- What Are Flavonoids?
- The flavonoid family
- Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease.
- Flavonoids, Inflammation And Cancer
Tissue injury by reactive oxygen species and the protective effects of flavonoids. Fundam Clin Pharmacol. Role of oxygen-derived free-radicals and metabolites in leukocyte-dependent inflammatory reactions. Am J Pathol. How flavonoids inhibit the generation of luminal-dependent chemiluminescence by activated human neutrophils. Chem Biol Interact. Effects of flavonoid on the release of reactive oxygen species by stimulated human neutrophils.
Multivariate analysis of structure activity relationships SAR. Biochem Pharmacol. Inhibitory activity of flavonoids from Prunus davidiana and other flavonoids on total ROS and hydroxyl radical generation. Arch Pharm Res. Antioxidant and chelating properties of flavonoids. Adv Pharmacol. Peroxynitrite scavenging by flavonoids. Biochem Biophys Res Commun. Inhibitory effect of isoflavones on peroxynitrite-mediated low density lipoprotein oxidation.
Biosci Biotechnol Biochem. The correlation between active oxygen scavenging and antioxidative effects of flavonoids. Free Radic Biol Med. Keery NL, Abbey M. Red wine and fractionated phenolic compounds prepared from red wine inhibit low density lipoprotein oxidation in vitro. Influence of the antioxidant quercetin in vivo on the level of nitric oxide determined by electron paramagnetic resonance in rat brain during global ischemia and reperfusion. Flavonoids as scavengers of nitric oxide radical. Inhibition of reactive nitrogen species effects in vitro and in vivo isoflavones and soy-based food extracts.
Sarkar A, Bhaduri A. Black tea is a powerful chemopreventor of reactive oxygen and nitrogen species: comparison with its individual constituents and green tea. Inhibition of inducible nitric oxide synthase gene expression and enzyme activity by epigallocatechin gallate, a natural product from green tea. Effects of purified green and black tea polyphenols on cyclooxygenase and lipoxygenase-dependent metabolism of arachidonic acid in human colon mucosa and colon tumor tissues. Protection against ultraviolet B radiation induced effects in the skin of SKH-1 hairless mice by a polyphenolic fraction isolated from green tea.
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- Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease;
Inhibition of mammalian 5-lipoxygenase and cyclooxygenase by flavonoids and phenolic dietary additives. Relationship to antioxidant activity to iron-reducing ability. Inhibition of xanthine oxidase by flavonoids. Jolly CA. Diet manipulation and prevention of aging, cancer and autoimmune disease. Combination of physical activity, nutrition, or other metabolic factors and vaccine response. Front Biosci. Dietary modulation of immune function by beta-glucans. Physiol Behav.
The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease and cancer. Pharmacol Rev. Rudd CE. Immunol Today. Protein tyrosine phosphorylation in T cell signaling. Protein tyrosine phosphorylation is induced in murine B lymphocytes in response to stimulation with anti-immunoglobulin. EMBO J. Protein tyrosine kinase activation is required for lipopolysaccharide induction of cytokines in human blood monocytes. J Immunol.
What Are Flavonoids?
Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem. Differential inhibition of T cell receptor signal transduction and early activation events by selective inhibitor of protein-tyrosine kinase. J Immunol ; Involvement of protein kinase C and protein tyrosine kinase in lipopolysaccharide-induced TNF-alpha and IL-1 beta production by human monocytes. Genistein, a selective protein tyrosine kinase inhibitor, inhibits interleukin-2 and leukotriene B4 production from human mononuclear cells.
Clin Immunol Immunopathol. Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure-activity relationship. Inhibitory effects of natural flavonoids on secretion from mast cells and neutrophils. Inhibition by quercetin of activation of polymorphonuclear leukocyte functions.
Stimulus-specific effects. Biochim Biophys Acta. Elastase release by stimulet neutrophils inhibited by flavonoids: importance of the catechol group. Z Naturforsch ; Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation. Exp Toxicol Pathol. Influence of anti-inflammatory flavonoids on degranulation and arachidonic acid release in rat neutrophils.
Z Naturforsch [C]. Inactivation of phospholipase A 2 by naturally ocurring biflavonoid, ochnaflavone. Morelloflavone, a novel biflavonoid inhibitor of human secretory phospholipase a 2 with anti-inflammatory activity. Effects of naturally prenylated flavonoids on enzymes metabolizing arachidonic acid: cyclooxygenases and lipoxygenases. Assay of inducible form of nitric oxide synthase activity: effect of flavonoids and plant extracts.
Methods Enzymol. Effects of prenilated flavonoids and biflavonoids on lipopolysaccharide-induced nitric oxide production from the mouse macrophage cell line RAW Planta Med ; — Effect of quercitin on human polymorphonuclear leukocyte lysosomal enzyme release and phospholipid metabolism. Life Sci. Lanni C, Becker EL. Inhibition of neutrophil phospholipase A2 by p -bromophenylacyl bromide, nordihydroguaiaretic acid, 5,8,11,eicosatetrayenoic acid and quercetin.
Inst Archs Allergy Appl Immunol. Lindahl M, Tagesson C. Selective inhibition of group II phospholipase A 2 by quercetin. Anti-inflammatory and side effects of cyclooxygenase inhibitors. Pharmacol Rep. Eicosanoids in inflammation: biosynthesis, pharmacology, and therapeutic frontiers. Curr Top Med Chem. Kuhn H. Biologic relevance of lipoxygenase isoforms in atherogenesis. Expert Rev Cardiovasc Ther. Flavonoids and related compounds as inhibitors of arachidonic acid peroxidation. Modification of platelet function and arachidonic acid metabolism by biflavonoids.
Structure—activity relations. Wakabayashi I, Yasui K. Wogonin inhibits inducible prostaglandin E 2 production in macrophages. Eur J Pharmacol.
Effect of wogonin, a plant flavone from Scutellaria radix , on the suppression of cyclooxigenase-2 and the induction of inducible nitric oxide synthase in lipopolysaccharide-treated RAW Biochem Pharmacol ; — Pharmacological effects of methanolic extract from root of Scutellaria baicalensis and its flavonoids on human gingival fibroblasts. Planta Med. Inhibition of lipoxygenase by soy isoflavones: Evidence of isoflavones as redox inhibitors. Arch Biochem Biophys. Modulation of arachidonic acid metabolism by curcumin and related beta-diketone derivates: effects on cytosolic phospholipase A 2 , cyclooxygenases and 5-lipoxygenase.
Nitric oxide: physiology, pathophysiology, and pharmacology. Suppression of inducible cyclooxygenase and inducible nitric oxide synthase by apigenin and related flavonoids in mouse macrophages. Inhibition of nitric oxide synthase expression by a methanolic extract of Crescencia alata and its derived flavonols. Effects of naturally occurring flavonoids on nitric oxide production in the macrophage cell line RAW Biochem Pharmacol ; Inhibition of inducible nitric oxide synthase and cyclooxygenase-2 expression by flavonoids in macrophage JA.
Life Sci ; — Suppression of effect of soy isoflavones on nitric oxide production in RAW Inhibition of nitric oxide synthase inhibitors and lipopolysaccharide induced inducible NOS and cyclooxygenase-2 gene expression by rutin, quercetin, and quercetin pentaacetate in RAW J Cell Biochem. Isoflavones regulate interleukin-6 and osteoprotegerin synthesis during osteoblast cell differentiation via an estrogen-receptor-dependent pathway. Regulation of interleukin-6 production in a human gastric epithelial cell line MKN Luteolin inhibits an endotoxin-stimulated phosphorylation cascade and proinflammatory cytokine production in macrophages.
J Pharmacol Exp Therap. Inhibitor of tumor necrosis factor-alpha production in lipopolysaccharide-stimulated RAW J Ethnopharmacol. Quercetin suppresses proinflammatory cytokines production through MAP kinases and NF-kappaB pathway in lipopolysaccharide-stimulated macrophage. Mol Cell Biochem. Protective effect of wogonin on endotoxin-induced lethal shock in d -galactosamine-sensitized mice. Microbiol Immunol. Polyphenols, intracellular signalling and inflammation. Ann Ist Super Sanita. Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: structure—activity relationship.
Jpn J Cancer Res. Genistein reduces the production of proinflammatory molecules in human chondrocytes. J Nutr Biochem ; — Luteolin suppresses inflammation-associated gene expression by blocking NF-kappaB and AP-1 activation pathway in mouse alveolar macrophages. Anti-inflammatory effects of flavonoids: genistein, kaempferol, quercetin, and daidzein inhibit STAT-1 and NF-kappaB activations, whereas flavone, isorhamnetin, naringenin, and pelargonidin inhibit only NF-kappaB activation along with their inhibitory effect on iNOS expression and NO production in activated macrophages.
Mediat Inflamm ; Su B, Karin M. Mitogen-activated protein kinase cascades and regulation of gene expression. Curr Opin Immunol.
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MAP kinases in the immune response. Annu Rev Immunol. Herlaar E, Brown Z. MAPK signaling cascades in inflammatory disease. Mol Med Today. Ono K, Han J. The p38 signal transduction pathway: activation and function. Cell Signal. Inhibitors of mitogen-activated protein kinases downregulate COX-2 expression in human chondrocytes.
Mediat Inflamm. Extracellular signal-related kinase ERK and p38 mitogen-activated protein MAP kinases differentially regulate the lipopolysaccharide-mediated induction of inducible nitric oxide synthase and IL in macrophages: Leishmania phosphoglycans subvert macrophage IL production by targeting ERK MAP kinase. J Immunol ; — Inhibition of LPS-stimulated pathways in macrophages by the flavonoid luteolin. J Leuk Biol. The role of p38 mitogen-activated protein kinase in IL-1 beta transcription. Both Erk and p38 kinases are necessary for cytokine gene transcription.
Pereira SG, Oakley F. Nuclear factor-kappaB1: regulation and function. Int J Biochem Cell Biol. Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med. Anti-inflammatory activity of herbal medicines: inhibition of nitric oxide production and tumor necrosis factor-alpha secretion in an activated macrophage-like cell line. Am J Chin Med. Luteolin reduces lipopolysaccharide-induced lethal toxicity and expression of proinflammatory molecules in mice.
Kim JS, Jobin C. The flavonoid luteolin prevents lipopolysaccharide-induced NK-kappaB signaling and gene expression by blocking I-kappaB kinase activity in intestinal epithelial cells and bone-marrow derived dendritic cells. Hanahan D, Weinberg RA. The hallmarks of cancer. Coussens LM, Werb Z. Inflammation and cancer. Shacter E, Weitzman SA.
The flavonoid family
Chronic inflammation and cancer. Inflammation, atrophy and gastric cancer. Inflammation and cancer: when NF-kappaB amalgamates the perilous partnership. Curr Cancer Drug Targets. YC Xiao H. Int J Cancer. Smoldering and polarized inflammation in the initiation and promotion of malignant disease. Cancer cell. The inflammatory tumor microenvironment and its impact on cancer development. Contrib Microbiol. Rivoli E, Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk.
Current epidemiologic studies to date have suggested that dietary factors play a crucial role in the development of colon cancer [ 4 , 5 ], and high fruit and vegetable was generally implicated in the prevention of colorectal cancer [ 6 — 8 ]. A possible protective role of flavonoids against colorectal cancer has been of enormous interest recently [ 9 — 13 ]. Flavonoids are a diverse group of polyphenolic compounds widely available in plant-based foods, such as fruits, vegetables, herbs, tea, and juices [ 14 ].
According to their chemical structure, flavonoids can be classified as flavones, flavonols, flavanones, flavanols flavanols , anthocyanins, isoflavoness [ 15 ]. Besides, proanthocyanidins are another important subclass of polyphenols [ 16 ]. In recent decades, accumulating studies have been conducted to investigate the relationship between diet flavonoids and colorectal cancer incidence.
However, existing data is still conflicting. For example, several studies indicated that flavonoids were inversely associated with colon cancer risk [ 12 , 13 , 17 — 21 ], however, other prospective cohort studies generally failed to detect such relationship [ 9 , 10 , 22 , 23 ]. Because of differences in study design and type of flavonoids, various studies yielded inconsistent results.
Nevertheless, Experimental studies provide evidence for potential mechanisms that relate flavonoids to cancer risk. For example, flavonoids could inhibit growth of colon cancer cell lines and colorectal carcinogenesis in animal models [ 25 , 26 ]. Different subclasses of flavonoids may have varying capacities to suppress neoplasm. There are several anti-carcinogenic mechanisms of flavonoids, including antioxidative and anti-inflammatory activities [ 27 ], induction of apoptosis and suppression of angiogenesis [ 28 , 29 ].
To better understand this association, we performed a meta-analysis of available studies to comprehensively evaluate dietary flavonoids intake as well as flavonoid specific subclasses in relation to colorectal cancer risk. Total 1, studies were identified through the literature searches. After review of the titles and abstracts, 1, studies were excluded and remaining 38 studies were reviewed with the full texts.
Thus 18 studies were finally included in final meta-analysis. Figure 1. Figure 1: Flow diagram summarizing study identification and selection. The characteristics of selected studies were outlined in Table 1. We identified five studies on total flavonoids intake and CRC risk and 16 studies that assessed subclasses of flavonoid consumption in relation to CRC incidence. These studies involved , participants with 16, CRC cases. Nine of them were prospective cohort studies and remaining were case-control studies. Food frequency questionnaires FFQs were used to assess exposure to certain dietary flavonoids in all but three studies [ 10 , 18 , 30 ], which adopted interview, food records, and diet diaries.
The diagnosis of colorectal cancer was based on histologic findings or data from cancer registry. Table 1A: Characteristics of included case-control studies on dietary flavonoids and risk of colorectal cancer.
Flavonoids as anti-inflammatory agents: implications in cancer and cardiovascular disease.
Table 1B: Characteristics of included cohort studies on dietary flavonoids and risk of colorectal cancer. The overall methodological quality of studies was summarized in Table 2. Using the Newcastle—Ottawa scale NOS quality tool, the score of all the studies ranged from 6 to 9, indicating moderate to high quality. Table 2A: Newcastle-Ottawa scale for assessment of quality of in included Cohort studies. Each asterisk represents if individual criterion within the subsection were fulfilled.
Table 2B: Newcastle-ottawa scale for assessment of quality of in included case-control studies. Five studies investigated the association of total flavonoids with incidence of colorectal cancer. The correlation between high vs low intake of flavones and CRC risk were presented in five studies. The summary analysis yielded a combined risk estimate of 0. There was no publication bias in analysis. We further conducted subgroup analyses by study design, sex and tumour location Table 3.
A significant association was found only for flavones intake and rectal cancer risk. However, no reduced risk of colorectal cancer was observed in the subgroup analyses by sex and design. Table 3: Stratified analyses of flavonoid subclasses and colorectal cancer risk. The correlation between high vs low intake of flavonols and CRC risk were presented in six studies. The summary risk estimate was 0. In subgroup analyses, the reduced risk of colorectal cancer was observed in pooled estimates of case-control studies, but not for cohort studies.
There was no other significant association detected. The correlation between high vs low intake of flavanones and CRC risk were presented in six studies. The summary risk estimate was 1. No publication bias was detected in the analysis. There were no significant associations found in subgroup analyses. The correlation between high vs low intake of flavanols and CRC risk were presented in seven studies. In subgroup analyses, the association was significant in case-control studies, but not in cohort studies.
The correlation between high vs low intake of anthocyanins and CRC risk were presented in four studies. There was no publication bias in the analysis.
The subgroup analysis by design produced a significant summary risk estimate for case-control studies, but not for cohort. Furthermore, reduced risk of CRC was observed in male, but not for female. The correlation between high vs low intake of isoflavones and CRC risk were presented in eleven studies.
The result should be interpreted with caution, since significant heterogeneity existed among included studies. We conducted stratified analyses of eleven studies between isoflavones and colorectal cancer risk to determine the impact of differences in study design, gender, and site of tumour. No significant association was detected in either analyses. The correlation between high vs low intake of procyanidins and CRC risk were presented in four studies.
There was no evidence of publication bias in analysis. The reduced risk of CRC was not only observed in male and female, but also in colon and rectum. Since studies included in this meta-analysis were all case-control, this protective association should be interpreted with caution. In the present study, five epidemiologic studies that assessed the association between total flavonoids consumption and colorectal cancer risk in humans.
Other studies evaluated the relationship between several subclasses of flavonoid and CRC risk. To our knowledge, this is the most comprehensive meta-analysis and evidence from our study indicated that total flavonoids intake were not significantly associated with reduced CRC risk. The lack of association is likely explained by the fact that limited numbers of included studies, which leaded limited power to detect an association. Furthermore, we assess potential relationships between flavonoid subclasses and CRC risk, respectively. Isoflavones and procyanidins, but not other subclasses, were inversely associated with the reduced CRC incidence.
Thus, these findings partially supported flavonoid subclasses might be considered as promising candidates for potential chemopreventive agents, such as aspirin, metformin, vitamin D [ 31 — 35 ]. Flavonoids, as a diverse group of polyphenol, are considered as a potential anti-carcinogenic agent. Although our analyses provided some evidence of an inverse association between specific subclasses and CRC incidence, several experimental studies, both in vitro and in vivo , supported its protective role against CRC.
Flavonoids have varying capacities to inhibit the development of colorectal cancer, for example, acting as antioxidants [ 27 , 36 , 37 ], anti-inflammatory agents [ 27 , 38 ], anti-proliferative agents [ 39 ]. In addition, flavones induced effectively apoptosis through down-regulation of cyclooxygenase-2 COX-2 , nuclear transcription factor kappaB [ 42 , 43 ]. However, effects of flavonoids among humans cannot be easily extrapolated from basic research. Since concentrations of flavonoids used in experimental studies were hardly reached through dietary intake, the evidence is less conclusive [ 39 ].
Therefore, whether flavonoids intake protect against colorectal cancer still needs further confirmation from epidemiologic studies and randomized clinical trials. Our meta-analyses showed that higher consumption of isoflavones and procyanidins might be associated with lower risk of colorectal cancer.
Isoflavones, a bioactive component rich in soy food, might have potential capacity in inhibition of cancer [ 45 ]. Our combined analysis also partially supported this hypothesise. Isoflavones, also known as phytoestrogens, might exerted anti-carcinogenic effects through hormonal and non-hormonal pathways [ 46 , 47 ]. Several epidemiological studies had reported a reduced risk for CRC among high isoflavones intake [ 11 , 12 , 18 , 21 , 48 ].
The protective association was more prominent among post-menopausal women than pre-menopausal women. However, our stratified analyses were unable to detect this significant association and this may relate to limited number of included studies. Procyanidins, also known as condensed tannins, occur ubiquitously in plants.
They can exert a wide variety of beneficial biological effects, such as antioxidant anti-inflammatory and anti-cancer [ 49 ]. Furthermore, this protective association was still consistent among subgroup analyses. It is important to note several limitations of our analysis. Firstly, most results included in our analyses were case-control studies. Although the methodological quality of these observational studies was medium to high, case-control studies were prone to introduce recall bias.
More prospective cohort studies need to test this association. Secondly, it was a challenge to evaluate the quantity of flavonoids intake accurately. Since the FFQ included limited flavonoid-rich food items and intake ranges, the specifically designed FFQ for flavonoids intake should be developed. In addition, flavonoid contents in food may vary depending on other factors, such as species, season and ripeness. These factors may introduce additional measurement error and therefore misestimate the relationship between flavonoids intake and cancer risk.
Thirdly, bioactive compounds in food are complex and highly correlated. It is hard to completely tease apart their interaction and rule out the possibility that potential unknown components in food may co-associate with flavonoids. Further intervention studies may be required to elucidate whether the main protective effects are actually due to these flavonoids.
In conclusion, our analyses supported that several subclasses of flavonoid, procyanidins and isoflavones, may potentially protect against colorectal cancer.
Flavonoids, Inflammation And Cancer
Well-designed cohort studies are needed to further investigate the effects of exposure to dietary flavonoids and subclasses. In addition, we scanned and examined the reference lists in relevant articles manually. In addition, case reports, editorials, reviews, animal studies or in-vitro researches were excluded. Besides, studies lacking relevant data also were excluded. When data from several publications were overlapping, we selected the publication with the most comprehensive data for inclusion in the meta-analysis.