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In addition to two major biological significance of D-fraction, immunomodulatory and antitumor/anticancer activities, antiviral activity could be another significant potential of D- fraction. Unlike bacterial infections, no antibiotics would work for viral infections, so that effective drugs/agents need to be found or developed, although a few antiviral drugs are currently available. Hence, potential antiviral activity of D-fraction may have clinical implications in several serious viral infections such as HIV/AIDS, hepatitis B, influenza and so forth.

AIDS with HIV is one the major epidemic viral infections and will require no further description. As a great number of AIDS research projects are underway worldwide, we are obtaining a better understanding and finding an improved therapeutic approach for this deadly infection. Incidentally, D-fraction is considered a potential anti-HIV agent for controlling or treating HIV infection. In 1992, the report on an in vitro anti-HIV screening test for D- fraction conducted by the NCI showed that D-fraction was highly effective against HIV,

preventing the HIV-mediated destruction of Th (CD4+) cells up to 97% [10]. Additionally, D- fraction was found to be as effective or powerful as azidothymidine (AZT), which is a common AIDS drug but with certain side effects. These findings are significant because evaluating CD4+ cells in AIDS patients is considered a benchmark in monitoring the progression of HIV. Following this report, one study of D-fraction on AIDS patients [70] showed that oral administration of D-fraction led to an increase in CD4+ cell counts to 1.4-1.8 folds and the improvements in other clinical parameters in AIDS patients. These good outcomes are believed to result from anti-HIV activity of D-fraction with direct inhibition of HIV replication and stimulation of the body‘s defense system against HIV [70]. Overall, ~85% of all patients treated with D-fraction were reported to have an increased sense of well- being regarding various symptoms and secondary diseases caused by HIV. Thus, it is conceivable that D-fraction could be a promising agent, encouraging its further trials on patients with HIV/AIDS.

Hepatitis can be caused by several different viruses. Among them, nearly 300 million people worldwide are estimated to suffer from hepatitis B caused by the hepatitis B virus (HBV) [71]. For the primary therapy, cytokines (interferon-2b etc.) are used to directly inactivate intracellular HBV and activate T cells to destroy the infected hepatocytes to control HBV infection [72]. However, this immunomodulatory therapy has many limitations with a poor efficacy, incapable of eradicating HBV from the body. Since no other viable options are currently available, a search for more effective anti-HBV drugs/agents or therapeutic modalities is required. As D-fraction has been shown to stimulate macrophages and dendritic cells that could attack and destroy HBV, the possible inhibitory effects of D-fraction and its combination with interferon-2b (IFN) were examined on HBV. Such study [9] showed that D-fraction or IFN alone significantly inhibited HBV with the 50% inhibitory concentration (IC50) of 0.59 mg/ml and 1,399 IU/ml, respectively. Yet, when D-fraction and IFN were combined, the anti-HBV activity of IFN increased by 9-fold (IC50 = 154 IU/ml), suggesting that D-fraction might synergize with IFN. Thus, these results suggest that the combination of D-fraction and IFN may offer a more effective therapeutic modality for HBV infections.

Furthermore, there is a very common infection, which is not as severe or fatal as HIV/AIDS or hepatitis, but it is a pandemic influenza infection. Without a doubt, influenza can still become serious and fatal with other complications. Both macrophages and monocytes are susceptible to the influenza virus [73] and an infection triggers the production of several inflammatory cytokines such as IL-1, IL-6, and TNF- [74]. Interestingly, TNF- was initially described as a tumor cell-killing factor but is also known to play a key role in the inflammatory response and host-resistance to pathogens [75, 76]. In fact, it has been shown that TNF- was capable of inhibiting the replication of various viruses including vesicular stomatitis virus, encephalomyocarditis virus, herpes simplex virus, influenza virus etc., presumably preventing cytopathic effects [77]. Since D-fraction is known to stimulate the production of certain cytokines including TNF- [14], whether it could induce such TNF- production in macrophages, ultimately inhibiting the influenza virus growth, was investigated. Several different forms (based on molecular weights) of D-fraction, a murine macrophage cell line (D1), and the Madin-Darby canine kidney (MDCK) cell line as a host, were prepared and used in this study [78]. Influenza virus-infected MDCK cells with direct treatment of various D-fractions showed no inhibitory effects on the virus growth, indicating no cytotoxic activity in these D-fractions. However, after D1 cells were first treated with

different D-fractions for 10 h and those conditioned media were added to the infected cells, the virus growth was inhibited at the different degrees. A conditioned medium with the highest (~40%) inhibitory growth effect was from one of the D-fractions with molecular weights ranging from 30 Kd to 100 Kd, which also induced the highest production of TNF- from D1 cells.

Addition of TNF- antibody (anti-TNF-) to this medium entirely diminished the inhibitory growth activity, confirming that TNF- is primarily responsible for such an antiviral effect. Thus, D-fraction may not have a direct cytotoxic effect on the influenza virus but can stimulate macrophages for the production of TNF-, which will then kill or destroy the virus. This is a typical case of host-mediated antiviral activity, implying D-fraction to be a preventative and therapeutic agent for influenza virus infection.

Summary

A number of in vitro and in vivo studies and limited clinical studies have demonstrated potent immunomodulatory and antitumor activities of Maitake D-fraction, implying its great potential in cancer treatment and prevention. Particularly synergistic potentiation of D- fraction with VC may further help improve the efficacy of currently ongoing treatments for various cancers. Although i.v. administration of VC could be an interesting and useful procedure, more clinical studies are required for assessing its safety and efficacy in cancer patients. It is also interesting that D-fraction may not only alleviate various side effects and improve quality of life of patients under chemotherapy but also have possible chemosensitizing effects to improve the efficacy of chemotherapy.

Moreover, the potential antiviral activity of D-fraction may have broad clinical implications in prevention and/or treatment of serious viral infections including AIDS, hepatitis, influenza, etc. Its stimulation of macrophages for TNF- production to execute antiviral activity is particularly interesting and deserves further studies.

Nevertheless, more comprehensive and controlled studies are required for the clinical demonstration of D-fraction. It is thus advised that physicians and professional health care providers actively participate in such studies to adequately and timely evaluate the clinical significance of D-fraction.

M

SX-F

(SXF)

Maitake SX-fraction (SXF) is a water-soluble bioactive glycoprotein with a ~20,000- dalton molecular weight, exhibiting hypoglycemic, hypotensive, anti-hypercholesterolemic, and anti-diabetic activities [79]. Particularly, its hyperglycemic or blood glucose-lowering activity has been demonstrated on diabetic mice and limited clinical studies of type 2 diabetic patients [80, 81]. Diabetes or diabetes mellitus is a metabolic disorder of persistent high blood glucose (hyperglycemia) affecting over 16 million people (yet excluding undetected patients) in the US [82]. The prevalence of diabetes is increasing by 4-5% every year with an estimated 40-45% of people over 65 years old at risk [83]. Currently, diabetes is classified into two types: type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes [84].

Type 1 diabetes is caused primarily by insulin deficiency (due to dysfunction of pancreatic - cells) and represents <20% of all cases of diabetes [85], while type 2 diabetes with a >80% incidence rate involves multiple factors such as defects in insulin secretion, insulin resistance at peripheral sites (muscle and adipose tissue), and elevated hepatic glucose production [85, 86]. Hence, type 2 diabetes has a higher prevalence with complex etiologies compared to type 1. Additionally, the incidence of type 2 diabetes is frequently associated with obesity and aging (over 40 years old), although the exact reason remains largely unknown.

A chronically high blood glucose level in all diabetic patients could cause serious clinical complications, such as retinopathy, neuropathy, nephropathy and lead to blindness, renal failure, amputation, coma, and death [84, 85]. Type 1 diabetes is more manageable through insulin injection, whereas the primary problem with type 2 diabetes is not insulin deficiency but insulin resistance, making it more difficult to treat/control [86]. In fact, due to this insulin resistance, current oral therapy using sulfonylurea derivatives [87], which primarily stimulate insulin secretion from pancreatic -cells, often failed to achieve the expected level of efficacy. Nevertheless, to enhance peripheral insulin sensitivity, pharmaceuticals such as troglitazone [88] and metformin [89] have also been developed. Some improved glycemic control with these drugs has been reported, but potential adverse effects had to be advised [90]. For instance, metformin may cause lactic acidosis, presenting as impairment of renal function, cardiogenic or septic shock, or liver failure [90]. Moreover, troglitazone has been taken off the U.S. market, due to severe hepatotoxicity. These issues then demand safe and alternative means to overcome such insulin resistance. As SX-fraction is a natural agent with little adverse effects, it may offer a safer and more effective modality for prevention and/or treatment of patients with type 2 diabetes.

It should be noted that SX-fraction has gone through the chronological transition since it was originally introduced as ―X-fraction‖ nearly 20 years ago. Strictly speaking, the physical/chemical compositions of SX-fraction are somewhat different from the original X- fraction, presenting the extensive physiological effects/benefits [79]. Hence, different names (from SX-fraction) such as maitake extract or maitake would be used in some of the following studies. Nonetheless, the outcomes of such studies (with different names) are practically relevant and comparable to those with SX-fraction.