Nutraceuticals in Inflammatory Diseases

The term inflammation means “to set on fire”. It is one of the natural responses of the body to the harmful pathogens that occurs as a form of acute and chronic type of inflammation (Kunnumakkara et al. 2018a; Gupta et al. 2018). The acute response forms a part of the innate immunity system through the persisting immune cells for a short duration. However, the chronic inflammation response can give rise to various chronic diseases which include arthritis, cancer, diabetes, cardiovascular diseases and so on, which might be due to deregulation of signaling pathways like S.T.A.T.3 (Signal transducer and activator of transcription 3) and N.F.-кВ (Kunnumakkara et al. 2018a). Inflammation can be characterized by swelling, pain, redness, heat and the body’s response to these irritations or injuries (Delfan et al. 2014). The production of reactive oxygen species induces oxidative stress and also promotes inflammatory processes through the stimulation of transcription factors like N.F.-кВ and activator protein 1 (A.P.l), resulting in production of T.N.F.a (Boots et al. 2008).

When polyphenols from concentrated apple extract with the dominant presence of chlorogenic acid are administered to rats afflicted with colitis induced by acetic acid, it could downregulate iNOS expression and conversely upregulate the levels of copper and zinc superoxide dismutase

(CuZnSOD) (Pastrelo et al. 2017). Another group of compounds, anthocyanins prevented the inflammation in the colitis-affected mice model and reduced the levels of pro-inflammatory cytokines such as I.F.N.-y, T.N.F. and I.L.-6 with the outcome of improved colon condition. In the case of ulcerative colitis-affected rats, the anthocyanins decreased the expression of I.F.N.-y R.2 and part of the I.F.N.-y receptor signal-transduction in colonic tissue, which resulted in inhibition of the I.F.N.-y-induced inflammatory activity in the colon and also elevated the concentrations of the I.L.- 22 and I.L.-10 tissue-protective cytokines in serum (Ghattamaneni et al. 2018). In D.S.S.-induced I.B.D. rats, a dietary complementation of quercetin along with fish oil containing eicosapentaenoic acid and docosahexaenoic acid improved the status of inflammation in the intestine (Camuesco et al. 2006]. Aloe and its components aloin, and aloe-gel have activity against inflammation, as they can reduce the T.N.F. and I.L.-lp expression levels in colon mucosa and decrease the plasma levels of L.T.B.4 and T.N.F. which can decrease the inflammation in the intestine of D.S.S.-induced I.B.D. mice (Park et al. 2011). Further, curcumin was shown to reduce the colonic inflammation by inhibiting pro-inflammatory pathways such as N.F.-кВ and M.A.P.K. pathways in the multidrug resistance minus gene (Mdrla-/-) I.B.D. mice (Nones et al. 2009). To add to this, the ellagic acid present in pomegranate was found to reduce the intestinal inflammation in D.S.S.-induced acute and chronic I.B.D. mice models which results in improved condition through COX2 and inducible nitric oxide synthase (iNOS) downregulation, thus inhibiting the signaling pathways like N.F.-кВ, signal transducer and activator of transcription 3 (S.T.A.T.3) and p38 M.A.P.K. (Marin et al. 2013).

Curcumin demonstrated anti-inflammatory properties through arachidonic acid cascades by suppressing N.F.-кВ and immunosuppressive properties through inhibition of I.L.-2 and T.N.F.-a levels. Boswellia serrata is another ayurvedic herb to cure the inflammatory state. It acts similarly through the arachidonic acid cascade and inhibition of leukotrienes resulting in reduction of pro-inflammatory cytokines. Another nutraceutical, apigenin, which forms the main constituent of wheatgrass inhibits the production of I.L.-lp, I.L.-8 and T.N.F. via inactivated N.F.-кВ (Parian et al. 2015). Quercetin resulted in inhibition of L.P.S.-induced T.N.F.a and I.L.8 levels in macrophages and lung cells respectively which might be due to the interaction between the oxidative stress and inflammation (Boots et al. 2008).

Additionally, in one clinical study, 40 patients (23 males, 17 females) suffering from bronchial asthma, and in the age group of 18-75 years, were treated with 300 mg gum resin of Boswellia thrice a week for 6 weeks. The treatment resulted in improved prognosis of 70% of the patients with relief from signs and symptoms of bronchial asthma and minimization of the attacks (Kunnumakkara et al. 2018b).

Nutraceuticals in Arthritis

The word arthritis is derived from the Greek words arthron meaning joint and -itis meaning inflammation. It is a disorder of the joints characterized by chronic inflammation in one or several joints resulting in pain and disability. Arthritis includes more than 100 forms such as osteoarthritis, psoriatic arthritis, rheumatoid arthritis and related autoimmune diseases (Daily et al. 2016). It arises due to inflammation of the joints and tissues that surround the joints and other connective tissues (Kunnumakkara et al. 2018b). Among all these, osteoarthritis followed by rheumatoid arthritis are the most common ones.

Many factors can lead to the development of osteoarthritis. They are aging, excessive exercise, obesity, immune disorders, genetic predisposition, poor nutrition, injury and infection (Gupta et al. 2016). Osteoarthritis is the most common form of arthritis and remains one of the few chronic diseases related to aging, with fewer treatment options (Felson 2009). The most important feature of osteoarthritis is the advanced destruction of articular cartilage that results in impaired joint motion and severe pain, leading to the person’s disability (Ameye and Chee 2006). The condition of osteoarthritis is not only limited to articular cartilage. It also affects the entire portion of the joint, including the subchondral bone, menisci, ligaments, periarticular muscle, capsule, adjacent connective tissue and the synovial membrane, giving rise to pain, swelling, deformity and instability (Sanghi et al. 2009; Ziskoven et al. 2010). Though osteoarthritis occurs in many joints, the knee, hip, hand and facet joints are mostly affected (Ziskoven et al. 2010). Osteoarthritis is one of the chronic diseases that forms an example for the pathology where the treatment could be addressed by proper nutrition (Ameye and Chee 2006).

Several nutraceuticals such as fish oil, black cumin extracts, fenugreek, licorice, coriander and dates were evaluated for their potential use in treatment of arthritis. Modified inflammatory biomarkers like erythrocyte sedimentation rate, C-reactive protein, seromucoids, fibrinogen, tumor necrosis factor-а (T.N.F.-a), prostaglandin E2, oxidative stress (malondialdehyde) and antioxidant status (total antioxidant capacity) were measured for evaluation. It was observed that these nutraceuticals can be used against inflammation and oxidation for alternative management of arthritis (Al-Okbi 2014). Intraperitoneal injection of curcuminoid extracts inhibited acute and chronic inflammation of joints, preventing induction of arthritis. Curcumin was reported to downregulate inflammatory enzymes such as that of nitric oxide synthase (iNOS), COX 2 and arachidonate5- lipoxygenase (ALOX5); pro-inflammatory cytokines TNF-a; interleukins such as I.L.-l, I.L.-2, I.L.-6,1.L.-8, I.L.-l2; and chemokines through NF-кВ inactivation (Alam et al. 2014). Gallic acid treatment in R.A. F.L.S. cells significantly decreased the expression of pro-inflammatory cytokines, chemokines, COX2 and matrix metalloproteinase 9, increased apoptotic protein caspase 3 and also regulated the expression of Bcl2, Bax, p53 and Akt proteins (Yoon et al. 2013). Genistein could suppress the growth of fibroblast-like synoviocytes in rheumatoid arthritis by stimulating I.L.-lp and T.N.F.-a cytokines and E.G.F. growth factor (Zhang et al. 2012).

Nutraceuticals in Obesity

Obesity can be understood as a disease that is related to imbalance of energy, which can increase the risk for other chronic diseases like cardiovascular disease, type 2 diabetes, hypertension, dyslip- idemia and some cancers. It is characterized by increased fat mass in the adipose tissue that serves as a storage center for consumed food (Singh et al. 2019). It is a multifaceted disorder with serious social and psychological extents, affecting people of all ages and socioeconomic groups (Chintale et al. 2013). In cases of obesity, like in most other chronic diseases, inflammation plays a major role and these states later lead to the development of another pro-inflammatory disease, atherosclerosis (Aggarwal. 2010). The main cause of obesity is increased high-fat availability and energy-dense foods. Thus, obesity is globally prevalent and nutrition and exercise play a role in its prevention and treatment (Nasri et al. 2014). The mixture of the dietary supplements of nutraceuticals fenugreek, glucomannan, Gymnema sylvestre, and vitamin C significantly decreased body weight and promoted fat loss in obese individuals (Chintale et al. 2013). The supplementation of conjugated linoleic acid that is found in flax seeds, nut oils, fish and eggs reduced the fat mass of obese individuals (Kasbia 2005). Supplementation of conjugated linoleic acid might also have a role towards insulin resistance which occurs in conjunction with obesity, and additionally, supplementation of conjugated linoleic acid to a high-fat diet of rodents has been shown to prevent the onset of obesity- induced muscle insulin resistance (Kasbia 2005).

Nutraceuticals in Cancer

Despite the advancement in cancer treatment modes such as surgery, radiation and chemotherapy, cancer still remains one of the most lethal diseases globally (Padmavathi et al. 2015; Banik et al. 2018; Ranaware et al. 2018; Sailo et al. 2018). Many natural products are used in herbal medicine, food supplements and as cooking spices. They are well-investigated in various cancer experimental settings in both in vitro and in vivo models (Tripathi et al. 2005). Similarly, nutritional modulations could also prove to be useful in treating cancer patients. Examples are foods that contain comparatively low simple carbohydrates and reasonable quantities of high-quality protein, fibers and fats

(omega-3 fatty acid). Additionally, supplementation of certain nutraceuticals, micronutrients and functional foods have a role in reducing the risk of cancer development or inhibit cancer progression and also reduce the toxicity that is associated with conventional cancer chemotherapy and radiation (Tripathi et al. 2005).

The common nutraceuticals used for this purpose include curcumin, capsaicin, genistein, fla- vopiridol, sanguinarine, resveratrol and tocotrienol (Gupta et al. 2019). Polyphenolic and flavonoid contents from fruits and vegetables are also proven for their anti-cancer ability to downregulate the expression of various genes, proteins and signaling pathways that are involved in tumor growth and progression (Khwairakpam et al. 2018). Phytochemicals like triterpenoids, fiavonoids and retinoids with their derivatives are multi-targeted agents with the properties of anti-angiogenesis and anti-inflammation mostly targeting A.M.P.K. and other metabolic pathways like the m.T.O.R axis (Albini et al. 2019). Curcumin, the golden nutraceutical, was shown to suppress the expression of inflammatory cytokines like I.L.-6,1.L.-8, and granulocyte macrophage colony stimulating factor and T.N.F.-a and I.K.K.p kinase in the saliva of head and neck cancer patients (Kunnumakkara et al. 2017).

The natural polyphenol calebin A, a novel derivative of turmeric, blocked the activation and nuclear translocation of p65-N.F.-B by T.N.F.-p (Buhrmann et al. 2019). The extract of gum resin from Boswellia serrata and its various analogues have shown cytostatic and apoptotic activity against glioma cells. Furthermore, one of its analogues in combination with curcumin showed antitumor effects in various experimental settings in both in vitro and in vivo conditions by regulating cancer-related miR.N.A.s like miR-34a and miR-27a in colon cancer (Roy et al. 2019). Curcumin induces cell cycle arrest and initiates apoptosis and also alters many targets such as T.N.F.-a, N.F.- kB and COX-2. The plant polyphenol butein could decrease the proliferation, cytotoxicity, migration and invasion by modulating various gene products such as COX-2, survivin, and M.M.P-9. Similar modulations of these cancer hallmarks in O.S.C.C. cells through regulation of N.F.-кВ and its regulated gene products were demonstrated (Bordoloi et al. 2019).

Resveratrol administered to breast cancer patients for 12 weeks showed a marked decline in the methylation of four genes which can cause an increase in the threat for breast cancer. In the case of prostate cancer, the effect of resveratrol in combination with curcumin encapsulated in the same liposome increased their anti-cancer effect (Ghani et al. 2019). The compound piceatannol was also shown to induce apoptosis in leukemic cells through the induced expression of F.A.S. and M.A.RK. (mitogen-activated protein kinase)-mediated c-Jun and A.T.F.-2 (activating transcription factor 2) pathways. It also activated caspases and downregulated В-cell lymphoma (Bcl2) (Liu and Chang 2010).

Further studies found the regulation of N.F.-кВ by the compounds that were involved in inflammatory and other signaling cascades in cancer cells (Banik et al. 2020). Honokiol prevents the progression of different cancers through the decreased expression of anti-apoptotic proteins, affects the mitochondrial-dependent pathways and elevates apoptosis through the modulation of Ca+2 channels and pro-apoptotic proteins. It affects metastatic activity by inhibiting M.M.Rs, P.I.3K./ Akt/mT.O.R., epithelial to mesenchymal transition, N.F.-кВ, S.T.A.T.3, and Wnt signaling pathways (Banik et al. 2019). The compound zerumbone could cause a decrease in cancer hallmarks such as survival, proliferation, angiogenesis, invasion and metastasis through the modulation of Akt, N.F.- кВ, and I.L.-6/J.A.K.2/S.T.A.T.3 pathways (Girisa et al. 2019).

Nutraceuticals in Chronic Respiratory Diseases

Chronic respiratory diseases are associated with a high economic burden, affecting the quality of life of patients (Sleurs et al. 2019). Mainly asthma and chronic obstructive pulmonary disease (C.O.P.D.), with their associated mortality, contribute to the public burden (Roth-Walter et al. 2019). Oxidative stress is strongly involved in increasing the conditions of asthma, C.O.P.D., infections and lung cancer (Dua et al. 2019). In previous studies, the use of various nutraceuticals in terms of nutrients or bioactive compounds from plants or microbes with potential health-improving effects has been widely explored (Rivellese et al. 2019). Epigallocatechin gallate showed its potential in inhibiting the chemo-attractants and regulated the inflammatory responses in several fibrotic diseases. Further, the in vivo studies with the compound proved to be beneficial in improving the condition of lung injuries in cigarette smoke-exposed rats (Hwang and Ho 2018).

 
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