014;5(3):634–48.
Sethi G, Ahn KS, Aggarwal BB. Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol Cancer Res. 2008;6(6):1059–70.
Tekeoglu I, Dogan A, Ediz L, Budancamanak M, Demirel A. Effects of thymoquinone (volatile oil of black cumin) on rheumatoid arthritis in rat models. Phytother Res. 2007;21(9):895–7.
Cingi C, Eskiizmir G, Burukoğlu D, Erdoğmuş N, Ural A, Ünlü H. The histopathological effect of thymoquinone on experimentally induced rhinosinusitis in rats. Am J Rhinol Allergy. 2011;25(6):e268–72.
Kim SH, Hong JH, Lee YC. Ursolic acid, a potential PPARγ agonist, suppresses ovalbumin-induced airway inflammation and Penh by down-regulating IL-5, IL-13, and IL-17 in a mouse model of allergic asthma. Eur J Pharmacol. 2013;701(1–3):131–43.
Chun J, Lee C, Hwang SW, Im JP, Kim JS. Ursolic acid inhibits nuclear factor-κB signaling in intestinal epithelial cells and macrophages, and attenuates experimental colitis in mice. Life Sci. 2014;110(1):23–34.
Gai WT, Yu DP, Wang XS, Wang PT. Anti-cancer effect of ursolic acid activates apoptosis through ROCK/PTEN mediated mitochondrial translocation of cofilin-1 in prostate cancer. Oncol Lett. 2016;12(4):2880–5.
Kang SY, Yoon SY, Roh DH, Jeon MJ, Seo HS, Uh DK, Kwon YB, Kim HW, Han HJ, Lee HJ, Lee JH. The anti-arthritic effect of ursolic acid on zymosan-induced acuteinflammation and adjuvant-induced chronic arthritis models. J Pharm Pharmacol. 2008;60(10):1347–54.
ABK and BLS collected the relevant literatures and drafted the manuscript. HC and KB contributed in the preparation of the tables and figures. SP, SCG and ACB edited the manuscript. BBA conceived the idea and framework of the review and made the final proof reading. All authors read and approved the final manuscript.
We are thankful to IIT Guwahati for providing the facilities for this work.
The authors declare that they have no competing interests.
Availability of data and material
Consent for publication
Ethics approval and consent to participate
The work was supported by Department of Biotechnology, Government of India—BT/556/NE/U-Excel/2016 awarded to Dr. Ajaikumar B. Kunnumakkara and DST-INSPIRE-IF140215 (Department of Science and Technology, Government of India) awarded to Bethsebie L. Sailo. Kishore Banik acknowledges the UGC for providing the fellowship. The study was supported by research grants (DST – PURSE Phase II/RC/2016/944; from DBT – 6242-P34/RGCB/PMD/DBT/ALCB/2015; ICMR – 5/13/38/2014 NCDIII-Eoffice73143; and intramural grants from University of Delhi) to Prof. Alok C. Bharti.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.