Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects – A review

Flavonoids are a family of polyphenolic compounds which are widespread in nature (vegetables) and are consumed as part of the human diet in significant amounts. There are other types of polyphenols, including, for example, tannins and resveratrol. Flavonoids and related polyphenolic compounds have significant antiinflammatory activity, among others. This short review summarizes the current knowledge on the effects of flavonoids and related polyphenolic compounds on inflammation, with a focus on structural requirements, the mechanisms involved, and pharmacokinetic considerations. Different molecular (cyclooxygenase, lipoxygenase) and cellular targets (macrophages, lymphocytes, epithelial cells, endothelium) have been identified. In addition, many flavonoids display significant antioxidant/radical scavenging properties. There is substantial structural variation in these compounds, which is bound to have an impact on their biological profile, and specifically on their effects on inflammatory conditions. However, in general terms there is substantial consistency in the effects of these compounds despite considerable structural variations. The mechanisms have been studied mainly in myeloid cells, where the predominant effect is an inhibition of NF-κB signaling and the downregulation of the expression of proinflammatory markers. At present there is a gap in knowledge of in vitro and in vivo effects, although the pharmacokinetics of flavonoids has advanced considerably in the last decade. Many flavonoids have been studied for their intestinal antiinflammatory activity which is only logical, since the gastrointestinal tract is naturally exposed to them. However, their potential therapeutic application in inflammation is not restricted to this organ and extends to other sites and conditions, including arthritis, asthma, encephalomyelitis, and atherosclerosis, among others.

Effects of Flavonoids and other Polyphenols on Inflammation

Cancer is a major public health concern in both developed and developing countries. Several plant-derived anti-cancer agents including taxol, vinblastine, vincristine, the campothecin derivatives, topotecan, irinotecan and etoposide are in clinical use all over the world. Other promising anti-cancer agents include flavopiridol, roscovitine, combretastatin A-4, betulinic acid and silvestrol. From this list one can well imagine the predominance of polyphenols, flavonoids and their synthetic analogs in the treatment of ovarian, breast, cervical, pancreatic and prostate cancer. Flavonoids present in human diet comprise many polyphenolic secondary metabolites with broad-spectrum pharmacological activities including their potential role as anti-cancer agents. A positive correlation between flavonoids-rich diet (from vegetables and fruits) and lower risk of colon, prostate and breast cancers lead to a question that whether flavonoids mediate the protective effects as chemopreventive agents or can interact with different genes and proteins to play role in chemotherapy. The current review emphasizes onto the therapeutic potential of flavonoids and their synthetic analogs as anti-cancer agents by providing new insights into the factors, regulation and molecular mechanisms along with their significant protein interactions.

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Anti-cancer potential of flavonoids: recent trends and future perspectives

Flavonoids are ubiquitous in nature. They are also in food, providing an essential link between diet and prevention of chronic diseases including cancer. Anticancer effects of these polyphenols depend on several factors: Their chemical structure and concentration, and also on the type of cancer. Malignant cells from different tissues reveal somewhat different sensitivity toward flavonoids and, therefore, the preferences of the most common dietary flavonoids to various human cancer types are analyzed in this review. While luteolin and kaempferol can be considered as promising candidate agents for treatment of gastric and ovarian cancers, respectively, apigenin, chrysin, and luteolin have good perspectives as potent antitumor agents for cervical cancer; cells from main sites of flavonoid metabolism (colon and liver) reveal rather large fluctuations in anticancer activity probably due to exposure to various metabolites with different activities. Anticancer effect of flavonoids toward blood cancer cells depend on their myeloid, lymphoid, or erythroid origin; cytotoxic effects of flavonoids on breast and prostate cancer cells are highly related to the expression of hormone receptors. Different flavonoids are often preferentially present in certain food items, and knowledge about the malignant tissue-specific anticancer effects of flavonoids could be purposely applied both in chemoprevention as well as in cancer treatment.

Cytotoxicity of dietary flavonoids on different human cancer types

Anti-cancer chalcones: Structural and molecular target perspectives.

Artocarpus heterophyllus Lam is a large evergreen tree cultivated throughout Southeast Asia for its fruits. Its leaves and roots have been used for medicinal purposes. The aim of this work was to study the in vitro anti-inflammatory effects of phenolic compounds isolated from the ethyl acetate extracts of the fruits of Artocarpus heterophyllus. Three phenolic compounds were characterized as artocarpesin [5,7,2',4'-tetrahydroxy-6-(3-methylbut-3-enyl) flavone] ( 1), norartocarpetin (5,7,2',4'-tetrahydroxyflavone) ( 2), and oxyresveratrol [ trans-2,4,3',5'-tetrahydroxystilbene] ( 3) by spectroscopic methods and through comparison with data reported in the literatures. The anti-inflammatory effects of the isolated compounds ( 1- 3) were evaluated by determining their inhibitory effects on the production of proinflammatory mediators in lipopolysaccharide (LPS)-activated RAW 264.7 murine macrophage cells. These three compounds exhibited potent anti-inflammatory activity. The results indicated that artocarpesin ( 1) suppressed the LPS-induced production of nitric oxide (NO) and prostaglandin E 2 (PGE 2) through the down-regulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) protein expressions. Thus, artocarpesin ( 1) may provide a potential therapeutic approach for inflammation-associated disorders.

Anti-inflammatory Effects of Phenolic Compounds Isolated from the Fruits of Artocarpus heterophyllus

Plenty of polyphenols, i.e. phenolic acids and flavonoids, were found in longan flower water extract (LFWE) through spectrophotometric and HPLC analyses. Antiobesity and hypolipidemic effects of polyphenol-rich longan flower water extract (LFWE) were investigated in this study. Eight male rats per group were assigned randomly to one of the following dietary groups: (1) normal-caloric diet and pure water (NCD + NDW); (2) hypercaloric diet and pure water (HCD + NDW); (3) HCD and 1.25% (w/v) LFWE (HCD + 1.25% LFWE); (4) HCD and 2.5% (w/v) LFWE (HCD + 2.5% LFWE) for 9 weeks. Body weight, size of epididymal fat, serum triglyceride level and atherogenic index, and hepatic lipids were decreased (p < 0.05) in HCD rats by drinking 2.5% LFWE which may result from downregulated (p < 0.05) pancreatic lipase activity, and sterol regulatory element binding protein-1c (SREBP-1c) and fatty acid synthase (FAS) gene expressions, as well as upregulated (p < 0.05) LDL receptor (LDLR) and peroxisome proliferator-activated-rec...

Antiobesity and Hypolipidemic Effects of Polyphenol-Rich Longan (Dimocarpus longans Lour.) Flower Water Extract in Hypercaloric-Dietary Rats

Over the last few decades, obesity has become a global epidemic in both developed and developing countries. Recent studies have indicated that obesity is closely associated with chronic inflammation characterized by abnormal levels of adipocytokines and inflammatory cytokines in adipocytes. The aim of this work was to study the effects of 21 polyphenolic compounds on tumor necrosis factor-α (TNF-α)-induced changes of adipokines and oxidative stress in 3T3-L1 adipocytes. The results showed that p-coumaric acid, quercetin, and resveratrol have greater inhibition (p < 0.05) of a TNF-α-induced increase in the production of interleukin-6 (IL-6) among 21 tested polyphenolic compounds. p-Coumaric acid, quercetin, and resveratrol demonstrated inhibitions of TNF-α-induced changes in levels of monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and intracellular reactive oxygen species (ROS) in 3T3-L1 adipocytes. Furthermore, p-coumaric acid, quercetin, and resveratrol increased levels (p < 0.05) of secreted adiponectin, superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and glutathione S-transferase (GST) in TNF-α-treated 3T3-L1 adipocytes. These results indicate that the inhibition of TNF-α-induced changes of adipokines and oxidative stress by some polyphenolic compounds might have further implications in preventing obesity-related pathologies.

Effects of Polyphenolic Compounds on Tumor Necrosis Factor-α (TNF-α)-Induced Changes of Adipokines and Oxidative Stress in 3T3-L1 Adipocytes

Orthosiphon aristatus (Blume) Miq., which can be used as a food ingredient, is grown throughout Southeast Asia and Australia. O. aristatus is frequently used for the treatment of renal inflammation, kidney stones and dysuria. The focus of the current work was to study the antioxidant and anti-inflammatory effects of methanol, ethanol and water extracts from O. aristatus (abbreviated as MEOA, EEOA and WEOA, respectively). The evaluation of antioxidant activity was determined by total phenolics, Trolox equivalent antioxidant capacity (TEAC), oxygen-radical absorbance capacity (ORAC) and cellular antioxidant activity (CAA) assays. These assays demonstrated a relatively high antioxidant activity for MEOA and EEOA. These results revealed that EEOA had the most prominent inhibitory effect on lipopolysaccharide (LPS)-stimulated nitric oxide (NO), prostaglandin E(2) (PGE(2)) and intracellular reactive oxygen species (ROS) production in RAW 264.7 cells. A high performance liquid chromatography profile indicated that MEOA and EEOA contained both ursolic acid and oleanolic acid. Moreover, ursolic acid significantly reduced NO production in LPS-stimulated RAW 264.7 cells. Both EEOA and ursolic acid inhibited LPS-stimulated protein and mRNA expression of both inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in these cells. These results demonstrate that EEOA and its bioactive compound, ursolic acid, suppress LPS-induced NO and PGE(2) production by inhibiting ROS generation, along with reducing expression of iNOS and COX-2 in RAW 264.7 cells.

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Antioxidant and Anti-Inflammatory Effects of Orthosiphon aristatus and Its Bioactive Compounds

Millettia reticulata Benth is cultivated in Asian countries. M. reticulata Benth has multiple biological functions and is one of the oldest tonic herbs in traditional Chinese medicine. It has been elevated to one of the most commonly used herbs in modern Chinese medicine. The aims of this work were to study the in vitro anticancer activity of flavonoid derivatives isolated from the stems of M. reticulata Benth. Six flavonoid derivatives including (-)-epicatechin (1), naringenin (2), 5,7,3',5'-tetrahydroxyflavanone (3), formononetin (4), isoliquiritigenin (5), and genistein (6) were isolated from the stems of M. reticulata Benth. The structures of 1-6 were determined by spectroscopic methods. The effects of flavonoid derivatives (1-6) on the viability of human cancer cells (including HepG2, SK-Hep-1, Huh7, PLC5, COLO 205, HT-29, and SW 872 cells) were investigated. The results indicated that genistein (6) had the strongest inhibitory activity with an IC(50) value of 16.23 microM in SK-Hep-1 human hepatocellular carcinoma cells. Treatment of SK-Hep-1 cells with genistein (6) caused loss of mitochondrial membrane potential. Western blot data revealed that genistein (6) stimulated an increase in the protein expression of Fas, FasL, and p53. Additionally, treatment with genistein (6) changed the ratio of expression levels of pro- and anti-apoptotic Bcl-2 family members and subsequently induced the activation of caspase-9 and caspase-3, which was followed by cleavage of poly(ADP-ribose) polymerase (PARP). These results demonstrate that genistein (6) induces apoptosis in SK-Hep-1 cells via both Fas- and mitochondria-mediated pathways.

Chin-Lin Hsu

Papers

Anti-inflammatory Effects of Phenolic Compounds Isolated from the Fruits of Artocarpus heterophyllus

Antiobesity and Hypolipidemic Effects of Polyphenol-Rich Longan (Dimocarpus longans Lour.) Flower Water Extract in Hypercaloric-Dietary Rats

Effects of Polyphenolic Compounds on Tumor Necrosis Factor-α (TNF-α)-Induced Changes of Adipokines and Oxidative Stress in 3T3-L1 Adipocytes

Antioxidant and Anti-Inflammatory Effects of Orthosiphon aristatus and Its Bioactive Compounds

Anticancer effects of flavonoid derivatives isolated from Millettia reticulata Benth in SK-Hep-1 human hepatocellular carcinoma cells.