Inflammatory Disorders

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The development of an inflammatory response is an important defensive mechanism. The inflammatory response is characterized by the movement of fluid, plasma proteins, cytokines, and other factors to the site of injury. However, this normal protective mechanism can cause problems if it is inadequate, uncontrolled, or inappropriate. Many chronic diseases, such as rheumatoid arthritis and systemic lupus erythematosus, involve chronic inflammation, and long-term anti-inflammatory treatment is required. These treatments, which include steroids, nonsteroidal anti-inflammatory drugs, and specific inhibitors of cycloxygenase, often bring their own problems (156,157).

G. lucidum reportedly has anti-inflammatory properties, but we have been unable to find any reports of clinical trials investigating this aspect of G. lucidum and its potential health benefits. A family of triterpenoids from the mushroom was reported to reduce inflammation induced by carageenan and croton oil, and a therapuetic role for G. lucidum has been suggested in arthritis and Alzheimer's disease (32). Streeper and Satsangi (156) studied the anti-inflammatory effect of both oral and topical treatment with water and ethyl acetate extracts of G. lucidum in a mouse model of croton-oil-induced irritation (to the ear). It was reported that orally administered ethyl acetate and water extracts of G. lucidum had significant activity that extended over a longer period of time than hydrocortisone, a commonly used antiinflammatory treatment. Topical application of the ethyl acetate extract also resulted in significant anti-inflammatory effect, comparing favorably with hydrocortisone. The water extract, on the other hand, had little or no topical effect. This group also reported that treatment with G. lucidum was not associated with thymic involution, a common side effect of corticosteroid treatment (156). In another animal study (158), both oral and topical adminstration of organic extracts of G. lucidum was reported to ameliorate chemical-induced irritation, as measured by effects on edema, weight, and volume of affected sites (ear and paw).

The anti-inflammatory components of G. lucidum in these organic extracts are believed to be the triterpenes (156). In the Handbook of Enzyme Inhibitors (159), the triterpenes, ganoderic acids R, S, and T, are referred to as having an inhibitory effect on the enzyme phospholipase A2 (PLA2) from pig pancreas. PLA2 catalyzes the rate-limiting step in the release of arachidonic acid, and mediates the inflammatory response. In addition, extracellular PLA2, such as that secreted into body fluids during inflammation, can directly attack cell membranes, inducing cell lysis and subsequent tissue damage (160).

Jain et al. (161) studied the anti-PLA2 activity of seven triterpenes isolated from G. lucidum. Three triterpenes, R, S, and T, were found to be active against enzymes from pig pancreas, but only ganoderic acid T was active also against the enzyme from bee venom and a human recombinant PLA2 from synovial fluid. No details are given of how the ganoderic acids were purified. Hot-water extracts of G. lucidum have also been found to induce marked inhibition of PLA2 from pig pancreas and bee venom (162). Giner-Larza et al. (158) also studied the PLA2 inhibitory effect of G. lucidum. Mice were given G. lucidum extract orally 90 min before being injected in the paw with snake venom PLA2 (from N. naja and N. mossambica). Edema of the affected paw was significantly decreased 60 min after treatment, when compared to controls. However, in an in vitro study using PLA2 from N. mossambica, no significant inhibitory effect of G. lucidum was seen (158). The reason for this conflict in PLA2 inhibition by G. lucidum is not clear. Analytical methods for testing PLA2 inhibition are varied and can be problematic (161). However, it is possible that the inhibitory components of G. lucidum are active against only certain types of PLA2; this deserves further study.

G. Allergy

Diagnosis of allergy is often based on identification of environmental allergens by skin tests and in vitro tests of allergen-specific IgE (157). G. lucidum is believed to help alleviate allergies (12). Triterpenes isolated from G. lucidum were shown to have an inhibitory action on histamine release from rat mast cells ex vivo; however, the methods and results in this study were poorly described (77). There are no published reports of an allergic response to ingestion of G. lucidum, but it should be noted that some basidiomycetes may be potential aeroallergens. Sensitization to G. lucidum has been reported in patients with from asthma and rhinitis (163-165), as positive skin prick and intradermal skin tests to both spores and the fruit body extract were reported in some patients (>16%), as well as elevated antibodies to the fungi and proteins separated from it. Inhalation of G. lucidum spores may stimulate a base level of allergic responsiveness in susceptible atopic patients. G. lucidum may, therefore, induce respiratory and skin allergy, and this clearly must be considered in any potential topical application of G. lucidum.

H. Antioxidant

Observations imply that reactive oxygen species may damage DNA, proteins, and lipids in vivo, thereby promoting development of various diseases, including cancer and CVD. Reactive oxygen species (ROS) are a partially reduced form of oxygen, and include the superoxide anion, hydrogen peroxide, and the highly reactive hydroxyl radical. These, and other ROS, are produced in various ways, such as during the course of normal aerobic metabolism, from activated phagocytes, during postischemic reperfusion, and from cigarette smoke, ionizing and ultraviolet (UV) radiation, drugs, and toxins (166-168). Oxidative damage to key biological sites is, therefore, a continuous and unavoidable physiological threat. An array of physiological antioxidants exists within the body to prevent production, inactivation, and removal of ROS, thus limiting oxidative damage. These antioxidants are of both endogenous and dietary origin. Plants contain many antioxidants, and diets rich in plant-based foods are known to be associated with improved health (166-168). While the precise components and mechanism of benefit of ''healthy'' diets remain to be established, it is hypothesized that antioxidants play a key role.

The antioxidant properties of G. lucidum have been examined in different models. Using a supercoiled bacterial DNA model, hot-water extract, water-soluble polysaccharides, and an isolated amino-polysaccharide (G009) from G. lucidum were reported to show good radioprotective ability, and conferred DNA protection against hydroxyl radical produced by metal-catalyzed Fenton reaction, UV irradiation, and photolysis of hydrogen peroxide (169). There were two suggested mechanisms by which the poly-saccharides exerted their protective effect, metal ion binding (which prevents the Fenton reaction) and hydroxyl radical scavenging (169,170). Using a human DNA model (Raji cells) the hot-water extract (but not a cold-water extract) of G. lucidum was also found to markedly protect DNA from damage induced by hydrogen peroxide (171). However, it must be noted that the concentration of G. lucidum extract used in these antioxidant studies was very high, starting from 0.5 mg/mL (169-171), and it is not currently clear whether this concentration could be achieved in vivo.

The antioxidant activity of G. lucidum has also been examined in other models. The terpene and polysaccharide fractions were separated from a hot-water extract, and were screened for their antioxidative effect against pyro-gallol-induced erythrocyte membrane oxidation using rat red blood cells (172). All three types (the hot-water extract and the isolated terpene and polysaccharide fractions) of extracts protected, but the polysaccharide and terpene fractions were effective at 0.1 mg/mL and above, whereas the hot-water extract was effective only at >0.25 mg/mL. The effect on lipid peroxidation was also assessed by Zhu et al. (172). Rat liver mitochondria were exposed to ferrous sulfate and ascorbic acid, which produces hydroxyl radicals, and the extent of lipid peroxidation was assessed using the thio-barbituric acid reactive substances (TBARS) reaction. TBARS levels were decreased by the addition of the G. lucidum extracts. The terpene fraction was the most effective, and at a concentration of 0.1 mg/mL almost all lipid peroxidation was prevented (172). A similar protocol was applied by Lee et al. (170), who used rat brain homogenate to test the amino polysaccharide (G009) fraction of G. lucidum at concentrations of 0.25-2.0 mg/mL. This inhibited formation of TBARS in a dose-dependent manner. Whether this was related to iron binding by the polysaccharide was not tested. In a separate experiment, the G009 polysaccharide was found to have hydroxyl-radical-scavenging effect when the hydroxylated products of hydroxyl radical trapped by salicylic acid were measured (170). This group also reported superoxide scavenging effects using two different systems of superoxide generation, a xanthine-xanthine oxidase system and a HL-60 cell culture model. In the xanthine-xanthine oxidase model, G009 mitigated superoxide-related oxidation of a chromophore in a dose-related manner. In the cell culture model, oxidation was inhibited by about 60% by 2.0 mg/mL of G. lucidum (170). Whether this was due to scavenging or inhibition of superoxide generation by the cells was not clear.

Using the ferric-reducing (antioxidant) power (FRAP) assay (173), we have found that hot-water extracts of G. lucidum show some antioxidant power, but this is not particularly high. Ascorbic acid (1 g), green tea (1 g), and G. lucidum (1 g) are estimated to contain 11,364 Amol, 272-1144 Amol, and

360 Amol of antioxidant power, respectively (174,175 and our unpublished data). However, we have found that there is a significant increase in plasma antioxidant capacity shortly after an oral dose of G. lucidum, indicating that some antioxidants in G. lucidum are bioavailable (Fig. 3) (175). Furthermore, using flow cytometric analysis of site-specific oxidation of membrane lipids in living cells ex vivo, we have found that membrane oxidation is inhibited by preincubation of cells with hot-water extracts of G. lucidum (Fig. 4) (our unpublished results).

From these, and other, data it is clear that G. lucidum has antioxidant properties, and that both polysaccharide and triterpene constituents contribute to these. However, it is not yet known which antioxidants are absorbed, nor is it clear whether absorbed antioxidants from G. lucidum have any in vivo protective effects and health benefits; further study is needed in this area.

I. Liver Injury

Hot-water and water-ether extracts of the fruit body of G. lucidum were found to have a potent hepatoprotective effect against carbon tetrachloride (CCl4)-induced liver injury in rats when given orally and intraperitoneally (176,177). The measured markers for liver injury included asaparate and alanine trans-

Figure 3 Mean + SEM change in plasma total antioxidant power (as the FRAP value) at 90 min postingestion of placebo (vertical lines), 1.1 g of G. lucidum extract (horizontal lines), and 3.3 g of G. lucidum extract (diagonal lines) in a human intervention trial (n = 10). A significant (*p < 0.05) increase in plasma FRAP was seen after the G. lucidum administration compared with the placebo intake, indicating an absorption of antioxidant compounds into plasma.

Figure 3 Mean + SEM change in plasma total antioxidant power (as the FRAP value) at 90 min postingestion of placebo (vertical lines), 1.1 g of G. lucidum extract (horizontal lines), and 3.3 g of G. lucidum extract (diagonal lines) in a human intervention trial (n = 10). A significant (*p < 0.05) increase in plasma FRAP was seen after the G. lucidum administration compared with the placebo intake, indicating an absorption of antioxidant compounds into plasma.

Time (min)

Time (min)

Figure 4 Effect of preincubation with Lingzhi (G. lucidum) on peroxidation within cell membranes. Each point represents the mean of three separate experiments, with 1 SD error bars shown (o = phosphate-buffered saline control; * = Lingzhi, 1.5% w/v). Preincubation with Lingzhi protected membranes, as seen by less quenching of membrane-bound fluorophore.

aminases (AST and ALT) and lactate dehydrogenase (LDH). One active compound of the extract was separated and identified as ganoderenic acid A. This was found to have potent inhibitory effect on h-glucuronidase, and the authors suggested that this inhibitory effect may have mediated the hepato-protection seen when this isolated compound was given (177). Protection was also reported in a study in which a hot-water extract of G. lucidum was given orally to mice 30 min before administration of ethanol. The extract was found to show an inhibitory effect against malodialdehyde (MDA) formation, which is a degradation product of lipid peroxides, in mouse liver and renal homogenate, with evidence of a dose-response seen (178).

Hepatoprotection may also be mediated by radical-scavenging properties of G. lucidum. It has been hypothesized that CCl4 and alcohol toxicity is associated with increased oxidative stress and free-radical-associated injury. Lin et al. (176) reported that hot-water extracts of G. lucidum showed significant radical-scavenging activity against both superoxide and hydroxyl radicals; however, the extracts were not further characterized. Interestingly, in a similar animal study of CCl4-induced liver damage (142), oral administration of the medium in which G. lucidum mycelia were grown (but not the mycelium alone) had marked benefical effects, as assessed by lower 96 hr postinjury serum AST and ALT activities. No decrease was seen in the actual damage caused, as 24-hr transaminase activites were not different from levels in control animals, implying that the mycelium-medium may have promoted recovery in some way. The release of a hepatoprotective component from G. lucidum mycelium was also reported by Song et al. (179). In this study, an extracellular peptidoglycan (a polysaccharide/amino acid complex named WK-003) produced during mycelium fermentation was administered orally to rats for 4 days prior to CCl4 intoxication. Serum ALT levels were significantly reduced (by 70%; p < 0.01) at 24 hr postinjury compared with untreated, intoxicated rats. The AST levels decreased by 27%; however, this was not statistically significant. These studies of a possible mycelial product with hepatoprotective activity being extruded into the culture medium are of interest because the mycelia of G. lucidum are much easier and less costly to cultivate than the fruit body.

Polysaccharides extracted from G. lucidum were found by Park et al. (180) to have antifibrotic properties and to ameliorate cirrhosis induced by biliary ligation. The polysaccharides were given orally for 28 days postliga-tion, and this was found to lower collagen (hydroxyproline) content in rats liver and improved the liver morphology in comparison to control animals. The polysaccharide treatment also significantly decreased the ligation-in-duced increases in serum biochemical markers of liver damage (AST, ALT, alkaline phosphatase, and total bilirubin). These data suggest that polysac-charides from G. lucidum could be a promising antifibrotic therapy; however, no mechanisms of this putative hepatoprotective action were described, and further study is needed (180).

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