Antiviral Effects

Lentinan showed marked antiviral activity and increased host resistance against various kinds of viral infections, such as adenovirus, vesicular stomatitis virus (VSV)-encephalitis virus, Abelson virus, human immunodeficiency virus (HIV), and influenza virus.

The effect of lentinan on influenza virus infection has also been determined and reported by Irinoda et al. (97) and Maeda et al. (93). A significant level of protection in NMRI mice was noticed, even at low dosage (50 |Ag) of lentinan when administrated intranasally or intravenously. In 2001, Yap and Ng (22) showed that the administration of lentinan to AKR mice interfered with the maturation process of the murine leukemia retrovirus (Fig. 2).

Nude mice

Lentinan

LuVo

SW48

SW620

SW480

SW403

SWI116

(TIR%)

85.84

87.3

88.38

88.69

89.94

91.43

SCII> mice

Lentinan

74.69

Test not

70.18

Test not

Test not

Test not

(TIR%)

done

done

done

done

Lentiiian-fed Buffer-fed

Lentiiian-fed Buffer-fed

Figure 4 The efficacy of "lentinan-activated" lymphocytes in nude and SCID mice. Lymphocytes from AKR mice that had been fed with lentinan for 7 days were extracted and inoculated into nude or SCID mice. After inoculation of the "lentinan-activated" lymphocytes, human colon carcinoma cells were also inoculated into these mice to induce tumors. Six different human colon carcinoma cell lines were used. LoVo and SW48 represent a well-differentiated stage with signet ring formation, SW620 and SW480 are moderately differentiated, and SW403 and SW1116 are poorly differentiated with little or no signet ring formation. The tumor from the buffer-fed mouse is rather large when compared to that of the mouse that is fed with lentinan. The summary table shows that ''lentinan-activated'' lymphocytes do have good efficacy against tumor formation in these immunodeficient mice.

Figure 4 The efficacy of "lentinan-activated" lymphocytes in nude and SCID mice. Lymphocytes from AKR mice that had been fed with lentinan for 7 days were extracted and inoculated into nude or SCID mice. After inoculation of the "lentinan-activated" lymphocytes, human colon carcinoma cells were also inoculated into these mice to induce tumors. Six different human colon carcinoma cell lines were used. LoVo and SW48 represent a well-differentiated stage with signet ring formation, SW620 and SW480 are moderately differentiated, and SW403 and SW1116 are poorly differentiated with little or no signet ring formation. The tumor from the buffer-fed mouse is rather large when compared to that of the mouse that is fed with lentinan. The summary table shows that ''lentinan-activated'' lymphocytes do have good efficacy against tumor formation in these immunodeficient mice.

The progeny virus particles found in the induced murine lymphoma cells were defective as observed using electron microscopy.

Many AIDS patients die of opportunistic infections due to immuno-dysfunction, and prevention of the development of symptoms by enhancing the immune system would be useful. Effects against HIV have been found in some of the carcinostatic h-D-glucans (lentinan and others) isolated from shiitake mushrooms (98-101). A tolerance study of lentinan in HIV patients has been carried out and showed that lentinan was well tolerated and produced increases in neutrophils and natural killer (NK) cells activity (35). Lentinan also produced a trend toward improvement in CD4 cells generation and a decline in p24 antigen levels.

Tochikura et al. (101) and Iizuka (102) reported that when used in combination with azidothymidine (AZT), lentinan suppressed the surface expression of HIV on T cells more efficiently than AZT alone. It enhanced the effects against viral replication in vitro. Lentinan therefore qualified as a participant in future multidrug studies in HIV (35).

Lentinan

Lentinan

Immune responses (defenses)

Programmed cell death - Apoptosis

Tumor cells and viruses

Tumor regression and disruption of virus replication

Figure 5 A proposed immunomodulation pathway of lentinan. Lentinan first comes in contact with macrophages, which in turn stimulate and activate the T cells, resulting in cytokine production. The immune response acts on the tumor cells causing apoptosis and regression of the tumor.

Lentinan has been used as an immune modulator in combination with didanosine (DDI) in a controlled study with HIV-positive patients. In vitro studies have indicated that anti-HIV effects of lentinan and DDI were additive. With promising results, it is reasonable to test the combined use of lentinan and DDI in HIV-infected individuals as well (35).

D. Antibacterial Effects

Lentinan's effectiveness against bacterial infections has been demonstrated using Mycobacterium tuberculosis as the test organism in IRC mice. A marked anti-infective activity was observed, and all mice completely survived when lentinan was injected intravenously once from 4 to 10 days before the infection (103). In mouse experiments, it has also been proven to be effective against relapse of tuberculosis infections (60). Peritoneal macrophages secretory activity of active oxygen was activated by lentinan and the cytokines produced enhanced the ability of polymophonuclear leukocytes to produce active oxygen with bactericidal effect (104).

E. Antiparasitic Activity of Lentinan

Lentinan was shown to be effective against parasitic infections caused by Schistosoma mansoni, S. japonicum, and Mesocestoides corti (93,105,106). The mechanism was concluded to be through cell-mediated immunity and was T-cell-dependent as the antiparasitic activities were not illustrated in nude mice.

VI. OTHER COMPONENTS OF LESSER INTEREST

Another active component, a-mannan peptide (KS-2), extracted from cultured mycelium of L. edodes was shown to be effective against sarcoma 180 and Ehrlich's carcinoma. Antitumor activity of KS-2 in mice has demonstrated a macrophage tumoricidal effect, though the actual mechanism of action of KS-2 is not clear (100).

A water-soluble, pale-brownish powder designated LEM was prepared from the culture medium of shiitake mushroom mycelia before the formation of fruit bodies. LEM is a glycoprotein containing glucose, galactose, xylose, arabinose, mannose, fructose, and various nucleic acid derivatives, vitamin B compounds, especially B1 (thiamine), B2 (riboflavin), and ergosterol (107). Two alcohol-insoluble fractions, LAP1 and LAP2, can be separated from LEM (108,109). LAP is a glycoprotein containing glucose, galactose, xylose, arabinose, mannose, and fructose (102). In turn, a heteroglycan fraction

(LAF1) can be prepared from LAP1 by DEAE-sepharose CL-6B column chromatography. Xylose is the major sugar in LAP or LAP1. The fraction LAF1 is composed mainly of xylose, arabinose, mannose, glucose, and galactose (111).

Both LEM and LAP components displayed strong antitumor activities (111,112). The growth of cancerous liver tumors was slowed in rats when LEM was given by injection (60). Administration of LEM (intraperitoneally) suppressed the cell proliferation of ascites hepatoma. The LEM fraction was also observed to activate the murine macrophage functions and promoted the proliferation of bone marrow cells in vitro. Cytotoxicity of NK cells was noted, and macrophages and T cells were also activated (112). LEM was found to inhibit the expression of cytopathic effects of herpes simplex virus, western equine enchepalitis virus, poliovirus, measles virus, mumps virus, and HIV (100,101,113).

The same effect was achieved when LAP was administered. The fraction LAP2 also suppressed cell proliferation of the ascites hepatoma, but the survival rate of hepatoma-bearing rats was not improved (108,109). Thus, the action of LAP1 was not cytocidal. Both LAP1 and LAF1 fractions might act as mitogens for mouse splenic macrophages and/or monocytes that are involved in cytokine induction (109,110). A protein fraction of L. edodes fruiting bodies known as fruiting body protein (FBP) is noted to prevent infection of plants with tobacco mosaic virus (TMV) (14).

The antiviral and immunopotentiating activities of the water-soluble, lignin-rich fraction of LEM, JLS-18, was proven. JLS-18 showed about 70 times higher antiviral activity than LEM in vitro. Release of herpes simple virus type 1 in animals is blocked by JLS-18 (9).

Studies have shown that L. edodes is also able to lower blood serum cholesterol (BSC) via a factor known as eritadenine (also called ''lentinacin'' or ''lentysine''). Eritadenine was isolated from 80% ethanol extraction of L. edodes mushroom fruiting bodies by absorption on an Amberlite IR-120 (H+) column, followed by elution with 4% NH4OH (21). Addition of eritadenine (0.005%) to the diet of rats caused a 25% decrease in total cholesterol in 1 week. Eritadenine apparently reduces serum cholesterol in mice by accelerating the excretion of ingested cholesterol and its metabolic decomposition (13,114).

VII. MYCOVIRUS

Mycovirus or virus-like particles have been found in various species of fungi and most possess double-stranded RNA (ds-RNA) (115-122). These myco-viruses are heritable viruses (25) and are unusual in that they do not lyse or cause any detrimental effects in their hosts (119). The spores are an effective means for serial transmission. Three morphologically groups (25, 30, and 39 nm in diameter) have been found in partially purified preparations from both fruit bodies and mycelia of L. edodes (122-126).

In 1979 and 1981, Takehara and co-workers (127,128) demonstrated that viruses isolated from L. edodes mushrooms (including their RNA) exhibited antiviral activities in cell culture studies. It was proposed that the efficacy was from its interferon-inductive effect. Certain ds-RNA of natural and synthetic origin has been found to inhibit the growth of various transplanted tumors or leukemia in animals (58,129,130).

Suzuki and co-workers (131) reported that ds-RNA fractions extracted from L. edodes are highly active as an interferon inducer. They also showed the inhibitory activity was against solid tumor but not against the ascites form of the tumor, which suggested the involvement of a host-mediated immunological response to the tumor. However, Takehara and co-workers (127) demonstrated antitumor activity against Ehrlich ascites carcinoma in mice.

Owing to the lack of detailed study on the medical significance of these mycovirus, Sudhir and Ng (132) and Subha and Ng (unpublished data) carried out several experiments on this component of the L. edodes mushrooms. Prefeeding of AKR mice with mycovirus-extract conferred the best antitumor activity with a tumor inhibition rate (TIR) of 80.7%. Simultaneous feeding and administration of extract on induced tumors were also effective with TIR of 73.8% and 67.6%, respectively. The tumor cells used to induce the tumor were K36 murine lymphoma cells. Tumor cells in the prefeeding regime also exhibited extensive apoptotic cell death, which could be the mechanism of destroying the tumor cells (132). In addition, elevated production of T-helper lymphocytes, IFN-g, and TNF-a was observed after oral administration of mycovirus extract.

The antiviral effect of the produced interferons appeared to interfere with the infectious retrovirus morphogenesis. The virus particles found in the mycovirus-fed tumor cells were mostly empty, i.e., without the virus genome. The defective progeny virus particles could explain the strong inhibition of tumor development in the prefed cohort.

Antiviral activity of the mycovirus was demonstrated with avian influenza virus in primary chick embryo cells. Cytopathic effects caused by the influenza virus were inhibited when the chick cells were pretreated with a suspension of the mycovirus before exposure to influenza virus (Subha and Ng, unplublished data). The mycovirus suspension was also tested against a range of bacteria (Bacillus subtilis, Corynebacterium diptheriae, Micrococcus luteus, Streptococcus pyogenes, Staphylococcus aureus, Enterobacter aero-genes, Escherichia coli, Klebsiella pneumoniae, Salmonella typhi, Vibrio para-chaemolyticus, Bacteroides fragilis, Clostridium perfringes, and Clostridium sporogenes). The mycovirus suspension was not effective in the inhibition of any bacterial growth.

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