br Health benefits of mushroom DF Compared to

Health benefits of mushroom DF Compared to Asian countries such as China, Korea and Japan, the application of medicinal mushrooms in the Western countries is more recent [35–37]. Medicinal mushrooms are characterized by having cell wall polysaccharides and proteins as well as fungal secondary metabolites including lignins, triperpenes and phenolics that have a broad spectrum of pharmacological activities [35,36]. On the other hand, edible mushrooms are rich in DF with NDCs including β-glucans, polysaccharide–protein complexes (PSPC) and chitin that also has a wide range of health benefits to humans. The beneficial health effects of mushroom DF that have been studied include the immune-enhancing and antitumor activity as well as blood glucose and lipid attenuation [38–43]. Some commercial β-glucans isolated from the fruiting bodies of Lentinus edodes (lentinan) and Grifola frondosa (D-fraction) as well as PSPC from Trametes versicolor were shown to stimulate the non-specific immune system in animals to inhibit cancer cell proliferation [38]. They are regarded as immunomodulators and have been used as adjuvant in cancer therapy with certain success [44–46]. It has recently been shown that a PSPC isolated from an edible mushroom Pleurotus pulmonarius can suppress in vitro and in vivo liver cancer development and progression through inhibition of VEGF-induced PI3K/AKT signaling pathway [47]. Apart from β-glucans, heteropolysaccharides such as glucuronoxylomannan isolated from the fruiting bodies of Tremella fuciformis and Tremella mesenterica exhibited immunomodulatory and hypoglycemic effects in animal studies [42,48].
Biopharmacological effect of sclerotial DF As mentioned earlier, mushroom sclerotium is a rich source of DF source and contains extremely high level of β-glucans (>80% DM) that can have a number of biopharmacological effects that are beneficial to humans [49]. It has been reported that both the innate and adaptive immunity of the host could be stimulated by sclerotial β-glucans to trigger strong immunomodulatory mediated by cytokine production and signaling cascade as well as direct inhibition of cancer cells via keap1-nrf2 pathway arrest and cytotoxicity [50–54]. Native sclerotial β-glucans isolated from the P. tuber-regium could induce apoptosis of acute promyelocytic leukemic cells (HL-60) [52], while their carboxymethylated counterparts could induce both in vitro cell cycle arrest and apoptosis of human breast cancer cells (MCF-7) mediated by the down-regulation of cyclin D1 and cyclin E expressions at the G1 phase as well as and the up-regulation of the expression of the Bax/Bcl-2 ratio, respectively [53]. Chemical modifications of native sclerotial β-glucans from P. tuber-regium by carboxymethylaion and sulfation could enhance the immunomodulatory and anti-tumor activities of these new derivatives when they were administered intraperitoneally on BALB/c mice bearing Sarcoma 180 solid tumor [55,56]. The mechanisms of the in vivo immunomodulatory and anti-tumor activities of sclerotial β-glucans are not well understood but it is very likely that some kind of surface receptor interactions between the immune cells and β-glucans might have been involved. Dectin-1 has been identified as a β-glucan receptor found on the surface of a number of innate immune cells including monocytes, macrophages, NK cells and dendritic cells in human and mice recently [57,58]. Dectin-1 receptor was able to recognize β-glucans derived from yeast to trigger immunomodulation in both humans and mice [59,60]. The new approach of identifying similar or novel β-glucans receptor(s) that are specific to sclerotial β-glucans on the surface of innate human primary cells would be a promising new one and would provide new insights in explaining the immunomodulatory and anti-tumor effects of sclerotial β-glucans [50]. There are other biopharmacological activities of sclerotial polysaccharides isolated from P. tuber-regium that have been reported. These include hepatic protection against acute liver injury induced by carbon tetrachloride in mice and lowering of fasting blood glucose level in alloxan-induced diabetic mice [61]. Chemically modified sclerotial β-glucans derived from P. tuber-regium also have interesting biological activities that could not be found in their native counterparts. For instance, sulfated sclerotial β-glucans isolated from P. tuber-regium possessed anti-viral activity against human simplex virus including HSV-1 and HSV-2 which was probably due to their increased aqueous solubility and more opened chain conformation compared to the native ones [62,63]. Both sulfated and carboxymethylated sclerotial β-glucans obtained from P. tuber-regium could scavenge superoxide and hydroxyl radicals and protect the oxidative damage of liver mitochondria and DNA [64–66].