Table 1.

Classification of phytochemicals (adapted from Gonzalez-Castejon and Rodriguez-Casado [36, 92, 107]).

Dietary phytochemicals	Functional derivatives		Sources	Therapeutics effect
Polyphenols	Phenolic acid    Curcuminoids  Flavonoids      Chalcones  Stilbenes  Lignans    Isoflavonoids	Caffeic acid Ferulic acid Chlorogenic acid Curcumin Flavonols, Flavanones Anthocyanins Flavanonoles Phlorizin Resveratol Sesamin Pinoresinol Genistein Daidzein	Coffee beans, soybeans    Turmeric  Tea, fruits (citrus, apple, grapes) Vegetables    Tomatoes, tea  Grapes, red wine  Whole grains, legumes    Soya	Antioxidative effect: (1) Curcumin, resveratrol, tea polyphenol, and isothiocyanates ↑ the phase II detoxifying and antioxidant enzymes like HO-1, GST by modulation transcription factor Nrf2 [20, 24]. (2) Curcumin protects against neuronal degeneration by ↓ ROS neutralizing NO induced free radicals. Curcumin ↑ intracellular GSH pool by triggering specific transcription factors (e.g., TPA, EpRE) [44, 45]. (3) Isoflavones target eNOS and redox sensitive gene expression and regulate vascular reactivity [37, 40]. (4) Aged rats fed soy protein diet rich in genistein and daidzein, which interact with estrogen receptors, ↑ eNOS and antioxidant enzymes expression [39]. (5) Resveratrol, anthocyanin, blocking activation of NF-kB, MAPK, and PGE2, protect neuronal disorder [51, 52]. Anti-inflammatory effect: (1) Procyanidins ↓ expression of iNOS and COX-2 inhibit inflammatory phenomenon. Procyanidins also significantly ↓ expression of TNF-α and IL-1β by blocking NF-kB activity via ↓ of MAPK and P38 pathways [52]. (2) Tea and/or red wine polyphenol inhibit expression of COX-2, LOX and exert anti-inflammatory effect. Similarly kaempferol, a flavonoid rich in fruits, vegetables (broccoli) ↓ reduce inflammation by inhibiting the generation of PGE2 [64–66]. (3) Oral supplementation of curcumin (45 mg/kg) in male mice ↓ stemic inflammation by blocking the release of TNF-α and CRP [68]. (4) Cinnamon bark extract (content TAPP) protects from AHR or asthma by reducing inflammatory mediators like IL-4 and IL-13 [69]. (5) Cinnamon bark extract protects against systemic inflammation in rheumatoid arthritis by reducing CRP and stimulating autoimmune system by ↓ expression of many inflammatory mediators (prostaglandin E2, NO) in RA rats [69]. Metabolism regulation: (1) Anthocyanin and myrtillin of blueberry extract show hypoglycemic effect in humans. Supplementation of 3% blueberry enriched diet for 8 weeks and/or 0.5% GSE-supplemented diet significantly reduced the arterial blood pressure in SHRs via endothelium mediated stimulation of NO metabolism and activation of COX-induced product [74, 75]. (2) TAPP, the main active component of Cinnamon extract, significantly ↓ the blood HbA1c level and improves the insulin signaling in diabetic animal study [73]. (3) Phenolic compounds, namely, chlorogenic acid and ferulic acid, and a plant alkaloid, berberine, are considered as potent antidiabetic agent, as these phytochemicals enhance the uptake of 2DG in time- and dose-dependent manner and significantly upregulate the expression of GLUT4 and PPAR-γ and PK13K expression [90, 91]. Antiproliferative effect: (1) Tea polyphenols exert antiproliferative effects by interacting with MMP system. Tea polyphenol ↓ SMC proliferation by blocking cyclin D1 and Cyclin E and/by inhibiting the cell growth markers PCNA [94, 95]. (2) Resveratrol ↑ apoptosis by upregulation of tumor suppressor genes p21Cip1/WAF1, p53, the proapoptotic protein Bax expression, ↑ caspase apoptotic signals, and ↓ antiapoptotic proteins Bcl-2, Bcl-XL, and survivin expression [103, 104]. (3) Polyphenols (resveratrol, genistein, curcumin, C-phycocyanin, and quercetin) inhibit proliferation and motility of cells by suppression of cell adhesion molecule CD44 expression [102]. (4) Ellagic acid, isovitexin ↓ SMC proliferation might be by ↓ ROS generation and ↓ of ERK1/2 and iNOS expression [101]. Antiangiogenic effect: (1) Ellagic acid significantly ↓ angiogenesis in hamster buccal punch by ↓ PI3K/Akt and MAPK and VEGF signaling pathways, suppressing HDAC6 and hypoxia-inducible HIF-1α responses [105]. (2) Tephrocia purpurea rich in flavonoids was found to exert wound healing effect by significant ↑ of angiogenesis or blood vessels formation, fibroblast cells, and generation of collagen fibres [106]. (3) Astaxanthin (non-provitamin A carotenoid) predominantly distributed in microalgae, fungi, plants, and sea foods, inhibits tumor progression by regulating STAT3/JAK-2 [108].
Terpenoids	Carotenoids     Sesquiterpenes	Lycopene Lutein Carotene Acyclic compound (Farnesol, Nerolidol) Cyclic compound (Abscisic acid)	Tomatoes, spinach, carrot     Fruits, vegetables	Antioxidative effect: consumption of lycopene (rich in tomato, spinach, etc.) significantly ↑ antioxidant enzymes SOD, GSH-Px, GR, and GSH and ↓ levels of MDA in hypertensive patients. Lycopene ↓ MDA levels and ↑ GSH levels in postmenopausal women and protects from cardiovascular disorder. Anti-inflammatory effect: lycopene ↓ the release of proinflammatory cytokine TNF-α by ↓ NF-kB activation and induces anti-inflammatory effect. Moreover significant inhibition of lipid peroxidation by the combination of ascorbic acid and α-tocopherol is the complementary to the anti-inflammatory effect of lycopene.
Organosulfur		Allicin Allyl sulfide	Garlic, onion	Metabolism regulation: (1) In vivo antidiabetic effect of garlic is well documented in diabetic rats and mice. Allicin (main active component) induces pancreatic secretion of insulin or its release from bound insulin [80, 81]. (2) Garlic and garlic protein diet significantly ↓ serum cholesterol, triglyceride, and LDL cholesterol by allicin mediated inhibition of cholesterol synthesis [83–85]. (3) Gamma-glutamylcysteines component of garlic ↓ blood pressure by inhibiting angiotensin-converting enzyme [14, 80, 85].
Phytosterols	Sterol, Stanols, Campestanols	Diosgenin	Fenugreek, wild yam	Metabolic regulation: phytosterol, inhibiting cholesterol absorption [83, 85, 89]