Schizophyllan (SPG) is an orally active extracellular β-glucan produced by the fungus Schizophyllum commune. Schizophyllan improves mitochondrial function and protects against metabolic liver injury by activating the SIRT3 pathway. Schizophyllan inhibits osteoclastogenesis and promotes osteoblast differentiation by suppressing the phosphorylation of JNK/p38, as well as downregulating PGC1β/PPARγ, c-Fos and NFATc1. Recognized via Dectin-1, schizophyllan enables precise delivery of oligonucleotide drugs and antigens to antigen-presenting cells, thus holding great potential in the treatment of inflammatory diseases and vaccine development [1] [2] [3].
In Vivo, Schizophyllan (25 mg/mouse; s.c.; daily; 9 days) significantly inhibits LPS -induced osteoclast formation and bone erosion in male ICR mice, reducing TRAP-positive osteoclast area by ~40% and osteoclast counts by ~36% compared to LPS-only treated animals[1]. Schizophyllan (100 mg/kg; p.o.; daily; 4-8 weeks) induces SIRT3 expression in mouse liver and adipose tissue, activates SOD2 via deacetylation, and improves hepatic mitochondrial function in a SIRT3-dependent manner[3]. Schizophyllan (100 mg/kg; p.o.; daily; 4-8 weeks) induces SIRT3-dependent deacetylation and activation of SDHA in mouse brown adipose tissue[3]. Schizophyllan (100 mg/kg; p.o.; daily; 6 weeks) reduces chronic ethanol-induced liver damage in wild-type mice via activation of the SIRT3-SOD2 pathway, restoring liver function and morphology[3]. Schizophyllan (100 mg/kg; p.o.; daily; 20 weeks) reduces CLA-induced metabolic adverse effects in wild-type mice via activation of the SIRT3-SDHA pathway, restoring tissue weights and serum chemistry markers[3].
In Vitro, Schizophyllan (5-200 μg/mL; 4-7 h) dose-dependently inhibits RANKL-induced osteoclast differentiation, TRAP activity, F-actin ring formation, and bone resorption in mouse bone marrow-derived macrophages. At the concentration of 200 μg/mL, it reduces the number of mature osteoclasts by approximately 95% and almost completely blocks bone resorption[1]. Schizophyllan (200 μg/mL; 0-4 d) downregulates the expression of RANKL-induced osteoclast differentiation marker genes, and inhibits key signaling pathways (JNK/p38 MAPK, PGC1β/PPARγ) and transcription factors (c-Fos, NFATc1) during osteoclastogenesis in mouse bone marrow-derived macrophages[1]. Schizophyllan (50-200 μg/mL; 1-6 d) dose-dependently inhibits osteoclast formation in a co-culture system of mouse bone marrow mononuclear cells and osteoblasts, and downregulates the expression of osteoclastogenic factors *Csf1* and *Tnfsf11* in mouse calvarial osteoblasts at the concentration of 200 μg/mL[1]. Schizophyllan (200 μg/mL; 7-24 d) slightly enhances mineralized nodule formation in mouse calvarial osteoblasts and upregulates the expression of osteoblast differentiation marker genes and transcription factors[1]. Schizophyllan (30 μg/mL) specifically binds to soluble recombinant mouse Dectin-1 protein, among which dA60 (S)/SPG exhibits the strongest binding activity[2]. Schizophyllan specifically hybridizes with target TNF-α sense RNA in vitro and does not dissociate from SPG[2]. Schizophyllan delivers the OVA257-264 peptide to murine peritoneal macrophages, and its antigen-presenting efficacy is comparable to that of the free conjugate[2]. Schizophyllan (0-24 h) is preferentially taken up by mouse RAW264 macrophages, and the uptake amount increases continuously within 24 h[2]. Schizophyllan (100 μg/mL; 1-2 d) regulates the acetylation level and expression of SOD2 in primary hepatocytes from SOD2−/− mice, and reduces mitochondrial ROS production in primary hepatocytes from wild-type mice in a SIRT3-dependent manner[3].
References:
[1]. Kim SH, et al. The effect of Schizophyllan on the differentiation of osteoclasts and osteoblasts. Biochem Biophys Res Commun. 2024;710:149860.
[2]. Mochizuki S, et al. Oligonucleotide delivery to antigen presenting cells by using schizophyllan. Drug Metab Pharmacokinet. 2022;42:100434.
[3]. Lee D, et al. Dietary schizophyllan reduces mitochondrial damage by activating SIRT3 in mice. Arch Pharm Res. 2020;43(4):449-461.
In Vivo, Schizophyllan (25 mg/mouse; s.c.; daily; 9 days) significantly inhibits LPS -induced osteoclast formation and bone erosion in male ICR mice, reducing TRAP-positive osteoclast area by ~40% and osteoclast counts by ~36% compared to LPS-only treated animals[1]. Schizophyllan (100 mg/kg; p.o.; daily; 4-8 weeks) induces SIRT3 expression in mouse liver and adipose tissue, activates SOD2 via deacetylation, and improves hepatic mitochondrial function in a SIRT3-dependent manner[3]. Schizophyllan (100 mg/kg; p.o.; daily; 4-8 weeks) induces SIRT3-dependent deacetylation and activation of SDHA in mouse brown adipose tissue[3]. Schizophyllan (100 mg/kg; p.o.; daily; 6 weeks) reduces chronic ethanol-induced liver damage in wild-type mice via activation of the SIRT3-SOD2 pathway, restoring liver function and morphology[3]. Schizophyllan (100 mg/kg; p.o.; daily; 20 weeks) reduces CLA-induced metabolic adverse effects in wild-type mice via activation of the SIRT3-SDHA pathway, restoring tissue weights and serum chemistry markers[3].
In Vitro, Schizophyllan (5-200 μg/mL; 4-7 h) dose-dependently inhibits RANKL-induced osteoclast differentiation, TRAP activity, F-actin ring formation, and bone resorption in mouse bone marrow-derived macrophages. At the concentration of 200 μg/mL, it reduces the number of mature osteoclasts by approximately 95% and almost completely blocks bone resorption[1]. Schizophyllan (200 μg/mL; 0-4 d) downregulates the expression of RANKL-induced osteoclast differentiation marker genes, and inhibits key signaling pathways (JNK/p38 MAPK, PGC1β/PPARγ) and transcription factors (c-Fos, NFATc1) during osteoclastogenesis in mouse bone marrow-derived macrophages[1]. Schizophyllan (50-200 μg/mL; 1-6 d) dose-dependently inhibits osteoclast formation in a co-culture system of mouse bone marrow mononuclear cells and osteoblasts, and downregulates the expression of osteoclastogenic factors *Csf1* and *Tnfsf11* in mouse calvarial osteoblasts at the concentration of 200 μg/mL[1]. Schizophyllan (200 μg/mL; 7-24 d) slightly enhances mineralized nodule formation in mouse calvarial osteoblasts and upregulates the expression of osteoblast differentiation marker genes and transcription factors[1]. Schizophyllan (30 μg/mL) specifically binds to soluble recombinant mouse Dectin-1 protein, among which dA60 (S)/SPG exhibits the strongest binding activity[2]. Schizophyllan specifically hybridizes with target TNF-α sense RNA in vitro and does not dissociate from SPG[2]. Schizophyllan delivers the OVA257-264 peptide to murine peritoneal macrophages, and its antigen-presenting efficacy is comparable to that of the free conjugate[2]. Schizophyllan (0-24 h) is preferentially taken up by mouse RAW264 macrophages, and the uptake amount increases continuously within 24 h[2]. Schizophyllan (100 μg/mL; 1-2 d) regulates the acetylation level and expression of SOD2 in primary hepatocytes from SOD2−/− mice, and reduces mitochondrial ROS production in primary hepatocytes from wild-type mice in a SIRT3-dependent manner[3].
References:
[1]. Kim SH, et al. The effect of Schizophyllan on the differentiation of osteoclasts and osteoblasts. Biochem Biophys Res Commun. 2024;710:149860.
[2]. Mochizuki S, et al. Oligonucleotide delivery to antigen presenting cells by using schizophyllan. Drug Metab Pharmacokinet. 2022;42:100434.
[3]. Lee D, et al. Dietary schizophyllan reduces mitochondrial damage by activating SIRT3 in mice. Arch Pharm Res. 2020;43(4):449-461.