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Flavonoids are a large class of naturally occurring compounds widely present in fruits, vegetables and beverages derived from plants. These molecules have been reported to possess a wide range of activities in the prevention of common diseases, including CHD, cancer, neurodegenerative diseases, gastrointestinal disorders and others. The effects appear to be related to the various biological/pharmacological activities of flavonoids. A large number of publications suggest immunomodulatory and anti-inflammatory properties of these compounds. However, almost all studies are in vitro studies with limited research on animal models and scarce data from human studies. The majority of in vitro research has been carried out with single flavonoids, generally aglycones, at rather supraphysiological concentrations. Few studies have investigated the anti-inflammatory effects of physiologically attainable flavonoid concentrations in healthy subjects, and more epidemiological studies and prospective randomised trials are still required. This review summarises evidence for the effects of fruit and tea flavonoids and their metabolites in inflammation and immunity. Mechanisms of effect are discussed, including those on enzyme function and regulation of gene and protein expression. Animal work is included, and evidence from epidemiological studies and human intervention trials is reviewed. Biological relevance and functional benefits of the reported effects, such as resistance to infection or exercise performance, are also discussed. Flavonoids are biologically active polyphenolic compounds ubiquitously found in fruits, vegetables, nuts and plant-derived beverages, such as tea or wine. The composition of flavonoids in different fruit species varies greatly. Quercetin, kaempferol, myricetin and isorhamnetin are common flavonols, with quercetin being the predominant one. A second flavonoid group in fruits is proanthocyanidins and their monomer units, catechins (procyanidin) or gallocatechins (prodelphinidins), which are the natural substrates of polyphenol oxidases and are, therefore, involved in the browning phenomenon of fruits. The main anthocyanins in fruits are glycosides of different anthocyanidins, mainly cyanidin, that are widespread and commonly contribute to the pigmentation of fruits. Citrus fruits differ in their flavonoid profiles from other fruit species, containing flavanones and flavones (hesperidin and naringenin) that are not common in other fruits (1) . The major polyphenolic constituents present in green tea are epicatechin, epigallocatechin, epicatechin-3-gallate and epigallocatechin-3-gallate. In addition to small amount of catechins, black tea contains thearubigins and theaflavins, which are the polymerised forms of catechin monomers and are the major components formed during enzymatic oxidation and the fermentation process (2) . Flavonoids have been reported to possess a wide range of activities in the prevention of common diseases, including CHD, cancer, neurodegenerative diseases, gastrointestinal disorders ...

We investigated whether quercetin protects from steatosis and limits the expression of proinflammatory and fibrogenic genes in C57BL/6J mice with nonalcoholic steatohepatitis (NASH) induced by feeding a methionine-choline-deficient (MCD) diet. Quercetin (50 mg/kg) was given by oral route daily. Mice were randomly divided into 4 groups that received for 2 or 4 wk: the control diet plus vehicle, control diet plus quercetin, MCD diet plus vehicle, and MCD diet plus quercetin. At both 2 and 4 wk, feeding the MCD diet resulted in liver steatosis, inflammatory cell accumulation, oxidative stress evaluated by the concentration of TBARS, and fibrosis evidenced by the staining of α-smooth muscle actin-positive cells in the liver. At both 2 and 4 wk, the MCD diet induced an increase in the mRNA levels of Il6, Tnf, Ptgs2, and Hmgb1 and increased the protein concentrations of Toll-like receptor-4, c-Jun terminal kinase, and p65 NFκB subunit compared with control rats. Feeding the mice the MCD diet also triggered an increase of Col1a1, Col3a1, Plod3, Tgfb1, Smad3, Smad7, Pdgfb, Ctgf, Areg, Mmp9, and Timp1 mRNA levels. These effects were totally or partially prevented by treatment with quercetin. The data obtained suggest that attenuation of multiple profibrotic and proinflammatory gene pathways contributes to the beneficial effects of quercetin in mice with MCD diet-induced steatohepatitis.

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Acute hepatic failure (AHF) is a severe liver injury accompanied by hepatic encephalopathy which causes multiorgan failure with an extremely high mortality rate, even if intensive care is provided. Management of severe AHF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the procedure is limited by shortage of donor organs. Although a number of clinical trials testing different liver assist devices are under way, these systems alone have no significant effect on patient survival and are only regarded as a useful approach to bridge patients with AHF to liver transplantation. As a result, reproducible experimental animal models resembling the clinical conditions are still needed. The three main approaches used to create an animal model for AHF are: surgical procedures, toxic liver injury and infective procedures. Most common models are based on surgical techniques (total/partial hepatectomy, complete/transient devascularization) or the use of hepatotoxic drugs (acetaminophen, galactosamine, thioacetamide, and others), and very few satisfactory viral models are available. We have recently developed a viral model of AHF by means of the inoculation of rabbits with the virus of rabbit hemorrhagic disease. This model displays biochemical and histological characteristics, and clinical features that resemble those in human AHF. In the present article an overview is given of the most widely used animal models of AHF, and their main advantages and disadvantages are reviewed.

Cardiac muscle tissue, when stimulated by acute exercise, presents increased signs of cell damage. This study was designed to investigate whether overexpression of inflammatory mediators induced in the heart by acute exercise could be prevented by melatonin and whether the protective effect of melatonin was related with inhibition of nuclear factor kappa B (NF-kappaB) activation. Male Wistar rats received melatonin i.p. at a dose of 1.0 mg/kg body weight 3 min before being exercised for 60 min on a treadmill at a speed of 25 m/min and a 10% slope. Exercise was associated with a significant increase in myeloperoxidase activity and in TNF-alpha, IL-1 and IL-6 mRNA levels. Both mRNA level and protein concentrations of intercellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 were also significantly elevated. A significant activation of nuclear factor kappa B (NF-kappaB) was observed in exercised rats. These effects were totally or partially prevented by melatonin administration. Data obtained indicate that melatonin protects against heart damage caused by acute exercise. Impaired production of noxious mediators involved in the inflammatory process and down-regulation of the NF-kappaB signal transduction pathway appear to contribute to the beneficial effects of melatonin.

Inhibition of the expression of proinflammatory mediators that are regulated by the NF-kappaB and STAT signaling pathways contribute to the therapeutical effect of glutamine in the TNBS model of experimental colitis. These effects may be brought about by inhibition of oxidative stress and reduced expression of proinflammatory cytokines.