The Potential Role of Nutraceuticals in Inflammation and Oxidative Stress

Nutraceuticals are defined as a food or food ingredients that prevent and treat diseases. They contain dietary supplements like proteins, vitamins and minerals, compound derived from natural sources. They have functions about delaying, preventing and treating chronic inflammatory diseases due to the presence of the phytochemicals. They have anti-inflammatory effects by inhibiting of the activation of NF- κ B, blocking the overexpression of tumor necrosis factor and interleukin-1, downregulation of the overexpression of cell adhesion molecules and inhibiting phospholipase A2, COX-2, lipoxygenease, iNOS, myeloperoxidase and inhibiting reactive oxygen species (ROS) generating enzyme activity and increasing ability to scavenge ROS. They have antioxidative role that can reduce the level of ROS and free radicals. They have effects on the process of lipid oxidation that inhibit or slow the formation of free alky radicals and cut off the free radical chain reactions.


Introduction
In recent years, the consumption of natural products or functional foods are increased and enlarged segment of food industry. At the same time, Nutraceuticals are increased using as an alternative for pharmaceutical industry especially variety of diseases and cancers in humans and animals.
Firstly, nutraceutical is a term used by Stefane De Felice Nutraceuticals is defined as a food, bioactive products or food ingredients that prevent and treat diseases [1][2][3][4]. They are not drugs but they have pharmacologically active substance [2]. They contain dietary supplements like proteins, vitamins and minerals, compounds derived from natural sources. They provide health and medical benefits that delay, prevent and treat chronic inflammatory diseases due to the presence of the phytochemicals [1][2][3][4].
They have anti-inflammatory effects by inhibiting of the activation of NF-κB, blocking the overexpression of tumor necrosis factor and interleukin-1, downregulation of the overexpression of cell adhesion molecules and inhibiting phospholipase A2, COX-2, 5-LOX, iNOS, myeloperoxidase and inhibiting ROS generating enzyme activity and increasing ability to scavenge ROS. They have antioxidative role that can reduce the level of ROS and free radicals. They have effects on the process of lipid oxidation that inhibit or slow the formation of free alky radicals and cut off the free radical chain reactions. They have intracellular signaling pathway modular effects [2][3][4].
People's interest about nutraceuticals is increasing day by day due to various diseases. According to the global market data, China will be first nutraceutical market as lifestyle. The nutraceutical sector is affected by the stringent regulations and approval process of European Union. Due to the country, there are different names of laws on nutraceuticals. Nutraceuticals are using different definitions and terms including dietary supplement in USA, Natural Health Product in Canada, complementary medicines in Australia, food supplements in European Union and foods for special dietary in India [7].
With the increasing technology in the food, health and pharmaceutical sectors, the orientation to functional foods is increasing and the competition is accelerating. The sales of global market for nutraceuticals are expected to be US$250 billion by 2018 [8].
When nutraceuticals are evaluated by consumers, the consumption of food has undergone changes in the past three decades. The easing of access to media and internet, increasing in scientific studies and obesity related diseases are increased to sale nutraceutical products by consumers. Between 2018 and 2025 years, the growth rate of this sector is assumed to exceed 9.7%. The countries including Brazil, China, India, South Korea, Poland and Mexico are increasing to use functional foods. The global market of nutraceuticals is assumed to be $578.23 billion by 2025 at CAGR of 8.8% [9].
Inflammation is a protective response against the initial cause of cell injury. Inflammation is classified as acute and chronic. Acute inflammation is first response mechanism against infections, trauma, physical and chemical agents, which are induced wound healing. If this mechanism occurs persistent, it takes chronic phase [3,10]. The process of inflammation contain vascular and cellular changes including of swollen, redness, local heating and loss of function. The permeability of capillaries is increased, exudate including the fluid and other elements leak into the body cavities. The inflammatory cells, leucocytes and other phagocytic cells migrate through the affected region. The lytic enzymes release from lysosomes of cells. During the inflammation, chemical mediators are synthesized proinflammatory cytokines (histamine, 5-hydroxytryptamine, bradykinin, leukotrienes and prostaglandins), selectins, integrins and immunoglobulins are stimulated for releasing [1]. Arachidonic acid metabolites including prostaglandins and leukotrienes are stimulated by the increasing expression of phospholipase A2. ROS are released from the inflammatory cells including neutrophils and macrophages. NADPH oxidase, xanthine oxidase and myeloperoxidase are seen increasing due to the ROS. The inflammatory cytokines, cell adhesion molecules and enzymes are regulated by the activation of the transcription factor NF-κB [3,11].
ROS generate intracellularly as natural by endogenous and exogenous sources. Endogenous ROS including superoxide, hydrogen peroxide and nitric oxide (NO) have functions in cell signaling and homeostasis [12]. ROS has functions in regulation of cell survival. At the moderate levels of ROS signaling support cell proliferation and survival. At the upper levels of ROS cause cell death [12,13]. There is a relationship between ROS production and oxidative stress that play a role on redox signaling from the organelle to the cytosol to nucleus [12,14].
ROS are present in different cancer types and age related diseases as neurodegeneration, inflammation, diabetes, vision and sensory loss [12]. ROS and reactive nitrogen species damage significant biological molecules which are lipids, DNA, essential cellular proteins. Oxidative stress is imbalance between the formation of free radicals and antioxidant defense mechanism [15,16].
Enzymatic and nonenzymatic antioxidant systems which are superoxide dismutase, catalase, glutathione peroxidase, lipid soluble vitamin E, carotenes and water soluble vitamin C arrange between ROS and antioxidants [4,17,18].
Oxidative stress starts the oxidation of polyunsaturated fatty acids (PUFA), proteins, DNA and sterols. The oxidative stress reduce in the body with consumption of fruits and vegetables including high amounts of anti-oxidative nutraceuticals and for this reason, incidence of cancer and cardiovascular diseases decrease [4,6]. According to the recent studies, there is a relationship between ROS and atherosclerosis, vasospasm, cancers, trauma, stroke, asthma, hyperoxia, arthritis, heart attack, age pigments, dermatitis, cataractogenesis, retinal damage, hepatitis, liver injury and periodontitis [4,19,20].

Vitamin E
Vitamin E (alpha-, beta-, gamma-and delta-tocopherol, alpha-, beta-, gammaand delta-tocotrienol) is quite effective antioxidant and beneficial aspects for rheumatoid arthritis [4,21,22]. Also, vitamin E has anti-inflammatory effects in animal recent studies [4,23]. Tocopherols and tocotrienols have nonpolar structures and consist in the lipid phase. Tocopherols are member of biological membranes and. Tocopherols have antioxidants property that defend polyunsaturated fatty acids into the membrane and LDL [4,24]. The anti-inflammatory and anti-oxidant effects of Vitamin E and its derivatives are summarized in Table 1.

Vitamin E and derivatives
Anti-oxidant and anti-inflammatory effects References (Different doses, review literature study) Prevents and treats a multitude of age related diseases. Ameliorates of lipid profile and modulates suppression of the senescence-associated secretory phenotype Malavolta et al. [26] (The randomized clinical trials, ranging doses 33-800 IU)

Effects lonely cardiovascular diseases by reducing myocardial infarction
Loffredo et al. [27] (The clinical review literature study) Preventive and therapeutic functions in cardiovascular diseases.
Jain et al. [28] (The consumption of different doses, review of literature study in human) Prevents various types of cancer, heart disease and chronic ailments Shahidi [29] (The ranging doses between 500 IU/kg for 4 weeks in rats, 600 mg/kg in rats, 45 and 60 mg/kg in rats) Anti-oxidant roles by decreasing the distribution of free radicals and modulating plasmatic lipoproteins in traumatic brain injury related dementia Dobrovolny et al. [30]  Antimutagenic effect Polivkova et al. [37] (Daily oral dose 10 mg/kg body weight and intraperitoneally 25 mg/kg body weight in female Wistar rats) Neuroprotective activity Sandhir et al. [38] (Lycopene complex including 6% lycopene, 1.5% tocopherols, 1% phytoene and phytofluene, 0.2% betacarotene for 10 days in rats at 6 mg/kg body weight) Nephroprotective activity Sahin et al. [39] (The prospective randomized study in 159 primigravidas at the gestational time with the consumption of 2 mg oral lycopene daily for 77 women, placebo daily for 82 women) Prevents preclampsia Banerjee et al. [40] (375 men and 576 women with hip fracture and nonvertebral fracture in elderly ages at different amounts of consumption of carotenoid and lycopene) Decreases risk of hip fracture Sahni et al. [41] (The literature review study) Anti-obesity functions by modulating insulin resistance and reducing blood glucose levels by regulation of cytokine expression from white adipose tissue Gammone [42] (
Flavonoids, which are water-soluble [3], are popular group of polyphenols and classified as flavones, flavonols, catechin or flavanols, anthocyanins and isoflavones. Flavonoids consist as free aglycones or with sugars connected the chemical structures to generate glycosides. Flavonoids have anti-inflammatory functions by inhibiting the enzymes responsible for production of phospholipase A2, cyclooxygenase and lipoxygenase [2,3,63]. The beneficial effects to health of phenolic compounds are listed below in Table 3.
The effects of phenolic compounds, relevant to anti-inflammatory and anti-oxidant activity.

Flavonols
They are protective functions from UV radiation [2]. They are including kaempferol, quercetin, myricetin, galangin and morin [2]. They have beneficial effects on different conditions and diseases related oxidative stress and inflammation. These effects are summarized in Table 5. (The review article studies) Decreases the expression of tumor necrosis factor alpha and interleukin-6 in macrophages cells Chatterjee et al. [63], Wu and Schauss [73] (The review article study) Anti-arthritic functions Laev et al. [74] (The review article study in vitro and in vivo)

Anti-inflammatory functions for neurodegenerative disease
Nabavi et al. [75] (The review article study about antioxidant, anti-cancer, anti-tumoral activity, anti-inflammatory and hepatoprotective functions of dietary flavonoids)

Inhibits thromboxane synthesis in animal model and decreases iNOS and COX-2 expression
Xiao et al. [76] (50 mg/kg of body weight doses of apigenin was injected intraperitoneally in Male C57BL/6J mice) Immunomodulatory effects that reduces NF-κB activity in the lungs and inhibits leukocyte infiltration Cardenas et al. [77] (

Flavanones
They have important effects that regulate on the inflammatory process and oxidative stress. These beneficial effects are summarized in Table 6.

Catechin or flavanols
They are found in variety of fruits (apples, apricots, blackberries and grapes), red wine, black tea and cocoa [2]. For example; the long-term consumption of tea Anti-oxidant activity on cell apoptosis Hsu et al. [81] (The oral treatment doses at 2.8 g/kg in male Wistar rats, aged 8-10 weeks) Anti-oxidant and renoprotective effects in streptozotocin-diabetic rats Liu et al. [82] (The extracts of Ficus carica Linn. (Moraceae) leaves and fruits and Morus alba Linn. root barks (Moraceae) were given 50 and 150 mg/kg in adult female Swiss albino rats) Hepatoptotective effects on tetrachloriderelated oxidative stress and injury in rat liver tissue Singab et al. [83] (At the dose of 5 μM kaempferol was added cell culture medium including rat osteoblast-like UMR106 cells)

Regulates bone sialoprotein gene transcription and new bone formation
Yang et al. [84] (At the doses of 50 and 100 mg/kg kaempferol were given orally in animal model study) Regulates cyclooxygenase, inhibits production of nitric oxide Mahat et al. [85] (The review article study), (The doubleblind study was given orally 4 x 500 mg quercetin in non-smoking, un-treated sarcoidosis individuals) Decreases of oxidative stress and inflammation in sarcoidosis, colonic damage and allergic airway conditions Chatterjee et al. [63], Boots et al. [86] (The mice were fed Western diet including 0.05% quercetin for 18 weeks) Modulates on accumulation and activation of immune cells and increases expression of mitochondrial gene in adipose tissue.
Kobori et al. [87] (At the doses of 10 and 50 mg/kg quercetin were given intraperitoneally to the male Sprague Dawley rats) Neuroprotective and anti-oxidant effects in subarachnoid hemorrhage, inhibits brain damage and edema.
Dong et al. [88] (At the doses of 0 and 210 μM quercetin or taraxasterol were added cell culture medium including human umbilical vein endothelial cells) Anti-atherosclerotic and cardioprotective effects against the oxidative stress and inflammation Yang et al. [89]  inhibits low grade inflammation [73]. The chronic consumption of dark chocolate reduces serum C-reactive protein concentrations in blood circulation [63,73]. The other effects on inflammatory and oxidative stress are summarized in Table 7.
Flavanones Anti-oxidant and anti-inflammatory effects References (The review article study) Inhibitory effects on carcinogenesis Kinghorn et al. [68] (At the concentrations of 5 and 25 μM of chalcones and flavanones were given in the vitro study)

Regulate LDL oxidation in atherosclerosis
Miranda et al. [90] (The review article study) Have functions in anti-malarial chemotherapy Kumar et al. [91] (The review article study) Anti-inflammatory effects Kontogiorgis et al. [92] (The review article study) Anti-angiogenic effects Mojzis et al. [93] (At the treatment daily doses of 100 mg/kg naringenin were applied to the female BALB/ c mice) Decrease lung metastases in a breast cancer model Qin et al. [94] (At the dose of 50 mg/kg naringenin was applied to the adult male albino rats) Anti-oxidative stress related hepatic damage in rats Prabu et al. [95] (At the concentration of 0.25 mmol of naringin derivatives was applied by agar dilution technique and direct contact assaying)

Anti-bacterial roles in pathogenic strains
Celiz et al. [96] (At the doses of 50 mg/kg of quercetin and naringenin were applied to mice intraperitoneally) Protect DNA in alloxan-induced diabetic mice Orsolic et al. [97] (

Conclusion
Nutraceuticals are alternative or functional foods or ingredients that prevent or treatment of inflammatory and oxidative stress induced diseases. Nutraceuticals are cheaper and easier availability than prescription drugs. For this reason, consumer's demand has increased in recent years.
The effecting on pathogenesis and activity of diseases are also essential scientific subject for animal and human health. When the effects of nutraceuticals on oxidative stress and inflammatory related disease are discovered, usages of nutraceuticals in Pharmacology and scientific studies are seen huge growth. The relation between beneficial effects of nutraceuticals and diseases are required to research long-term multidisciplinary studies.
People are searching minimally processed food and want to benefit nutritional values and live healthy. For this reason nutraceutical market is growing day by day.
The aging, fast rising population, changing lifestyle and lifestyle induced diseases, healthcare research, increasing cases of cancer, economic and public problems are directed people to benefit better choices.
As a conclusion, nutraceuticals are important for nutrition of human and animal. The consumption of nutraceuticals is necessary to reduce effects of the oxidative stress and inflammation related diseases.

Conflict of interest
There is no conflict of interest for this chapter.

Catechin
Anti-oxidant and anti-inflammatory effects