Perilla frutescens

Perilla frutescens (PF) is an annual herbaceous plant belonging to the family of Lamiaceae, which has been used in traditional Asian medicine for millennia. Whereas its leaves are a popular garnish, food coloring and seasoning, its seeds are commonly used for the p odu tio of oil i h i α-linolenic acid [148]. In traditional Chinese medicine PF is often applied in the form of mixtures containing different herbs for the treatment of mental disorders such as depression and depression-associated diseases [149-151]. Various in vitro and animal studies indicate a variety of promising effects of PF, which range beyond the alleviation of mental disorders to the treatment of stomach and bowel discomfort, to the amelioration of cold and flu-like symptoms, to beneficial effects in terms of food or fish allergy or poisoning as well as to the administration as sedative [112, 152-156]. Although in vitro experimental results might not unconditionally be transferable to the impact of PF on human health in vivo, there are indications for diverse wholesome properties of PF and its constituents, which are ascribed to its antioxidant, allergic, antiviral and anti-inflammatory effects. PF exerts is antioxidant activity either by direct scavenging of ROS or via metal-chelating activity [112]. Moreover the expression of antioxidant enzymes was found to increase in macrophages [157], whereas ROS generation was decreased in stimulated human neutrophils after the application of PF extract [158, 159]. PF is also able to downregulate a variety of inflammatory markers, including the expression of proinflammatory TNF-α, IL-17A and IL-6 in vitro and in vivo [160-163] as well as the neutrophil-recruiting chemokine IL-8 and cyclooxygenase-2 [157, 162]. Amongst others the suppression of inflammatory processes has been observed by researchers with regard to airway and colon inflammation in mice [164-166]. Furthermore distinct anti-allergic properties of PF could be demonstrated in several in vivo rat or mice model studies, respectively [167-170]. Its application was found to cause the suppression of the Th2 immune response towards an allergen. Moreover the downregulation of allergy-associated cytokines and chemokines and the reduction of eosinophils and histamine release was reported after the administration of PF or the major PF compound rosmarinic acid (RA) in a murine model of allergic asthma [165, 168]. Consequently some studies attribute the anti-allergic activity of PF to high quantities of RA [167, 168]. However Asada et al. also suggested an isolated PF glycoprotein as active macromolecular compound against allergy-related

18 processes [171]. Besides PF anti-inflammatory and anti-allergic effects, suppression of human lung and colon cancer cell line [111, 112] as well as a human hepatoma cell line proliferation [110] and apoptosis-inducing genes was observed [110]. In rat or mice model studies as well as in in vitro cell culture experiments PF has furthermore been observed to possess beneficial effects on disorders affecting the kidneys [172-174] and on obesity and hyperlipidemia, thus potentially protecting against arteriosclerosis [175]. A high-fat diet animal model in combination with PF extract application caused less weight gain as well as lower triglyceride and less total cholesterol and LDL levels in the plasma. This finding was accompanied with the downregulation of related adipogenic genes [175, 176]. Kishi et al.

reported a lowered glucose level and a decelerated development of diabetes in vivo after the application of PF tea in rats [177]. Moreover PF compounds luteolin and RA have been demonstrated to be effective inhibitors of α-glucosidase and aldose reductase in vitro, both of which potential targets for the treatment of diabetes [178, 179]. Apart from the administration of total PF extracts, a plethora of studies focus on RA as the major active component in PF due to its potent antioxidant activity [180, 181], its carcinogenic, anti-allergic and anti-inflammatory effects. RA was observed to suppress the release of histamine from mast cells, neutrophilic infiltration in inflammation and the tumorgenesis of murine skin carcinogenesis [182-186]. Moreover suppression of mesangial cell proliferation in vitro was partly due to the presence of RA, which also caused the downregulation of cytokines and further genes involved in the development of various renal diseases [187]. Beyond that, RA was found to protect against liver injury, due to its antioxidant activity [188] and its ability to suppress proliferation genes in cells activated during liver injury [189]. However hepatic protection was found to be more pronounced by simultaneous administration of caffeic acid (CA), which resulted in the upregulation of de novo GSH synthesis and antioxidant enzymes [190]. CA was furthermore reported to enhance the activity of ɣ -glutamylcysteine synthetase [191], thus contributing to cellular protection mechanisms against ROS as well as to the detoxification of xenobiotics and adverse ROS reaction products. Protection against oxidative stress and inflammation in ethanol induced liver injury was also reported for perillyl alcohol, which downregulated proinflammatory cytokine TNF-α as well as restored alcohol related suppression of antioxidant enzyme and non-enzyme cellular defense systems [192]. Luteolin, a further PF compound, has been demonstrated to

19 possess anti-inflammatory, anti-allergic and antioxidant effects [193, 194] and was found to alleviate carcinogenesis of induced skin tumor in mice [118]. It also inhibited several proinflammatory cytokines including TNF-α and IL-6 [166] as well as allergic edema in vivo [193]. In addition PF compound apigenin exerted its effect on inflammation via the upregulation of anti-inflammatory cytokine IL-10 [166]. Since effects of PF have been observed in vitro and in vivo, it became a popular functional food within recent years.

However, further in vivo studies will be necessary to include intestinal absorption and metabolism and thus the generation of metabolic products into the equation.

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